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1. Infection of lung megakaryocytes and platelets by SARS-CoV-2 anticipate fatal COVID-19

Author: Aiwei Zhu, Fernando Real, Claude Capron, Arielle R. Rosenberg, Aymeric Silvin, Garett Dunsmore, Jaja Zhu, Andréa Cottoignies-Callamarte, Jean-Marc Massé, Pierre Moine, Simon Bessis, Mathieu Godement, Guillaume Geri, Jean-Daniel Chiche, Silvana Valdebenito, Sandrine Belouzard, Jean Dubuisson, Geoffroy Lorin de la Grandmaison, Sylvie Chevret, Florent Ginhoux, Eliseo A. Eugenin, Djillali Annane, Elisabeth Cramer Bordé, Morgane Bomsel, Institut Cochin [IC UM3 (UMR 8104 / U1016)], Université de Versailles Saint-Quentin-en-Yvelines [UVSQ], Hôpital Ambroise Paré [AP-HP], Hôpital Cochin [AP-HP], Immunologie anti-tumorale et immunothérapie des cancers [ITIC], Institut Gustave Roussy [IGR], Infection et inflammation [2I], The University of Texas Medical Branch [UTMB], Institut Pasteur de Lille, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL], Hôpital Raymond Poincaré [Garches], Service de biostatistique et information médicale de l’hôpital Saint Louis (Equipe ECSTRA) [SBIM], Singapore Immunology Network [SIgN], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Service d'Hématologie et d'Immunologie [AP-HP Hôpital Ambroise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Institut Gustave Roussy (IGR), Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de réanimation médicale polyvalente [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], The University of Texas Medical Branch (UTMB), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Réseau International des Instituts Pasteur (RIIP), Université de Lille, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de biostatistique et information médicale de l’hôpital Saint Louis (Equipe ECSTRA) (SBIM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut national du cancer [Boulogne] (INCA)-Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), Hopital Saint-Louis [AP-HP] (AP-HP), Singapore Immunology Network (SIgN), Biomedical Sciences Institute (BMSI), Agency for science, technology and research [Singapore] (A*STAR), ANR-20-COVI-0024,MUCOLUNG,Rôle des cellules pulmonaires infectées par le SRAS-CoV-2 et réponse humoral dans l' évolution du COVID-19: de la physiopathologie au test de médicaments candidats dans les modèles de cellules muqueuses(2020), Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), School of Medicine [Shanghai Jiaotong University], Shanghai Jiaotong University, Accident Compensation Corporation, ACC, Fondation pour la Recherche Médicale, FRM, China Scholarship Council, CSC, The authors thank Professor John F. Martin (University College of London, UK) for fruitful advice and discussion on the role of NRP1 receptor and VEGF in COVID19 and resultant therapeutical implications, and for English editing. The authors greatly acknowledge Karine Bailly and Muriel Andrieu of the Cochin Cytometry and Immunobiology Facility for cytokine analyses, as well as Thomas Guilbert from the Imag’IC facility for instruction on the IXplore Spin Confocal Imaging Microscope System (Olympus) and Livine Duban from Luminex corp for instruction on the Guava easyCyte 12HT base system (Millipore) during the COVID-19 confinement period. We also thank also Dr. Nicolas Chapuis (Hôpital Cochin, Paris, France) and Pr. Nicholas Heming (Hôpital Raymond Poincaré, Garches, France) for helpful discussion., Joint funding by the Agence Nationale de la Recherche (France) and Fondation pour la Recherche Médicale (France): Flash COVID ANR-FRM: ANR-20-COVI-0024. Funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the manuscript. AZ was supported by the China Scholarship Council and ACC by the Fondation pour la Recherche Médicale., and REAL, Fernando
Subjects: Blood Platelets, Pharmacology, Platelets, SARS-CoV-2, Macrophages, [SDV]Life Sciences [q-bio], Membrane Proteins, RNA-Binding Proteins, COVID-19, Thrombosis, Cell Biology, [SDV] Life Sciences [q-bio], Lung, Megakaryocytes, Cellular and Molecular Neuroscience, Humans, Molecular Medicine, Molecular Biology
Abstract: SARS-CoV-2, although not being a circulatory virus, spread from the respiratory tract resulting in multiorgan failures and thrombotic complications, the hallmarks of fatal COVID-19. A convergent contributor could be platelets that beyond hemostatic functions can carry infectious viruses. Here, we profiled 52 patients with severe COVID-19 and demonstrated that circulating platelets of 19 out 20 non-survivor patients contain SARS-CoV-2 in robust correlation with fatal outcome. Platelets containing SARS-CoV-2 might originate from bone marrow and lung megakaryocytes (MKs), the platelet precursors, which were found infected by SARS-CoV-2 in COVID-19 autopsies. Accordingly, MKs undergoing shortened differentiation and expressing anti-viral IFITM1 and IFITM3 RNA as a sign of viral sensing were enriched in the circulation of deadly COVID-19. Infected MKs reach the lung concomitant with a specific MK-related cytokine storm rich in VEGF, PDGF and inflammatory molecules, anticipating fatal outcome. Lung macrophages capture SARS-CoV-2-containing platelets in vivo. The virus contained by platelets is infectious as capture of platelets carrying SARS-CoV-2 propagates infection to macrophages in vitro, in a process blocked by an anti-GPIIbIIIa drug. Altogether, platelets containing infectious SARS-CoV-2 alter COVID-19 pathogenesis and provide a powerful fatality marker. Clinical targeting of platelets might prevent viral spread, thrombus formation and exacerbated inflammation at once and increase survival in COVID-19.
Published: 2022

2. Genomic Instability and Protumoral Inflammation Are Associated with Primary Resistance to Anti–PD-1 + Antiangiogenesis in Malignant Pleural Mesothelioma

Author: François-Xavier Danlos, Matthieu Texier, Bastien Job, Severine Mouraud, Lydie Cassard, Capucine Baldini, Andrea Varga, Andrey A. Yurchenko, Audrey Rabeau, Stéphane Champiat, Diane Letourneur, Delphine Bredel, Sandrine Susini, Yuna Blum, Aurelien Parpaleix, Cedric Parlavecchio, Lambros Tselikas, Jean-Eudes Fahrner, Anne-Gaelle Goubet, Mathieu Rouanne, Saloomeh Rafie, Alae Abbassi, Ines Kasraoui, Marie Breckler, Siham Farhane, Samy Ammari, Salim Laghouati, Anas Gazzah, Ludovic Lacroix, Benjamin Besse, Nathalie Droin, Marc Deloger, Sophie Cotteret, Julien Adam, Laurence Zitvogel, Sergey I. Nikolaev, Nathalie Chaput, Christophe Massard, Jean-Charles Soria, Carlos Gomez-Roca, Gerard Zalcman, David Planchard, Aurelien Marabelle, Institut Gustave Roussy (IGR), Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, École normale supérieure de Lyon (ENS de Lyon), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Département d'imagerie médicale [Gustave Roussy], Département de biologie et pathologie médicales [Gustave Roussy], Département de médecine oncologique, CRLCC Paul Strauss, Dynamique moléculaire de la transformation hématopoïétique (Dynamo), Département de médecine oncologique [Gustave Roussy], Prédicteurs moléculaires et nouvelles cibles en oncologie (PMNCO), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP), and Institut Claudius Regaud
Subjects: Oncology, [SDV.CAN]Life Sciences [q-bio]/Cancer
Abstract: Cancer immunotherapy combinations have recently been shown to improve the overall survival of advanced mesotheliomas, especially for patients responding to those treatments. We aimed to characterize the biological correlates of malignant pleural mesotheliomas’ primary resistance to immunotherapy and antiangiogenics by testing the combination of pembrolizumab, an anti–PD-1 antibody, and nintedanib, a pan-antiangiogenic tyrosine kinase inhibitor, in the multicenter PEMBIB trial (NCT02856425). Thirty patients with advanced malignant pleural mesothelioma were treated and explored. Unexpectedly, we found that refractory patients were actively recruiting CD3+CD8+ cytotoxic T cells in their tumors through CXCL9 tumor release upon treatment. However, these patients displayed high levels of somatic copy-number alterations in their tumors that correlated with high blood and tumor levels of IL6 and CXCL8. Those proinflammatory cytokines resulted in higher tumor secretion of VEGF and tumor enrichment in regulatory T cells. Advanced mesothelioma should further benefit from stratified combination therapies adapted to their tumor biology. Significance: Sequential explorations of fresh tumor biopsies demonstrated that mesothelioma resistance to anti–PD-1 + antiangiogenics is not due to a lack of tumor T-cell infiltration but rather due to adaptive immunosuppressive pathways by tumors, involving molecules (e.g., IL6, CXCL8, VEGF, and CTLA4) that are amenable to targeted therapies. This article is highlighted in the In This Issue feature, p. 799
Published: 2023

3. High serum LDH and liver metastases are the dominant predictors of primary cancer resistance to anti-PD(L)1 immunotherapy

Author: Laurent Dercle, Samy Ammari, Elvire Roblin, Amelie Bigorgne, Stéphane Champiat, Lokmane Taihi, Athèna Plaian, Sophie Hans, Sara Lakiss, Lambros Tselikas, Mathieu Rouanne, Eric Deutsch, Lawrence H. Schwartz, Mithat Gönen, Jessica Flynn, Christophe Massard, Jean-Charles Soria, Caroline Robert, Aurélien Marabelle, Institut Gustave Roussy (IGR), LaBoratoire d'Imagerie biOmédicale MultimodAle Paris-Saclay (BIOMAPS), Service Hospitalier Frédéric Joliot (SHFJ), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Département de radiologie, Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP), Hôpital Foch [Suresnes], Département de médecine oncologique [Gustave Roussy], and Prédicteurs moléculaires et nouvelles cibles en oncologie (PMNCO)
Subjects: Hyperprogression, Cancer Research, Survival, Liver Neoplasms, Lactate dehydrogenase, Cancer immunotherapy, [SDV.CAN]Life Sciences [q-bio]/Cancer, Prognosis, Liver metastases, Treatment Outcome, Oncology, Machine learning, Humans, Immunologic Factors, Prospective Studies, Immunotherapy, Melanoma, Retrospective Studies
Abstract: International audience; Aim: Anti-PD-(L)1 immunotherapies improve survival in multiple cancers but remain ineffective for most patients. We applied machine-learning algorithms and multivariate analyses on baseline medical data to estimate their relative impact on overall survival (OS) upon anti-PD-(L)1 monotherapies. Method: This prognostic/predictive study retrospectively analysed 33 baseline routine medical variables derived from computed tomography (CT) images, clinical and biological meta-data. 695 patients with a diagnosis of advanced cancer were treated in prospective clinical trials in a single tertiary cancer centre in 3 cohorts including systemic anti-PD-(L)1 (251, 235 patients) versus other systemic therapies (209 patients). A random forest model combined variables to identify the combination (signature) which best estimated OS in patients treated with immunotherapy. The performance for estimating OS [95%CI] was measured using Kaplan–Meier Analysis and Log–Rank test. Results: Elevated serum lactate dehydrogenase (LDHhi) and presence of liver metastases (LM+) were dominant and independent predictors of short OS in independent cohorts of melanoma and non-melanoma solid tumours. Overall, LDHhiLM+ patients treated with anti-PD-(L)1 monotherapy had a poorer outcome (median OS: 3.1[2.4–7.8] months]) compared to LDHlowLM-patients (median OS: 15.3[8.9-NA] months; P < 0.0001). The OS of LDHlowLM-patients treated with immunotherapy was 28.8[17.9-NA] months (vs 13.1[10.8–18.5], P = 0.02) in the overall population and 30.3[19.93-NA] months (vs 14.1[8.69-NA], P = 0.0013) in patients with melanoma. Conclusion: LDHhiLM+ status identifies patients who shall not benefit from anti-PD-(L)1 monotherapy. It could be used in clinical trials to stratify patients and eventually address this specific medical need.
Published: 2022

4. Tumor-intrinsic sensitivity to the pro-apoptotic effects of IFN-γ is a major determinant of CD4+ CAR T-cell antitumor activity

Author: Morgane Boulch, Marine Cazaux, Alexis Cuffel, Marion V. Guerin, Zacarias Garcia, Ruby Alonso, Fabrice Lemaître, Alexander Beer, Béatrice Corre, Laurie Menger, Capucine L. Grandjean, Florence Morin, Catherine Thieblemont, Sophie Caillat-Zucman, Philippe Bousso, Dynamiques des Réponses immunes - Dynamics of Immune Responses, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université Paris Cité (UPCité), Institut Gustave Roussy (IGR), Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), The work was supported by Institut Pasteur, INSERM, INCa (PLBIO21-104) and an Advanced grant (ENLIGHTEN) from the European Research Council (P.B.)., We thank members of the Bousso laboratory for critical review of the paper. We are grateful to F. Sepulveda for providing Prf1−/− mice. We acknowledge the mouse facility and CB UTechS at Institut Pasteur for support in conducting the present study, European Project: 741167,ERC-2016-ADG,ENLIGHTEN(2018), Immunologie anti-tumorale et immunothérapie des cancers (ITIC), and Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay
Subjects: Cancer Research, Oncology, [SDV]Life Sciences [q-bio]
Abstract: CD4+ T cells and CD4+ chimeric antigen receptor (CAR) T cells display highly variable antitumor activity in preclinical models and in patients; however, the mechanisms dictating how and when CD4+ T cells promote tumor regression are incompletely understood. With the help of functional intravital imaging, we report that interferon (IFN)-γ production but not perforin-mediated cytotoxicity was the dominant mechanism for tumor elimination by anti-CD19 CD4+ CAR T cells. Mechanistically, mouse or human CD4+ CAR T-cell-derived IFN-γ diffused extensively to act on tumor cells at distance selectively killing tumors sensitive to cytokine-induced apoptosis, including antigen-negative variants. In anti-CD19 CAR T-cell-treated patients exhibiting elevated CAR CD4:CD8 ratios, strong induction of serum IFN-γ was associated with increased survival. We propose that the sensitivity of tumor cells to the pro-apoptotic activity of IFN-γ is a major determinant of CD4+ CAR T-cell efficacy and may be considered to guide the use of CD4+ T cells during immunotherapy.
Published: 2023

5. The European MAPPYACTS Trial: Precision Medicine Program in Pediatric and Adolescent Patients with Recurrent Malignancies

Author: Pablo Berlanga, Gaelle Pierron, Ludovic Lacroix, Mathieu Chicard, Tiphaine Adam de Beaumais, Antonin Marchais, Anne C. Harttrampf, Yasmine Iddir, Alicia Larive, Aroa Soriano Fernandez, Imene Hezam, Cecile Chevassus, Virginie Bernard, Sophie Cotteret, Jean-Yves Scoazec, Arnaud Gauthier, Samuel Abbou, Nadege Corradini, Nicolas André, Isabelle Aerts, Estelle Thebaud, Michela Casanova, Cormac Owens, Raquel Hladun-Alvaro, Stefan Michiels, Olivier Delattre, Gilles Vassal, Gudrun Schleiermacher, Birgit Geoerger, Institut Català de la Salut, [Berlanga P] Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France. [Pierron G] Unité de Génétique Somatique, Service de Génétique, Hospital Group, Institut Curie, Paris, France. [Lacroix L] Department of Pathology and Laboratory Medicine, Translational Research Laboratory and Biobank, AMMICA, INSERM US23/CNRS UMS3655, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France. [Chicard M] INSERM U830, Laboratoire de Génétique et Biologie des Cancers, Research Center, PSL Research University, Institut Curie, Paris, France. [Adam de Beaumais T] Clinical Research Direction, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France. [Marchais A] INSERM U1015, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France. [Soriano Fernandez A] Grup de Recerca Translacional en Càncer en la Infància i l’Adolescència, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Hladun-Alvaro R] Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Servei d’Oncologia i Hematologia Pediàtriques, Vall d’Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Institut Gustave Roussy (IGR), Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Institut Curie [Paris], Department of Medical Oncology, Département de médecine oncologique [Gustave Roussy], Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme de Bioinformatique [Gustave Roussy], Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Centre de Recherche et de Documentation sur l'Océanie (CREDO), École des hautes études en sciences sociales (EHESS)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique [Châtenay-Malabry] (LabEx LERMIT), Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de biologie et pathologie médicales [Gustave Roussy], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Prédicteurs moléculaires et nouvelles cibles en oncologie (PMNCO), Centre Léon Bérard [Lyon], Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier universitaire de Nantes (CHU Nantes), Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo] (IRCCS), Oncostat (U1018 (Équipe 2)), Institut Gustave Roussy (IGR)-Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Immunologie des tumeurs et immunothérapie (UMR 1015), Vectorologie et thérapeutiques anti-cancéreuses [Villejuif] (UMR 8203), and Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS)
Subjects: neoplasias::procesos neoplásicos::recurrencia neoplásica local [ENFERMEDADES], Pediatria, Adolescent, [SDV]Life Sciences [q-bio], Carcinoma, High-Throughput Nucleotide Sequencing, Neoplasms [DISEASES], neoplasias [ENFERMEDADES], Càncer - Recaiguda, terapéutica::medicina de precisión [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Oncology, Mutation, Biomarkers, Tumor, Neoplasms::Neoplastic Processes::Neoplasm Recurrence, Local [DISEASES], Humans, Prospective Studies, Medicina personalitzada, Neoplasm Recurrence, Local, Precision Medicine, Child, Therapeutics::Precision Medicine [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Cell-Free Nucleic Acids
Abstract: Abstract MAPPYACTS (NCT02613962) is an international prospective precision medicine trial aiming to define tumor molecular profiles in pediatric patients with recurrent/refractory malignancies in order to suggest the most adapted salvage treatment. From February 2016 to July 2020, 787 patients were included in France, Italy, Ireland, and Spain. At least one genetic alteration leading to a targeted treatment suggestion was identified in 436 patients (69%) with successful sequencing; 10% of these alterations were considered “ready for routine use.” Of 356 patients with follow-up beyond 12 months, 107 (30%) received one or more matched targeted therapies—56% of them within early clinical trials—mainly in the AcSé-ESMART platform trial (NCT02813135). Overall, matched treatment resulted in a 17% objective response rate, and of those patients with ready for routine use alterations, it was 38%. In patients with extracerebral tumors, 76% of actionable alterations detected in tumor tissue were also identified in circulating cell-free DNA (cfDNA). Significance: MAPPYACTS underlines the feasibility of molecular profiling at cancer recurrence in children on a multicenter, international level and demonstrates benefit for patients with selected key drivers. The use of cfDNA deserves validation in prospective studies. Our study highlights the need for innovative therapeutic proof-of-concept trials that address the underlying cancer complexity. This article is highlighted in the In This Issue feature, p. 1171
Published: 2022

6. Epidemiological Study to Assess the Prevalence of Lung Cancer in patients with smoking-associated atherosclerotic cardiovascular diseases: PREVALUNG study protocol

Author: David Boulate, Marine Fidelle, Caroline Caramella, Justin Issard, Olivier Planché, Pauline Pradère, Daniel Garelik, Océane Hache, Lilia Lamrani, Marc Zins, Hélène Beaussier, Gilles Chatellier, Elie Fadel, Laurence Zitvogel, Benjamin Besse, Olaf Mercier, Méthodes computationnelles pour la prise en charge thérapeutique en oncologie : Optimisation des stratégies par modélisation mécaniste et statistique (COMPO), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Marie-Lannelongue, Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut Gustave Roussy (IGR), and Département de médecine oncologique [Gustave Roussy]
Subjects: Thoracic medicine, [SDV]Life Sciences [q-bio], Vascular medicine, General Medicine, Respiratory tract tumours, Chest imaging
Abstract: IntroductionEligibility criteria definition for a lung cancer screening (LCS) is an unmet need. We hypothesised that patients with a history of atheromatous cardiovascular disease (ACVD) associated with tobacco consumption are at risk of lung cancer (LC). The main objective is to assess LC prevalence among patients with ACVD and history of tobacco consumption by using low-dose chest CT scan. Secondary objectives include the evaluation LCS in this population and the constitution of a biological biobank to stratify risk of LC.Methods and analysisWe are performing a monocentric ‘single-centre’ prospective study among patients followed up in adult cardiovascular programmes of vascular surgery, cardiology and cardiac surgery recruited from 18 November 2019 to 18 May 2021. The inclusion criteria are (1) age 45–75 years old, (2) history of ACVD and (3) history of daily tobacco consumption for 10 years prior to onset of ACVD. Exclusion criteria are symptoms of LC, existing follow-up for pulmonary nodule, fibrosis, pulmonary hypertension, resting dyspnoea and active pulmonary infectious disease. We targeted the inclusion of 500 patients. After inclusion (V0), patients are scheduled for a low-dose chest CT and blood and faeces harvesting within 7 months (V1). Each patient is scheduled for a follow-up by telephonic visits at month 3 (V2), month 6 (V3) and month 12 (V4) after V1. Each patient is followed up until 1 year after V1 (14 February 2023). We measure LC prevalence and quantify the National Lung Screening Trial and Dutch-Belgian Randomized Lung Cancer Screening Trial (NELSON) trial eligibility criteria, radiation, positive screening, false positivity, rate of localised LC diagnosis, quality of life with the Short Form 12 (SF-12) and anxiety with the Spielberger State-Trait Anxiety Inventory A and B (STAI-YA and STAI-YB, respectively), smoking cessation and onset of cardiovascular and oncological events within 1 year of follow-up. A case–control study nested in the cohort is performed to identify clinical or biological candidate biomarkers of LC.Ethics and disseminationThe study was approved according the French Jardé law; the study is referenced at the French ‘Agence Nationale de Sécurité du Médicament et des Produits de Santé’ (reference ID RCB: 2019-A00262-55) and registered on clinicaltrial.gov. The results of the study will be presented after the closure of the follow-up scheduled on 14 February 2023 and disseminated through peer-reviewed journals and national and international conferences.Trial registration numberNCT03976804.
Published: 2022

7. Meningeal macrophages protect against viral neuroinfection

Author: Julie Rebejac, Elisa Eme-Scolan, Laurie Arnaud Paroutaud, Sarah Kharbouche, Matei Teleman, Lionel Spinelli, Emeline Gallo, Annie Roussel-Queval, Ana Zarubica, Amandine Sansoni, Quentin Bardin, Philippe Hoest, Marie-Cécile Michallet, Carine Brousse, Karine Crozat, Monica Manglani, Zhaoyuan Liu, Florent Ginhoux, Dorian B. McGavern, Marc Dalod, Bernard Malissen, Toby Lawrence, Rejane Rua, Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure de Lyon (ENS de Lyon), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Centre d'Immunophénomique (CIPHE), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), National Institutes of Health [Bethesda] (NIH), Shanghai Jiao Tong University School of Medicine, Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, and King‘s College London
Subjects: neuroinfection, Lipopolysaccharides, SARS-CoV-2, brain, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Macrophages, Immunology, COVID-19, virus, interferon, Lymphocytic Choriomeningitis, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Mice, Inbred C57BL, Mice, Meninges, Infectious Diseases, immunological barrier, Animals, Lymphocytic choriomeningitis virus, Immunology and Allergy, LCMV
Abstract: The surface of the central nervous system (CNS) is protected by the meninges, which contain a dense network of meningeal macrophages (MMs). Here, we examined the role of tissue-resident MM in viral infection. MHC-II� MM were abundant neonatally, whereas MHC-II+ MM appeared over time. These barrier macrophages differentially responded to in vivo peripheral challenges such as LPS, SARS-CoV-2, and lymphocytic choriomeningitis virus (LCMV). Peripheral LCMV infection, which was asymptomatic, led to a transient infection and activation of the meninges. Mice lacking macrophages but conserving brain microglia, or mice bearing macrophage-specific deletion of Stat1 or Ifnar, exhibited extensive viral spread into the CNS. Transcranial pharmacological depletion strategies targeting MM locally resulted in several areas of the meninges becoming infected and fatal meningitis. Low numbers of MHC-II+ MM, which is seen upon LPS challenge or in neonates, corelated with higher viral load upon infection. Thus, MMs protect against viral infection and may present targets for therapeutic manipulation., Authors affiliations: (1) Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, Inserm, CNRS, Marseille, France (2) Ecole Normale Supérieure de Lyon, Université Claude Bernard – Lyon I, Université de Lyon, Lyon, France (3)Centre d'Immunophénomique, Aix Marseille Université , Inserm, CNRS, Marseille, France (4) TERI (Tumor Escape, Resistance and Immunity) Department, Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, Université Claude Bernard – Lyon 1, Université de Lyon, Inserm, CNRS, Lyon, France (5) Viral Immunology and Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA (6) Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China (7) University Paris-Saclay, Inserm U1015, Gustave Roussy Cancer Center, Villejuif, France (8) Singapore Immunology Network, A*STAR, Singapore, Singapore (9) Centre for Inflammation Biology and Cancer Immunology, Cancer Research UK King's Health Partners Centre, School of Immunology and Microbial Sciences, King's College London, London SE1 1UL, UK (10) Lead contact
Published: 2022
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8. Intestinal microbiota influences clinical outcome and side effects of early breast cancer treatment

Author: Andrew Maltez Thomas, Aude Sirven, Filippo Pietrantonio, Romy Aarnoutse, Carlos Caldas, Sibille Everhard, Marine Fidelle, Valerio Iebba, Fanny Aprahamian, Stergios Christodoulidis, Sylvère Durand, Lisa Derosa, Sibylle Loibl, Janine Ziemons, François Ghiringhelli, Carsten Denkert, Suzette Delaloge, Nicola Segata, Edoardo Pasolli, Anne-Laure Martin, Nitharsshini Nirmalathasan, Safae Terrisse, Laurence Zitvogel, Fabrice Andre, Marjolein L. Smidt, Guido Kroemer, Ines Vaz-Luis, Bertrand Routy, Claudia Iglesias, Terrisse, Safae, Derosa, Lisa, Iebba, Valerio, Ghiringhelli, Françoi, Vaz-Luis, Ine, Kroemer, Guido, Fidelle, Marine, Christodoulidis, Stergio, Segata, Nicola, Thomas, Andrew Maltez, Martin, Anne-Laure, Sirven, Aude, Everhard, Sibille, Aprahamian, Fanny, Nirmalathasan, Nitharsshini, Aarnoutse, Romy, Smidt, Marjolein, Ziemons, Janine, Caldas, Carlo, Loibl, Sibylle, Denkert, Carsten, Durand, Sylvere, Iglesias, Claudia, Pietrantonio, Filippo, Routy, Bertrand, André, Fabrice, Pasolli, Edoardo, Delaloge, Suzette, Zitvogel, Laurence, Institut Gustave Roussy (IGR), Faculté de médecine de l'Université Paris-Sud [Kremlin Bicêtre, Paris], Université Paris-Saclay, Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'Investigation Clinique Biothérapie [Paris] (CICBT), Institut Curie [Paris], Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Institut de médecine génomique et d’immunothérapie (Genomic and Immunotherapy Medical Institute) (institut GIMI), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), University of Trento [Trento], Università degli studi di Trieste = University of Trieste, Centre for Integrative Biology (CIBIO), University of Trento (CIBIO), Maastricht University [Maastricht], University of Cambridge [UK] (CAM), Goethe-University Frankfurt am Main, Philipps Universität Marburg = Philipps University of Marburg, IRCCS Istituto Nazionale dei Tumori [Milano], Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Prédicteurs moléculaires et nouvelles cibles en oncologie (PMNCO), University of Naples Federico II = Università degli studi di Napoli Federico II, ANR-16-RHUS-0008,LUMIERE,LUMIERE(2016), European Project: 825410,ONCOBIOME, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Surgery, MUMC+: MA Heelkunde (9), UNICANCER-UNICANCER-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-FHU TRANSLAD (CHU de Dijon), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPC), University of Trieste, University of Naples Federico II, Ghiringhelli, François [0000-0002-5465-8305], Kroemer, Guido [0000-0002-9334-4405], Christodoulidis, Stergios [0000-0002-8773-1070], Segata, Nicola [0000-0002-1583-5794], Thomas, Andrew Maltez [0000-0001-5789-3354], Aarnoutse, Romy [0000-0002-8713-9747], Ziemons, Janine [0000-0002-4559-5488], Caldas, Carlos [0000-0003-3547-1489], Zitvogel, Laurence [0000-0003-1596-0998], Apollo - University of Cambridge Repository, Terrisse, S., Derosa, L., Iebba, V., Ghiringhelli, F., Vaz-Luis, I., Kroemer, G., Fidelle, M., Christodoulidis, S., Segata, N., Thomas, A. M., Martin, A. -L., Sirven, A., Everhard, S., Aprahamian, F., Nirmalathasan, N., Aarnoutse, R., Smidt, M., Ziemons, J., Caldas, C., Loibl, S., Denkert, C., Durand, S., Iglesias, C., Pietrantonio, F., Routy, B., Andre, F., Pasolli, E., Delaloge, S., and Zitvogel, L.
Subjects: Oncology, medicine.medical_treatment, [SDV]Life Sciences [q-bio], GUT MICROBIOME, THERAPY, Breast cancer, Breast Neoplasms, Female, Gastrointestinal Microbiome, Humans, Prognosis, Prospective Studies, Treatment Outcome, TUMOR-INFILTRATING LYMPHOCYTES, Prospective cohort study, Cancer, Early breast cancer, Microbiota, ADENOSINE, SOLID TUMORS, Intestinal Microbiome, Immunotherapy, PATHOLOGISTS, Adjuvant, Shotgun metagenomics, medicine.medical_specialty, CARCINOMA, CANTO study, Article, Immune system, STANDARDIZED METHOD, Internal medicine, medicine, Chemotherapy, Clinical significance, metagenomic, IMMUNOTHERAPY, Molecular Biology, metagenomics, business.industry, neoadjuvant, Cell Biology, Translational research, EFFICACY, networks, network, business
Abstract: The prognosis of early breast cancer (BC) relies on cell autonomous and immune parameters. The impact of the intestinal microbiome on clinical outcome has not yet been evaluated. Shotgun metagenomics was used to determine the composition of the fecal microbiota in 121 specimens from 76 early BC patients, 45 of whom were paired before and after chemotherapy. These patients were enrolled in the CANTO prospective study designed to record the side effects associated with the clinical management of BC. We analyzed associations between baseline or post-chemotherapy fecal microbiota and plasma metabolomics with BC prognosis, as well as with therapy-induced side effects. We examined the clinical relevance of these findings in immunocompetent mice colonized with BC patient microbiota that were subsequently challenged with histo-compatible mouse BC and chemotherapy. We conclude that specific gut commensals that are overabundant in BC patients compared with healthy individuals negatively impact BC prognosis, are modulated by chemotherapy, and may influence weight gain and neurological side effects of BC therapies. These findings obtained in adjuvant and neoadjuvant settings warrant prospective validation.
Published: 2021

9. Sustained-hepatic arterial infusion of oxaliplatin: pharmacokinetic advantages over hepatic arterial infusion using a preclinical animal tumour model

Author: Laurence Moine, Lambros Tselikas, Shinji Motoyama, Thomas Isoardo, Frederic Deschamps, Michel Ducreux, Thierry de Baere, Masako Tasaki, Dragica Paunovic, Institut Gustave Roussy (IGR), Imagerie thérapeutique (radiologie interventionnelle), Département d'imagerie médicale [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Université Paris-Saclay, Oncologie digestive, Département de médecine oncologique [Gustave Roussy], Institut Galien Paris-Sud (IGPS), and Université Paris-Sud - Paris 11 (UP11)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
Subjects: medicine.medical_specialty, Cmax, Pharmaceutical Science, [SDV.CAN]Life Sciences [q-bio]/Cancer, 02 engineering and technology, 030226 pharmacology & pharmacy, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Therapeutic index, Hepatic arterial infusion, Pharmacokinetics, Internal medicine, medicine, Lung, business.industry, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 021001 nanoscience & nanotechnology, medicine.disease, 3. Good health, Oxaliplatin, medicine.anatomical_structure, Hepatocellular carcinoma, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Lipiodol, 0210 nano-technology, business, medicine.drug
Abstract: International audience; Hepatic arterial infusion (HAI) of oxaliplatin allows greater liver tumour drug exposure compared to systemic infusion. However, the therapeutic index of HAI oxaliplatin remains poor. Using Pickering emulsion technology, we developed a platform able to provide sustained releases of oxaliplatin. The goal of this study was to evaluate the pharmacokinetic advantages of sustained-HAI oxaliplatin over HAI using a preclinical animal tumour model. Injections of 0.6 mg oxaliplatin in 20 min were selectively done in left hepatic arteries of 20 rabbits bearing a VX2 liver tumour in the middle left-lobe, using HAI (n = 10) or sustained-HAI (n = 10). In each group, half of the rabbits were sacrificed at 24 h and half at 72 h. Mass spectrometry was used to quantify drug pharmacokinetics in blood and oxaliplatin concentrations in tumour tissues, right- and middle left-liver lobes, spleen and lung. Compared to HAI, sustained-HAI of oxaliplatin resulted in lower plasmatic peak (Cmax: 275 ± 41 vs. 416 ± 133 ng/mL, p = 0.02) and higher concentration in the tumour at 24 h (2118 ± 2107 vs. 210 ± 93 ng/g, p = 0.008). After HAI, oxaliplatin concentration in tumours was significantly higher than in lung at 24 h (p = 0.03) but no other difference was found between oxaliplatin concentrations in tumours and in liver lobes, spleen or lung, neither at 24 h nor at 72 h. On the opposite, sustained-HAI resulted in higher concentrations of oxaliplatin in tumour compared to oxaliplatin concentrations in the middle left lobe (163 ± 86 ng/g at 24 h, p = 0.01, and 90 ± 15 ng/g at 72 h, p = 0.04), right lobe (174 ± 112 ng/g at 24 h, p = 0.01, and 112 ± 35 ng/g, p = 0.04 at 72 h), spleen (142 ± 21 ng/g at 24 h, p = 0.01, and 98 ± 12 ng/g at 72 h, p = 0.04), and lung (85 ± 11 ng/g at 24 h, p = 0.01, and 52 ± 4 ng/g at 72 h, p = 0.03). Sustained-HAI improves the therapeutic index of HAI oxaliplatin and offers a great potential for patients suffering from unresectable colorectal liver metastases or hepatocellular carcinoma.
Published: 2021

10. Dual ontogeny of disease-associated microglia and disease inflammatory macrophages in aging and neurodegeneration

Author: Aymeric Silvin, Stefan Uderhardt, Cecile Piot, Sandro Da Mesquita, Katharine Yang, Laufey Geirsdottir, Kevin Mulder, David Eyal, Zhaoyuan Liu, Cecile Bridlance, Morgane Sonia Thion, Xiao Meng Zhang, Wan Ting Kong, Marc Deloger, Vasco Fontes, Assaf Weiner, Rachel Ee, Regine Dress, Jing Wen Hang, Akhila Balachander, Svetoslav Chakarov, Benoit Malleret, Garett Dunsmore, Olivier Cexus, Jinmiao Chen, Sonia Garel, Charles Antoine Dutertre, Ido Amit, Jonathan Kipnis, Florent Ginhoux, Institut Gustave Roussy (IGR), Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Weizmann Institute of Science [Rehovot, Israël], Shanghai Jiao Tong University School of Medicine, Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Singapore Immunology Network (SIgN), Biomedical Sciences Institute (BMSI), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Agency for science, technology and research [Singapore] (A*STAR), Collège de France - Chaire Neurobiologie et immunité, and Collège de France (CdF (institution))
Subjects: Aging, Membrane Glycoproteins, [SDV]Life Sciences [q-bio], Macrophages, Immunology, Brain, Mice, Infectious Diseases, Alzheimer Disease, Immunology and Allergy, Animals, Humans, Microglia, Receptors, Immunologic
Abstract: Brain macrophage populations include parenchymal microglia, border-associated macrophages, and recruited monocyte-derived cells; together, they control brain development and homeostasis but are also implicated in aging pathogenesis and neurodegeneration. The phenotypes, localization, and functions of each population in different contexts have yet to be resolved. We generated a murine brain myeloid scRNA-seq integration to systematically delineate brain macrophage populations. We show that the previously identified disease-associated microglia (DAM) population detected in murine Alzheimer's disease models actually comprises two ontogenetically and functionally distinct cell lineages: embryonically derived triggering receptor expressed on myeloid cells 2 (TREM2)-dependent DAM expressing a neuroprotective signature and monocyte-derived TREM2-expressing disease inflammatory macrophages (DIMs) accumulating in the brain during aging. These two distinct populations appear to also be conserved in the human brain. Herein, we generate an ontogeny-resolved model of brain myeloid cell heterogeneity in development, homeostasis, and disease and identify cellular targets for the treatment of neurodegeneration.
Published: 2022

11. Escherichia coli-Specific CXCL13-Producing TFH Are Associated with Clinical Efficacy of Neoadjuvant PD-1 Blockade against Muscle-Invasive Bladder Cancer

Author: Anne-Gaëlle Goubet, Leonardo Lordello, Carolina Alves Costa Silva, Isabelle Peguillet, Marianne Gazzano, Maxime Descartes Mbogning-Fonkou, Cassandra Thelemaque, Cédric Lebacle, Constance Thibault, François Audenet, Géraldine Pignot, Gwenaelle Gravis, Carole Helissey, Luca Campedel, Morgan Roupret, Evanguelos Xylinas, Idir Ouzaid, Agathe Dubuisson, Marine Mazzenga, Caroline Flament, Pierre Ly, Virginie Marty, Nicolas Signolle, Allan Sauvat, Thomas Sbarrato, Mounia Filahi, Caroline Davin, Gabriel Haddad, Jacques Bou Khalil, Camille Bleriot, François-Xavier Danlos, Garett Dunsmore, Kevin Mulder, Aymeric Silvin, Thibault Raoult, Baptiste Archambaud, Shaima Belhechmi, Ivo Gomperts Boneca, Nadège Cayet, Maryse Moya-Nilges, Adeline Mallet, Romain Daillere, Etienne Rouleau, Camelia Radulescu, Yves Allory, Jacques Fieschi, Mathieu Rouanne, Florent Ginhoux, Gwénaël Le Teuff, Lisa Derosa, Aurélien Marabelle, Jeroen Van Dorp, Nick Van Dijk, Michiel S. Van Der Heijden, Benjamin Besse, Fabrice Andre, Miriam Merad, Guido Kroemer, Jean-Yves Scoazec, Laurence Zitvogel, Yohann Loriot, Université Paris-Saclay, Institut Gustave Roussy (IGR), Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, NF-kappaB, Différenciation et Cancer (OncokappaB (URP_7324)), Université Paris Cité (UPCité), Immunologie intégrative des tumeurs et immunothérapie des cancers (INTIM), Institut Curie [Paris], Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Petites Molécules de neuroprotection, neurorégénération et remyélinisation, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital d'Instruction des Armées Begin, Service de Santé des Armées, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP), Direction de la recherche clinique [Gustave Roussy], Service de biostatistique et d'épidémiologie (SBE), Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Département de médecine oncologique [Gustave Roussy], Département de biologie et pathologie médicales [Gustave Roussy], Oncologie gynécologique, ANR-16-RHUS-0008, ANR-21-RHUS-0017, Bristol-Myers Squibb, BMS, Pfizer, Astellas Pharma US, APUS, AstraZeneca, Genentech, Merck, Roche, Gilead Sciences, Meso Scale Diagnostics, MSD, Janssen Pharmaceuticals, Merck Sharp and Dohme, MSD, Horizon 2020 Framework Programme, H2020: 19-CE15-0029-01, 825410, Clovis Oncology, Seerave Foundation, Fondation Philanthropia, Advanced Accelerator Applications, AAA, Agence Nationale de la Recherche, ANR: ANR-10-LABX-62-IBEID, Fondation pour la Recherche Médicale, FRM, Daiichi-Sankyo, Fondation ARC pour la Recherche sur le Cancer, ARC, Ligue Contre le Cancer, Institut Universitaire de France, IUF, Institut National Du Cancer, INCa, Cancéropôle Ile de France, Association Française d'Urologie, AFU, Labex Immuno-Oncology, The trial was conducted by the French Genitourinary Group (GETUG) and funded by MSD, which provided the drug. This study was approved by the ethics committee CPP Est-III in December 2017 and the French National Agency for the Safety of Medicines and Health Products (ANSM) in November 2017, and was conducted in accordance with the protocols and Good Clinical Practice Guidelines defined by the International Conference for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use and the principles of the Declaration of Helsinki., C. Alves Costa Silva reports grants from MSD Avenir Foundation during the conduct of the study. C. Thibault reports personal fees and nonfinancial support from Pfizer, Merck, MSD, Janssen, and Ipsen, grants, personal fees, and nonfinancial support from AstraZeneca, We thank pathologists, nurses, and clinical research associates from Hôpital Européenn George Pompidou, Hôpital Begin, Institut Paoli-Calmettes, Hôpital Bichat, and Hôpital Pitié-Salpétrière for their participation in the PANDORE clinical trial. We are thankful to the flow and mass cytometry facility team of Gustave Roussy (Philippe Rameau and Cyril Catelain). We thank Fluidigm for their support. We are grateful for support for equipment from the French Government Programme Investissements d’Avenir France BioImag-ing (FBI, No. ANR-10-INSB-04-01) and the French Government (Agence Nationale de la Recherche) Investissement d’Avenir program, Laboratoire d’Excellence 'Integrative Biology of Emerging Infectious Diseases' (ANR-10-LABX-62-IBEID). A.-G. Goubet was supported by Fondation pour la Recherche Médicale. C. Alves Costa Silva was supported by MSD Avenir. F.-X. Danlos was supported by Fondation Philantropia. M. Roupret was supported by Fondation Foch and the Association Française d’Urologie (AFU). L. Zitvogel was funded by the RHU Torino Lumière (ANR-16-RHUS-0008). L. Zitvogel and L. Derosa were supported by RHU5 'ANR-21-RHUS-0017' IMMUNOLIFE, SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE), as well as the SIGN’IT ARC foundation. L. Zitvogel was supported by European Union’s Horizon 2020 research and innovation programme under grant agreement number 825410 [project acronym: ONCOBIOME, project title: Gut OncoMicrobiome Signatures (GOMS) associated with cancer incidence, prognosis, and prediction of treatment response]. L. Zitvogel also received an ANR grant–French-German Ileobiome 19-CE15-0029-01. L. Zitvogel and G. Kroemer received a donation from the Seerave Foundation. L. Zitvogel and G. Kroemer were supported by the Ligue contre le Cancer (équipe labelisée), ANR projets blancs, Cancéropôle Ile-de-France, Fondation pour la Recherche Médicale (FRM), a donation by Elior, Institut National du Cancer (INCa), Inserm (HTE), Institut Universitaire de France, the LabEx Immuno-Oncology, and FHU CARE, Dassault, and Badinter Philantropia. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact., Bristol Myers Squibb, and Sanofi, and personal fees from Astellas and AAA during the conduct of the study, as well as personal fees and nonfinancial support from Pfizer, Merck, MSD, Janssen, and Ipsen, grants, personal fees, and nonfinancial support from AstraZeneca, Bristol Myers Squibb, and Sanofi, and personal fees from Astellas and AAA outside the submitted work. F. Audenet reports personal fees from Astellas, Urodiag, Vitadx, and Bristol Myers Squibb, and nonfinancial support from Ipsen outside the submitted work. G. Gravis reports grants from Bristol Myers Squibb, and other support from MSD, Bristol Myers Squibb, and Merck–Pfizer alliance outside the submitted work. C. Helissey reports personal fees from Janssen-Cilag, Roche, Bayer, AstraZeneca, and Astellas outside the submitted work. L. Cam-pedel reports personal fees from MSD, Pfizer, Bristol Myers Squibb, and Bayer outside the submitted work. T. Sbarrato reports personal fees from Veracyte during the conduct of the study. T. Raoult reports grants, personal fees, and nonfinancial support from Merck Sharp & Dohme during the conduct of the study. E. Rouleau reports grants from AstraZeneca, Roche, Clovis, Bristol Myers Squibb, and MSD outside the submitted work. Y. Allory reports other support from Astra-Zeneca, MSD, and Bristol Myers Squibb outside the submitted work. J. Fieschi reports personal fees from Veracyte during the conduct of the study. A. Marabelle reports grants, personal fees, nonfinancial support, and other support from MSD, Bristol Myers Squibb, and AstraZeneca, and personal fees, nonfinancial support, and other support from Roche/Genentech and Pfizer outside the submitted work. J. Van Dorp reports other support from Bristol Myers Squibb during the conduct of the study. M.S. van der Heijden reports grants from Bristol Myers Squibb during the conduct of the study, as well as grants and personal fees from Bristol Myers Squibb, Roche, and AstraZeneca, grants from 4SC, and personal fees from MSD/Merck, Janssen, Pfizer, and Seagen outside the submitted work. B. Besse reports grants from 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Celgene, Cergentis, Chu-gai Pharmaceutical, Cristal Therapeutics, Daiichi Sankyo, Eli Lilly, Eisai, Genzyme Corporation, GSK, Inivata, Ipsen, Janssen, Onxeo, OSE Immunotherapeutics, Pfizer, Roche/Genentech, Sanofi, Takeda, Tolero Pharmaceuticals, and Turning Point Therapeutics during the conduct of the study. F. Andre reports grants and other support from AstraZeneca and Daiichi Sankyo, grants from Lilly and Sanofi, and other support from Novartis and Relay outside the submitted work. M. Merad reports grants and personal fees from Regeneron, personal fees from Compugen, Morphic Therapeutics, Myeloid Therapeutics, Nirogy, DrenBio, Oncoresponse, Asherbio, Pionyr, Owkin, and Larkspur, other support from Innate Pharma, Genenta, DBV, and OSE Immunotherapeutics, and grants from Boehringer outside the submitted work. G. Kroemer reports grants from Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Sotio, Tollys, Vascage, and Vasculox/Tioma, and personal fees from Reithera outside the submitted work, is on the Board of Directors for Bristol Myers Squibb Foundation France, and is a scientific cofounder of EverImmune, Osasuna Therapeutics, Samsara Therapeutics, and Therafast Bio. L. Zitvogel reports grants and personal fees from EverImmune, and grants from 9 Meters and Pileje during the conduct of the study, grants from Daiichi Sankyo outside the submitted work, and a patent for B220028EPA pending. Y. Loriot reports grants from MSD and personal fees from MSD during the conduct of the study, personal fees from Bristol Myers Squibb, Pfizer, Merck Serono, AstraZeneca, Seattle Genetics, Gilead, Taiho, and Astel-las, grants and personal fees from Janssen, and grants from Roche and Celsius outside the submitted work, and a patent for EP2305181.4 pending. No disclosures were reported by the other authors., and FHU CARE, Dassault, and Badinter Philantropia., ANR-16-RHUS-0008,LUMIERE,LUMIERE(2016), and ANR-21-RHUS-0017,IMMUNOLIFE,Microbiota-centered interventions to solve antibiotics-induced primary resistance to immune checkpoint inhibitors(2021)
Subjects: [SDV]Life Sciences [q-bio], Muscles, Programmed Cell Death 1 Receptor, T-Lymphocytes, Helper-Inducer, Chemokine CXCL13, B7-H1 Antigen, Neoadjuvant Therapy, Treatment Outcome, Oncology, Urinary Bladder Neoplasms, Immunoglobulin G, Escherichia coli, Humans, Immune Checkpoint Inhibitors
Abstract: Biomarkers guiding the neoadjuvant use of immune-checkpoint blockers (ICB) are needed for patients with localized muscle-invasive bladder cancers (MIBC). Profiling tumor and blood samples, we found that follicular helper CD4+ T cells (TFH) are among the best therapeutic targets of pembrolizumab correlating with progression-free survival. TFH were associated with tumoral CD8 and PD-L1 expression at baseline and the induction of tertiary lymphoid structures after pembrolizumab. Blood central memory TFH accumulated in tumors where they produce CXCL13, a chemokine found in the plasma of responders only. IgG4+CD38+ TFH residing in bladder tissues correlated with clinical benefit. Finally, TFH and IgG directed against urothelium-invasive Escherichia coli dictated clinical responses to pembrolizumab in three independent cohorts. The links between tumor infection and success of ICB immunomodulation should be prospectively assessed at a larger scale. Significance: In patients with bladder cancer treated with neoadjuvant pembrolizumab, E. coli–specific CXCL13 producing TFH and IgG constitute biomarkers that predict clinical benefit. Beyond its role as a biomarker, such immune responses against E. coli might be harnessed for future therapeutic strategies. This article is highlighted in the In This Issue feature, p. 2221
Published: 2022

12. Plasmacytoid urothelial carcinoma (UC) are luminal tumors with similar CD8+ Tcell density and PD-L1 protein expression on immune cells as compared to conventional UC

Author: Nicolas Signolle, T. Lebret, Anaïs Dziegielewski, Mathieu Rouanne, Myriam Kossai, Julien Adam, Mathilde Sibony, Camelia Radulescu, Yves Allory, Hôpital Foch [Suresnes], Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre hospitalier Saint-Joseph [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Immunologie intégrative des tumeurs et immunothérapie des cancers (INTIM), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut Gustave Roussy (IGR), Université Paris-Saclay, Hôpital Cochin [AP-HP], Institut Curie [Paris], Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Immunologie anti-tumorale et immunothérapie des cancers (ITIC), and Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Subjects: Adult, Male, Plasmacytoid variant, Urology, [SDV]Life Sciences [q-bio], CD8-Positive T-Lymphocytes, B7-H1 Antigen, Tumor-infiltrating lymphocytes, Molecular subtype, Immune system, PD-L1, Humans, Medicine, Pathological, Aged, Aged, 80 and over, Carcinoma, Transitional Cell, biology, business.industry, GATA3, Middle Aged, Phenotype, Urinary Bladder Neoplasms, Oncology, biology.protein, Cancer research, Female, Urothelial carcinoma, Antibody, business, CD8
Abstract: International audience; Background: Plasmacytoid urothelial carcinoma (UC) is a rare pathological variant of UC with low chemotherapeutic sensitivity and dismal outcomes. The molecular and immune profiles of such tumors remain poorly investigated. Methods: Herein, we investigated the phenotypical features of a cohort of plasmacytoid UC (n=32) by comparison to a control group of conventional high-grade UC with matched clinicopathological characteristics (n=30). Histopathological analysis included the following antibodies: p63, GATA3, CK5/6, CK20 and HER2. In addition, the density of intra-tumor CD8+ lymphocytes, and PD-L1 expression in tumor (TC) and immune cells (IC) were evaluated. Results: Plasmacytoid UC expressed GATA3 (97% vs 86% P=0.18), CK20 (59% vs 36% P=0.08) markers and showed a significantly higher rate of HER2 overexpression (2+ and 3+ score: 25% vs 0%, P
Published: 2022

13. Local Anti-CTLA4 Cancer Immunotherapy From Bench to Bedside

Author: Tselikas, Lambros, Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Université Paris-Saclay, Thierry Debaere, Aurélien Marabelle, and STAR, ABES
Subjects: [SDV.IMM] Life Sciences [q-bio]/Immunology, Intratumoral, Interventionnel radiology, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Local immuntherapy, Anti-CTLA4, Immunothérapie locale, Immuno-Oncology, Radiologie Interventionnelle, [SDV.CAN] Life Sciences [q-bio]/Cancer, Immuno-Oncologie, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, Melanoma, Mélanome
Abstract: Local immunotherapy is a growing therapeutic strategy which requires a specific framework in order to perform effective translational research and evaluate properly the clinical outcomes. We report here the workflow and dedicated setting implemented in our institution for human intratumoral immunotherapy (HIT-IT). The cornerstone has been the creation of a weekly multidisciplinary HIT-IT board gathering multiple specialists (both clinicians and non-clinicians). Our initial experience with the first 100 patients treated with IT immunotherapies has proved the safety of the strategy and demonstrated some interesting signals of efficacy.One immunotherapy of specific interest has been the anti-CTLA4 monoclonal antibodies because of their dose/effect relationship.In a preclinical mouse model (CT26), IT anti-CTLA4 has shown a good safety profile and a high local and distant response rate.The development of a slow release, radiopaque PLGA delivery formulation did not allow to enhance efficacy, and low doses (10-fold lower than systemic doses) repeated regularly (4 injections) seemed to be the most favorable regimen.We also report the results of a randomized clinical trial (NIVIPIT) comparing anti-PD1 (nivolumab) blockade in combination with either intravenous or low dose intratumoral anti-CTLA4 (ipilimumab) in advanced melanoma patients.The intratumoral arm of the trial showed a favorable safety profile with significantly lower grade≥3 irAE and 72% response rate on injected lesions, while the overall ORR and OS were inferior to the systemic arm.The systemic exposure to ipilimumab was significantly lower in the IT arm (17 to 27-fold lower).The presence of CD4+CD25highCD39high in tumor biopsies at baseline was predictive of response whatever the treatment arm. This population of cells decreased among responders upon treatment.The presence of Granzyme B in the secretome of tumor biopsies at baseline and its increase at week 3 were also predictive of response.Finally, an increase in ICOS+ Tregs and in soluble CD25 under treatment were associated with grade≥3 treatment related irAEs., L’administration intratumorale (IT) d’immunothérapie est une stratégie thérapeutique en cours de développement rapide, qui nécessite une structuration spécifique pour permettre d’en évaluer les résultats et y adosser de la recherche translationnelle. Nous rapportons l’organisation mise en place au sein de notre groupe, avec comme élément central la création d’une réunion de concertation multidisciplinaire dédiée à l’intratumoral. L’expérience initiale, sur les 100 premiers patients traités par immunothérapie intratumorale à Gustave Roussy est rassurante sur la sécurité de cette méthode d’administration et montre des signaux d’efficacité intéressants.Une des immunothérapies, les anticorps anti-CTLA4 présente un intérêt particulier pour l’intratumoral du fait de leur propriété effet-dose.Nous avons confirmé la bonne tolérance et le bon taux de réponse locale et à distance sur un modèle murin (CT26).Le développement d’une formulation PLGA de relargage continu n’a pas permis d’améliorer l’efficacité de l’anti-CTLA4 en IT. La meilleure efficacité anti-tumorale étant obtenue par l’injection IT répétées de faibles doses d’anti-CTLA4 ( à une dose 10x inférieure à la dose IV).Nous rapportons également les résultats de l’essai clinique NIVIPIT qui a comparé de façon randomisée la sécurité d’utilisation et l’efficacité d’un anti-CTLA4 (ipilimumab) à faible dose par voie IT versus à dose normale en IV, en combinaison avec un anti-PD1 (Nivolumab) en IV chez des patients atteints de mélanome. Les patients traités dans le bras IT ont développé moins d’irAE de grade≥3, avec cependant un ORR et une OS inferieur au bras IV. L’exposition systémique d’Ipilimumab était entre 17 et 27 fois inferieure dans le bras IT comparativement au bras IV.Nous avons identifié que la présence d’une population CD4+CD25highCD39high dans les biopsies tumorales, ou de Granzyme B dans leur sécrétome était prédictif de réponse. Cette population de lymphocyte T diminue chez les répondeurs sous l’effet du traitement.De plus, une augmentation de l’expression de ICOS sur les Tregs et une augmentation de CD25 soluble étaient prédictifs d’irAEs de grade≥3 dans les deux bras.
Published: 2021

14. Identification of Biomarkers Associated With the Combination of Immunotherapy and Anti-Angiogenic Drugs in the Treatment of Mesothelioma : Translational Analyses of the PEMBIB Clinical Trial Combining the Anti-PD1 Monoclonal Antibody Embrolizumab and the Anti-Angiogenic Tyrosine Kinase Inhibitor Nintedanib

Author: Danlos, François-Xavier, Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Université Paris-Saclay, Aurélien Marabelle, and STAR, ABES
Subjects: Recherche translationnelle, Anti-Angiogénique, [SDV.CAN] Life Sciences [q-bio]/Cancer, Immunothérapie, Anti-Angiogenic drug, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Translational research, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, Immune checkpoint blockade, Cancer
Abstract: In oncology, the efficacy of monoclonal antiprogrammed death 1 (PD1) antibody immunotherapies remains insufficient for many patients. The association of these treatments with an anti-angiogenic molecule could improve their efficacy, by direct anti-tumor effects and by contributing to the development of an anti-tumor immune response., En oncologie, l'efficacité des immunothérapies par anticorps monoclonaux anti Programmed Death 1 (PD1) reste insuffisante pour de nombreux patients. L'association de ces traitements avec une molécule anti-angiogénique pourrait permettre d'en améliorer leur efficacité, par des effets directs anti-tumoraux et en contribuant au développement d'une réponse immunitaire anti-tumorale.
Published: 2021

15. A subset of Kupffer cells regulates metabolism through the expression of CD36

Author: Guochen Wan, Nicholas Ang, Shanshan W. Howland, Svetoslav Chakarov, Evan W. Newell, Gregoire Gessain, Wan Ting Kong, Cecilia Morgantini, Olivier N. F. Cexus, Bernett Lee, Zhaoyuan Liu, Xenia Ficht, Ping Chen, Giorgia De Simone, Emelie Barreby, Josephine Lum, Nicolas Venteclef, Francesco Andreata, Ahad Khalilnezhad, Myriam Aouadi, Jinmiao Chen, Connie Xu, Xiaomeng Zhang, Ivy Low, Foo Shihui, Garett Dunsmore, Anis Larbi, Laurent Yvan-Charvet, Camille Blériot, Wei Guo, Rhea Pai, Muhammad Faris Bin Mohd Kairi, Benoit Malleret, Radoslaw M. Sobota, Wint Wint Phoo, Florent Ginhoux, Lai Guan Ng, Valerio Azzimato, Marc Bajénoff, Raphaelle Ballaire, Matteo Iannacone, Valeria Fumagalli, Ankur Sharma, Akhila Balachander, Singapore Immunology Network (SIgN), Biomedical Sciences Institute (BMSI), Karolinska Institute, Institut Gustave Roussy (IGR), Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Inovarion, IRCCS San Raffaele Scientific Institute [Milan, Italie], Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), Equipe Electronique - Laboratoire GREYC - UMR6072, Groupe de Recherche en Informatique, Image et Instrumentation de Caen (GREYC), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Karolinska Institutet [Stockholm], Shangaï Jiao Tong University [Shangaï], Genome Institute of Singapore (GIS), National University of Singapore (NUS), University of Surrey (UNIS), Agency for science, technology and research [Singapore] (A*STAR), Aix Marseille Université (AMU), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Immunité et métabolisme dans le diabète = IMmunity and MEtabolism in DIABetes [CRC] (IMMEDIAB Lab), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS San Raffaele Pisana), Shanghai Jiao Tong University [Shanghai], Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden, Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Inserm Avenir Group, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), INSERM U1015, Unit of Immunology, Rheumatology, Allergy and Rare diseases, Milan (IRCCS San Raffaele Scientific Institute), E-institute of Shanghai University Immunology Division, Shanghai University, University of Surrey, - Biosciences and Medicine, Faculty of Health and Medical Sciences, Guildford, SingMass National Laboratory - Singapore, Bleriot, C., Barreby, E., Dunsmore, G., Ballaire, R., Chakarov, S., Ficht, X., De Simone, G., Andreata, F., Fumagalli, V., Guo, W., Wan, G., Gessain, G., Khalilnezhad, A., Zhang, X. M., Ang, N., Chen, P., Morgantini, C., Azzimato, V., Kong, W. T., Liu, Z., Pai, R., Lum, J., Shihui, F., Low, I., Xu, C., Malleret, B., Kairi, M. F. M., Balachander, A., Cexus, O., Larbi, A., Lee, B., Newell, E. W., Ng, L. G., Phoo, W. W., Sobota, R. M., Sharma, A., Howland, S. W., Chen, J., Bajenoff, M., Yvan-Charvet, L., Venteclef, N., Iannacone, M., Aouadi, M., Ginhoux, F., Bleriot, C, Barreby, E, Dunsmore, G, Ballaire, R, Chakarov, S, Ficht, X, De Simone, G, Andreata, F, Fumagalli, V, Guo, W, Wan, G, Gessain, G, Khalilnezhad, A, Zhang, X, Ang, N, Chen, P, Morgantini, C, Azzimato, V, Kong, W, Liu, Z, Pai, R, Lum, J, Shihui, F, Low, I, Xu, C, Malleret, B, Kairi, M, Balachander, A, Cexus, O, Larbi, A, Lee, B, Newell, E, Ng, L, Phoo, W, Sobota, R, Sharma, A, Howland, S, Chen, J, Bajenoff, M, Yvan-Charvet, L, Venteclef, N, Iannacone, M, Aouadi, M, Ginhoux, F, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)
Subjects: CD36 Antigens, Kupffer Cells, CD36, [SDV]Life Sciences [q-bio], Immunology, Population, Kupffer cell, macrophage, liver, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Immune system, scRNA-seq, medicine, Immunology and Allergy, Gene silencing, Macrophage, Animals, Obesity, education, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, education.field_of_study, biology, Fatty acid metabolism, high fat diet, medicine.disease, Phenotype, Cell biology, macrophages, single cell, Oxidative Stress, Infectious Diseases, chemistry, CD206, Liver, 030220 oncology & carcinogenesis, biology.protein, Steatosis, heterogeneity, metabolism
Abstract: Tissue macrophages are immune cells whose phenotypes and functions are dictated by origin and niches. However, tissues are complex environments, and macrophage heterogeneity within the same organ has been overlooked so far. Here, we used high-dimensional approaches to characterize macrophage populations in the murine liver. We identified two distinct populations among embryonically derived Kupffer cells (KCs) sharing a core signature while differentially expressing numerous genes and proteins: a major CD206loESAM– population (KC1) and a minor CD206hiESAM+ population (KC2). KC2 expressed genes involved in metabolic processes, including fatty acid metabolism both in steady-state and in diet-induced obesity and hepatic steatosis. Functional characterization by depletion of KC2 or targeted silencing of the fatty acid transporter Cd36 highlighted a crucial contribution of KC2 in the liver oxidative stress associated with obesity. In summary, our study reveals that KCs are more heterogeneous than anticipated, notably describing a subpopulation wired with metabolic functions.
Published: 2021

16. Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade

Author: Catalin Mihalcioiu, Charlotte E. Ariyan, Michael K. Wong, Aurélie Fluckiger, Julie M. Simon, Rossanna C. Pezo, Michael G. White, Padmanee Sharma, Michael A. Postow, Sapna Pradyuman Patel, Adi Diab, Isabella C. Glitza, Elizabeth M. Burton, Whijae Roh, Zachary A. Cooper, Laurence Zitvogel, Maria Paula Roberti, Wen-Jen Hwu, Alexandria P. Cogdill, Miles C. Andrews, Gladys Ferrere, Abdul Wadud Khan, Scott E. Woodman, Robert R. Jenq, Christine N. Spencer, James P. Allison, Lisa Derosa, Curtis Gumbs, Wei Shen Chen, Stephanie S. Watowich, Irina Fernandez Curbelo, Michael A. Davies, Paule Opolon, Connie P.M. Duong, Jennifer A. Wargo, Maryam Tidjani Alou, Courtney W. Hudgens, Vancheswaran Gopalakrishnan, Pierre Olivier Gaudreau, Michael T. Tetzlaff, Didier Raoult, Arielle Elkrief, Khalida Wani, Jeffrey E. Gershenwald, Margaret K. Callahan, Sarah B. Johnson, Alexandre Reuben, Joseph F. Petrosino, Latasha Little, Peter A. Prieto, Matthew Lastrapes, Valerio Iebba, Bertrand Routy, Matthew Adamow, Alexander J. Lazar, Jennifer L. McQuade, Nadim J. Ajami, Golnaz Morad, Rodabe N. Amaria, Matthew C. Wong, Erez N. Baruch, Hussein Abdul-Hassan Tawbi, Satoru Yonekura, Li Zhao, Reetakshi Arora, Luis M Vence, Lauren E. Haydu, Luigi Nezi, Patrick Hwu, P. Andrew Futreal, Jianhua Zhang, The University of Texas M.D. Anderson Cancer Center [Houston], Olivia Newton-John Cancer Research Institute [Heidelberg, VIC, Australia], Monash University [Melbourne], Institut Gustave Roussy (IGR), Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Saclay, Morsani College of Medicine [Tampa, USA], University of South Florida [Tampa] (USF), The Parker Institute, University of Copenhagen = Københavns Universitet (UCPH), AstraZeneca, Gaithersburg, MD, USA, University of Rochester Medical Center (URMC), Memorial Sloane Kettering Cancer Center [New York], Istituto Europeo di Oncologia, Milan, Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), McGill University Health Center [Montreal] (MUHC), University of Toronto, Baylor College of Medicine (BCM), Baylor University, ANR-16-RHUS-0008,LUMIERE,LUMIERE(2016), ANR-10-IAHU-0003,Méditerranée Infection,I.H.U. Méditerranée Infection(2010), European Project: 825410,ONCOBIOME, COMBE, Isabelle, LUMIERE - - LUMIERE2016 - ANR-16-RHUS-0008 - RHUS - VALID, Instituts Hospitalo-Universitaires - I.H.U. Méditerranée Infection - - Méditerranée Infection2010 - ANR-10-IAHU-0003 - IAHU - VALID, European Union’s Horizon 2020 research and innovation programme under grant agreement. - ONCOBIOME - 825410 - INCOMING, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Department of Radiology, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France, University of Copenhagen = Københavns Universitet (KU), Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPC), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), Faculté de médecine de l'Université Paris-Sud [Kremlin Bicêtre, Paris], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Malaria : parasites et hôtes - Malaria : parasites and hosts, Institut Pasteur [Paris], Ottawa Hospital Research Institute [Ottawa] (OHRI), Andrews, M. C., Duong, C. P. M., Gopalakrishnan, V., Iebba, V., Chen, W. -S., Derosa, L., Khan, M. A. W., Cogdill, A. P., White, M. G., Wong, M. C., Ferrere, G., Fluckiger, A., Roberti, M. P., Opolon, P., Alou, M. T., Yonekura, S., Roh, W., Spencer, C. N., Curbelo, I. F., Vence, L., Reuben, A., Johnson, S., Arora, R., Morad, G., Lastrapes, M., Baruch, E. N., Little, L., Gumbs, C., Cooper, Z. A., Prieto, P. A., Wani, K., Lazar, A. J., Tetzlaff, M. T., Hudgens, C. W., Callahan, M. K., Adamow, M., Postow, M. A., Ariyan, C. E., Gaudreau, P. -O., Nezi, L., Raoult, D., Mihalcioiu, C., Elkrief, A., Pezo, R. C., Haydu, L. E., Simon, J. M., Tawbi, H. A., Mcquade, J., Hwu, P., Hwu, W. -J., Amaria, R. N., Burton, E. M., Woodman, S. E., Watowich, S., Diab, A., Patel, S. P., Glitza, I. C., Wong, M. K., Zhao, L., Zhang, J., Ajami, N. J., Petrosino, J., Jenq, R. R., Davies, M. A., Gershenwald, J. E., Futreal, P. A., Sharma, P., Allison, J. P., Routy, B., Zitvogel, L., and Wargo, J. A.
Subjects: [SDV]Life Sciences [q-bio], medicine.medical_treatment, Interleukin-1beta, Programmed Cell Death 1 Receptor, Cancer immunotherapy, Gut flora, Inbred C57BL, Mice, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Medicine, CTLA-4 Antigen, Melanoma, ComputingMilieux_MISCELLANEOUS, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, 0303 health sciences, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Tumor, biology, General Medicine, 3. Good health, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 030220 oncology & carcinogenesis, Toxicity, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Female, [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Human, General Biochemistry, Genetics and Molecular Biology, Cell Line, 03 medical and health sciences, Immune system, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Cell Line, Tumor, Animals, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Microbiome, Colitis, 030304 developmental biology, Animal, business.industry, medicine.disease, biology.organism_classification, Mice, Inbred C57BL, Gastrointestinal Microbiome, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Immune checkpoint, CTLA-4, Immunology, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, business
Abstract: International audience; Treatment with combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 is associated with clinical benefit across tumor types, but also a high rate of immune-related adverse events. Insights into biomarkers and mechanisms of response and toxicity to CICB are needed. To address this, we profiled the blood, tumor and gut microbiome of 77 patients with advanced melanoma treated with CICB, with a high rate of any ≥grade 3 immune-related adverse events (49%) with parallel studies in pre-clinical models. Tumor-associated immune and genomic biomarkers of response to CICB were similar to those identified for ICB monotherapy, and toxicity from CICB was associated with a more diverse peripheral T-cell repertoire. Profiling of gut microbiota demonstrated a significantly higher abundance of Bacteroides intestinalis in patients with toxicity, with upregulation of mucosal IL-1β in patient samples of colitis and in pre-clinical models. Together, these data offer potential new therapeutic angles for targeting toxicity to CICB.
Published: 2021

17. Targeting the DNA damage response in immuno-oncology: developments and opportunities

Author: Christopher J. Lord, Philippe Pasero, Mathieu Rouanne, Roman M. Chabanon, Jean-Charles Soria, Sophie Postel-Vinay, Programme ATIP - Avenir, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Hôpital Foch [Suresnes], The institute of cancer research [London], Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP), Institut Gustave Roussy (IGR), Université Paris-Saclay, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), AstraZeneca, Roche, Association pour la Recherche sur le Cancer, ARC: PGA1 RF 20190208576, Boehringer Ingelheim, Merck KGaA, Ligue Contre le Cancer: INCa-DGOS-INSERM_12551, Cancéropôle Ile de France: 2017-1-EMERG-72, Fondation Bettencourt Schueller, Fondation des Treilles, The authors thank Y. L. Lin and H. Técher for their careful reading of the manuscript and insightful comments. The work in the laboratory of S.P.-V. is supported by programme grants from ATIP-Avenir INSERM / La Ligue Nationale Contre le Cancer, SIRIC SOCRATE-2 (INCa-DGOS-INSERM_12551), Cancéropôle Ile-de-France (2017-1-EMERG-72) and Association pour la Recherche contre le Cancer (ARC PGA1 RF 20190208576). R.M.C. received funding from Fondation Bettencourt-Schueller, Fondation des Treilles, Fondation Philanthropia-Lombard Odier, Institut Servier, and Cancéropôle Ile-De-France., and R.M.C., M.R. and P.P. have no conflicts of interest or financial interests to disclose. C.J.L. is a named inventor on patents describing the use of DNA repair inhibitors and stands to gain from their use as part of the Institute of Cancer Research Rewards to Inventor scheme. C.J.L. has received research funding from AstraZeneca, Merck KGaA, Artios and Pfizer, has received consultancy and/or advisory fees from Astra Zeneca, Merck KGaA, Artios, Tango and GLG, and is a shareholder of OviBio and Tango. J.-C.S. has received consultancy fees from Relay Therapeutics, is a shareholder of AstraZeneca, Gritstone and Daiichi Sankyo, and is a member of the Hookipa board of directors. S.P.-V. has received research funding from Merck KGaA, Boehringer Ingelheim and Roche for unrelated research projects. As part of the Drug Development Department (DITEP), S.P.-V. is a principal investigator or a subinvestigator on clinical trials by Abbvie, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca, Aveo, Bayer Healthcare AG, Bbb Technologies BV, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Chugai Pharmaceutical Co., Clovis Oncology, Daiichi Sankyo, Debiopharm S.A., Eisai, Eli Lilly, Exelixis, Forma, Gamamabs, Genentech Inc., Glaxosmithkline, H3 Biomedicine Inc., Hoffmann La Roche AG, Innate Pharma, Iris Servier, Janssen Cilag, Kyowa Kirin Pharmaceutical Development Inc., Loxo Oncology, Lytix Biopharma AS, Medimmune, Menarini Ricerche, Merck Sharp & Dohme-Chibret, Merrimack Pharmaceuticals, Merus, Millennium Pharmaceuticals, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology NV, Oncoethix, Onyx Therapeutics, Orion Pharma, Oryzon Genomics, Pfizer, PharmaMar, Pierre Fabre, Roche, Sanofi Aventis, Taiho Pharma, Tesaro Inc. and Xencor. S.P.-V. has participated in advisory boards for Merck KGaA.
Subjects: Antigenicity, DNA damage, General Mathematics, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Cancer immunotherapy, Medical Oncology, Genomic Instability, 03 medical and health sciences, 0302 clinical medicine, Immune system, Targeted therapies, Immunity, Adjuvanticity, Neoplasms, medicine, Animals, Humans, 030304 developmental biology, 0303 health sciences, business.industry, Applied Mathematics, Immunogenicity, Immunotherapy, 3. Good health, 030220 oncology & carcinogenesis, Cancer research, Immunogenic cell death, Tumour immunology, business, DNA Damage
Abstract: International audience; Immunotherapy has revolutionized cancer treatment and substantially improved patient outcome with regard to multiple tumour types. However, most patients still do not benefit from such therapies, notably because of the absence of pre-existing T cell infiltration. DNA damage response (DDR) deficiency has recently emerged as an important determinant of tumour immunogenicity. A growing body of evidence now supports the concept that DDR-targeted therapies can increase the antitumour immune response by (1) promoting antigenicity through increased mutability and genomic instability, (2) enhancing adjuvanticity through the activation of cytosolic immunity and immunogenic cell death and (3) favouring reactogenicity through the modulation of factors that control the tumour–immune cell synapse. In this Review, we discuss the interplay between the DDR and anticancer immunity and highlight how this dynamic interaction contributes to shaping tumour immunogenicity. We also review the most innovative preclinical approaches that could be used to investigate such effects, including recently developed ex vivo systems. Finally, we highlight the therapeutic opportunities presented by the exploitation of the DDR–anticancer immunity interplay, with a focus on those in early-phase clinical development.
Published: 2021

18. Multifaceted modes of action of the anticancer probiotic Enterococcus hirae

Author: Marion Leduc, Didier Raoult, Laura Mondragón, Kristina Iribarren, Anne-Gaëlle Goubet, Diane Derrien, Satoru Yonekura, Noélie Bossut, Valerio Iebba, Nicola Segata, Guo Chen, Ivo G. Boneca, Lisa Derosa, Adrien Joseph, Fabrice Andre, Sylvère Durand, Aurélie Fluckiger, Maryam Tidjani Alou, Fanny Aprahamian, Richard J. Wheeler, Maryse Moya-Nilges, Eugenie Pizzato, Bo Qu, Guido Kroemer, Oliver Kepp, Nicolas Pons, Romain Daillère, Fabien Lemaitre, Laurence Zitvogel, Department of Radiology, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France, Faculté de Médecine Paris-Saclay, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Université Paris-Saclay, Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Shanghai Jiao Tong University [Shanghai], Institut Gustave Roussy (IGR), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Ligue Nationale Contre le Cancer - Paris, Ligue Nationnale Contre le Cancer, UMR 1015 Immunologie des tumeurs et immunothérapie contre le cancer (ITIC), Plateforme BioImagerie Ultrastructurale – Ultrastructural BioImaging Platform (UTechS UBI), Institut Pasteur [Paris], MetaGenoPolis (MGP (US 1367)), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of Trento [Trento], Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Université de Paris (UP), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Karolinska University Hospital [Stockholm], Fondation pour la Recherche Médicale, Ligue contre le Cancer (équipes labellisées), Leducq Foundation, Seerave Foundation, SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE), SIRIC Cancer Research and Personalized Medicine (CARPEM), Fondation ARC pour la Recherche sur le Cancer, Région Ile-de-France, Chancellerie des universités de Paris (Legs Poix), FRM, European Research Area Network on Cardiovascular Diseases (ERA-CVD, MINOTAUR), Gustave Roussy Odyssea, Fondation Carrefour, High-end Foreign Expert Program in China: GDW20171100085 and GDW20181100051, Institut National du Cancer (INCA) France, Inserm (HTE), Institut Universitaire de France, ANR-10-COHO-0004,CANTO,Etude des toxicités chroniques des traitements anticancéreux chez les patientes porteuses cancer(2010), ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), ANR-16-RHUS-0008,LUMIERE,LUMIERE(2016), European Project: 680969,H2020,H2020-HCO-2015,ERA-CVD(2015), European Project: 825410, H2020-EU.3.1., H2020-EU.3.1.2.,ONCOBIOME (2019), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Ligue Nationale Contre le Cancer (LNCC), Institut Pasteur [Paris] (IP), Université Paris Cité (UPCité), Goubet, A. -G., Wheeler, R., Fluckiger, A., Qu, B., Lemaitre, F., Iribarren, K., Mondragon, L., Tidjani Alou, M., Pizzato, E., Durand, S., Derosa, L., Aprahamian, F., Bossut, N., Moya-Nilges, M., Derrien, D., Chen, G., Leduc, M., Joseph, A., Pons, N., Le Chatelier, E., Segata, N., Yonekura, S., Iebba, V., Kepp, O., Raoult, D., Andre, F., Kroemer, G., Boneca, I. G., Zitvogel, L., Daillere, R., Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPC), Université Paris Cité (UPC), Immunologie des tumeurs et immunothérapie (UMR 1015), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Université Paris-Saclay, Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), and European Project: 825410,ONCOBIOME
Subjects: 0301 basic medicine, medicine.medical_treatment, [SDV]Life Sciences [q-bio], microbiome, law.invention, Probiotic, Mice, 0302 clinical medicine, Cancer immunotherapy, Enterococcus hirae, law, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Neoplasms, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, CD137, 3. Good health, Bifidobacterium animalis, Anti-Bacterial Agents, 030220 oncology & carcinogenesis, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Female, immunotherapy, Immunotherapy, microbiota, cancer, tumor, probiotic, intratumoral IFNγ, Biology, Article, Microbiology, 03 medical and health sciences, Memory T Cells, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, medicine, Animals, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Microbiome, Molecular Biology, Probiotics, Autophagy, Cell Biology, biology.organism_classification, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Gastrointestinal Microbiome, Mice, Inbred C57BL, 030104 developmental biology, Dysbiosis
Abstract: International audience; A deviated repertoire of the gut microbiome predicts resistance to cancer immunotherapy. Enterococcus hirae compensated cancer-associated dysbiosis in various tumor models. However, the mechanisms by which E. hirae restored the efficacy of cyclophosphamide administered with concomitant antibiotics remain ill defined. Here, we analyzed the multifaceted modes of action of this anticancer probiotic. Firstly, E. hirae elicited emigration of thymocytes and triggered systemic and intratumoral IFN gamma-producing and CD137-expressing effector memory T cell responses. Secondly, E. hirae activated the autophagy machinery in enterocytes and mediated ATG4B-dependent anticancer effects, likely as a consequence of its ability to increase local delivery of polyamines. Thirdly, E. hirae shifted the host microbiome toward a Bifidobacteria-enriched ecosystem. In contrast to the live bacterium, its pasteurized cells or membrane vesicles were devoid of anticancer properties. These pleiotropic functions allow the design of optimal immunotherapies combining E. hirae with CD137 agonistic antibodies, spermidine, or Bifidobacterium animalis. We surmise that immunological, metabolic, epithelial, and microbial modes of action of the live E. hirae cooperate to circumvent primary resistance to therapy.
Published: 2021

19. Metabolomic analyses of COVID-19 patients unravel stage-dependent and prognostic biomarkers

Author: Giulia Baciarello, Guido Kroemer, Fanny Pommeret, Allan Sauvat, Eric Solary, Delphine Bredel, Nitharsshini Nirmalathasan, Agathe Dubuisson, Lisa Derosa, Annabelle Stoclin, Frank Griscelli, Mathilde Roumier, Fabrice Andre, Jean-Marie Michot, Frédéric Pène, Claudia Grajeda-Iglesias, Jean-Charles Soria, François-Xavier Danlos, Fabrice Barlesi, Jérôme Duchemin, Flore Rozenberg, Caroline Pradon, Françoise Levavasseur, Anne-Gaëlle Goubet, Julien Rohmer, Luc Mouthon, Laurence Zitvogel, Laurence Albiges, Severine Mouraud, Jean-Eudes Fahrner, Christophe Willekens, Sylvère Durand, Emeline Colomba, Aurélien Marabelle, Félix Ackerman, Syrine Ellouze, Michaela Fontenay, Georges Jourdi, Marc Vasse, Delphine Cantin, Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut Gustave Roussy (IGR), Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), Métabolisme, Cancer et Immunité (CRC - UMR_S 1138), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service de Médecine Interne [Hôpital Foch, Suresnes] (SMI), Hôpital Foch [Suresnes], Oncologie gynécologique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Centre de Référence National des Syndromes Hyperéosinophiliques (CEREO), Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Hémostase, Inflammation, Thrombose (HITH - U1176 Inserm - CHU Bicêtre), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Université Paris-Saclay, Université Paris-Saclay, Département de biologie et pathologie médicales [Gustave Roussy], Département de soins aigus [Gustave Roussy] (DSA), Direction de la recherche [Gustave Roussy], ANR-16-RHUS-0008,LUMIERE,LUMIERE(2016), ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), and European Project: 825410,ONCOBIOME
Subjects: Male, Cancer Research, Kynurenine pathway, Metabolite, [SDV]Life Sciences [q-bio], Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Disease, Pharmacology, Antibodies, Monoclonal, Humanized, Article, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Metabolomics, Tocilizumab, Intensive care, medicine, Metabolome, Humans, lcsh:QH573-671, Pneumonitis, SARS-CoV-2, business.industry, lcsh:Cytology, COVID-19, Cell Biology, Prognosis, medicine.disease, COVID-19 Drug Treatment, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, chemistry, Viral infection, Female, business, Biomarkers
Abstract: The circulating metabolome provides a snapshot of the physiological state of the organism responding to pathogenic challenges. Here we report alterations in the plasma metabolome reflecting the clinical presentation of COVID-19 patients with mild (ambulatory) diseases, moderate disease (radiologically confirmed pneumonitis, hospitalization and oxygen therapy), and critical disease (in intensive care). This analysis revealed major disease- and stage-associated shifts in the metabolome, meaning that at least 77 metabolites including amino acids, lipids, polyamines and sugars, as well as their derivatives, were altered in critical COVID-19 patient’s plasma as compared to mild COVID-19 patients. Among a uniformly moderate cohort of patients who received tocilizumab, only 10 metabolites were different among individuals with a favorable evolution as compared to those who required transfer into the intensive care unit. The elevation of one single metabolite, anthranilic acid, had a poor prognostic value, correlating with the maintenance of high interleukin-10 and -18 levels. Given that products of the kynurenine pathway including anthranilic acid have immunosuppressive properties, we speculate on the therapeutic utility to inhibit the rate-limiting enzymes of this pathway including indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase.
Published: 2021

20. Isoginkgetin derivative IP2 enhances the adaptive immune response against tumor antigens

Author: Dolor Renko, Romain Darrigrand, Marine Rouillon, Mouad Alami, Mathilde Boulpicante, Julien Marcoux, Michael Ghosh, Camille Garcia, Alison Pierson, David Bouyssié, Sébastien Apcher, Emmanuelle Mouton-Barbosa, Institut Gustave Roussy (IGR), Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Biomolécules : Conception, Isolement, Synthèse (BioCIS), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-CY Cergy Paris Université (CY), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut Jacques Monod (IJM (UMR_7592)), Université de Paris (UP)-Centre National de la Recherche Scientifique (CNRS), and University of Tübingen
Subjects: 0301 basic medicine, Fibrosarcoma, T-Lymphocytes, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Medicine (miscellaneous), Adaptive Immunity, Lymphocyte Activation, Epitope, Mice, 0302 clinical medicine, Cancer immunotherapy, Tumor Microenvironment, Biology (General), Cancer, biology, Drug discovery, Chemistry, Tumor Burden, 3. Good health, 030220 oncology & carcinogenesis, Tumour immunology, Female, General Agricultural and Biological Sciences, Cell activation, Spliceosome, QH301-705.5, Immunology, Antigen presentation, Major histocompatibility complex, Cancer Vaccines, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, Antigen, Antigens, Neoplasm, Cell Line, Tumor, MHC class I, medicine, Animals, Biflavonoids, Cell Proliferation, Histocompatibility Antigens Class I, Antineoplastic Agents, Phytogenic, Mice, Inbred C57BL, 030104 developmental biology, biology.protein, Cancer research, Imidazoline Receptors
Abstract: The success of cancer immunotherapy relies on the induction of an immunoprotective response targeting tumor antigens (TAs) presented on MHC-I molecules. We demonstrated that the splicing inhibitor isoginkgetin and its water-soluble and non-toxic derivative IP2 act at the production stage of the pioneer translation products (PTPs). We showed that IP2 increases PTP-derived antigen presentation in cancer cells in vitro and impairs tumor growth in vivo. IP2 action is long-lasting and dependent on the CD8+ T cell response against TAs. We observed that the antigen repertoire displayed on MHC-I molecules at the surface of MCA205 fibrosarcoma is modified upon treatment with IP2. In particular, IP2 enhances the presentation of an exon-derived epitope from the tumor suppressor nischarin. The combination of IP2 with a peptide vaccine targeting the nischarin-derived epitope showed a synergistic antitumor effect in vivo. These findings identify the spliceosome as a druggable target for the development of epitope-based immunotherapies., Darrigrand, Pierson et al. study the effect of mRNA splicing inhibitors on the generation of the MHC class I ligands. They developed a derivative of the spliceosome inhibitor isoginkgetin which is less toxic and more effective at enhancing antigen presentation and CD8+ T cell activation and showed greater antitumour activity in vivo. These findings identify the spliceosome as a druggable target for the development of epitope-based immunotherapies.
Published: 2021

21. A TLR3 Ligand Reestablishes Chemotherapeutic Responses in the Context of FPR1 Deficiency

Author: Francesca Castoldi, Maria Chiara Maiuri, Julie Le Naour, Julien Taieb, Allan Sauvat, Suzette Delaloge, Charles-Antoine Dutertre, Jessica Zucman-Rossi, Juliette Paillet, Erika Vacchelli, Liwei Zhao, Giulia Cerrato, Guido Kroemer, Claire Mulot, Isabelle Martins, Oliver Kepp, Federico Pietrocola, Pierre Laurent-Puig, Aymeric Silvin, Florent Ginhoux, Fabrice Andre, Peng Liu, Laurence Zitvogel, Sandy Adjemian, Cornelia Richter, Zoltan Szallasi, Peter Vandenabeele, Zsofia Sztupinszki, Jonathan Pol, Gautier Stoll, Khady Mangane, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Institut Gustave Roussy (IGR), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), Universidade de São Paulo = University of São Paulo (USP), Boston Children's Hospital, Harvard Medical School [Boston] (HMS), Cancer Research and Personalized Medicine - CARPEM [Paris], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Agency for science, technology and research [Singapore] (A*STAR), Singapore Immunology Network (SIgN), Biomedical Sciences Institute (BMSI), School of Medicine [Shanghai Jiaotong University], Shanghai Jiaotong University, Métabolisme, Cancer et Immunité (CRC - UMR_S 1138), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Oslo (UiO), Direction de la recherche [Gustave Roussy], Département de médecine oncologique [Gustave Roussy], Pathologie mammaire, Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, ANR-16-RHUS-0008,LUMIERE,LUMIERE(2016), European Project: 825410,ONCOBIOME, Le Naour, Julie, Liu, Peng, Zhao, Liwei, Adjemian, Sandy, Sztupinszki, Zsofia, Taieb, Julien, Mulot, Claire, Silvin, Aymeric, Dutertre, Charles-Antoine, Ginhoux, Florent, Sauvat, Allan, Cerrato, Giulia, Castoldi, Francesca, Martins, Isabelle, Stoll, Gautier, Paillet, Juliette, Mangane, Khady, Richter, Cornelia, Kepp, Oliver, Maiuri, Maria Chiara, Pietrocola, Federico, Vandenabeele, Peter, André, Fabrice, Delaloge, Suzette, Szallasi, Zoltan, Laurent-Puig, Pierre, Zucman-Rossi, Jessica, Zitvogel, Laurence, Pol, Jonathan G, Vacchelli, Erika, Kroemer, Guido, École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPC), Universidade de São Paulo (USP), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPC)-Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPC)-École pratique des hautes études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC)
Subjects: 0301 basic medicine, Anthracycline, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Mice, Transgenic, Ligands, 03 medical and health sciences, Mice, 0302 clinical medicine, Immune system, Medicine, Animals, Humans, ComputingMilieux_MISCELLANEOUS, business.industry, Pattern recognition receptor, Wild type, Immunotherapy, Receptors, Formyl Peptide, Toll-Like Receptor 3, Disease Models, Animal, 030104 developmental biology, Cell Transformation, Neoplastic, Poly I-C, Oncology, 030220 oncology & carcinogenesis, Cancer cell, TLR3, Cancer research, business, Colorectal Neoplasms, Annexin A1
Abstract: For anthracycline-based chemotherapy to be immunogenic, dying cancer cells must release annexin A1 (ANXA1) that subsequently interacts with the pattern recognition receptor, formyl peptide receptor 1 (FPR1), on the surface of dendritic cells (DC). Approximately 30% of individuals bear loss-of-function alleles of FPR1, calling for strategies to ameliorate their anticancer immune response. Here, we show that immunotherapy with a ligand of Toll-like receptor-3, polyinosinic:polycytidylic acid (pIC), restores the deficient response to chemotherapy of tumors lacking ANXA1 developing in immunocompetent mice or those of normal cancers growing in FPR1-deficient mice. This effect was accompanied by improved DC- and T-lymphocyte–mediated anticancer immunity. Of note, carcinogen-induced breast cancers precociously developed in FPR1-deficient mice as compared with wild-type controls. A similar tendency for earlier cancer development was found in patients carrying the loss-of-function allele of FPR1. These findings have potential implications for the clinical management of FPR1-deficient patients. Significance: The loss-of-function variant rs867228 in FPR1, harbored by approximately 30% of the world population, is associated with the precocious manifestation of breast, colorectal, esophageal, and head and neck carcinomas. pIC restores deficient chemotherapeutic responses in mice lacking Fpr1, suggesting a personalized strategy for compensating for the FPR1 defect. This article is highlighted in the In This Issue feature, p. 211
Published: 2021

22. BCG therapy downregulates HLA-I on malignant cells to subvert antitumor immune responses in bladder cancer

Author: Mathieu Rouanne, Julien Adam, Camélia Radulescu, Diane Letourneur, Delphine Bredel, Séverine Mouraud, Anne-Gaëlle Goubet, Marion Leduc, Noah Chen, Tuan Zea Tan, Nicolas Signolle, Amélie Bigorgne, Michael Dussiot, Lambros Tselikas, Sandrine Susini, François-Xavier Danlos, Anna K. Schneider, Roman Chabanon, Sophie Vacher, Ivan Bièche, Thierry Lebret, Yves Allory, Jean-Charles Soria, Nicholas Arpaia, Guido Kroemer, Oliver Kepp, Jean Paul Thiery, Laurence Zitvogel, Aurélien Marabelle, Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Columbia University [New York], Hôpital Foch [Suresnes], Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR), Immunologie intégrative des tumeurs et immunothérapie des cancers (INTIM), École normale supérieure de Lyon (ENS de Lyon), Département de médecine oncologique [Gustave Roussy], National University of Singapore (NUS), Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP), The institute of cancer research [London], Institut Curie [Paris], Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Pôle de biologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Bristol-Myers Squibb, BMS, Ipsen, Boston Scientific Corporation, BSC, Daiichi-Sankyo, Institut National de la Santé et de la Recherche Médicale, Inserm, Fondation Gustave Roussy, Seerave Foundation, Association pour la Recherche sur le Cancer, ARC, Institut National de la Santé et de la Recherche Médicale, Inserm: CIC1428, Agence Nationale de la Recherche, ANR: UMS3655, Institut National Du Cancer, INCa, Institut Universitaire de France, IUF: ANR-18-IDEX-0001, Fondation Leducq, Cancéropôle Ile de France, National Cancer Institute, NCI, National Institutes of Health, NIH: U01CA247573, Fondation pour la Recherche Médicale, FRM, Association Française d'Urologie, AFU, Conflict of interest: Over the past 2 years, JCS has received consultancy fees and shares from Relay Therapeutics and Gritstone bio, was on the board of directors of Hookipa Pharmaceuticals (2018–2021), was full-time employee (2017–2019) at AstraZeneca, and has been a full-time employee at Amgen since August 2021. Over the past 7 years, AM has received institutional funding grants from AstraZeneca, Merus, Bristol Myers Squibb (BMS), Boehringer Ingelheim, Transgene, Fondation MSD Avenir, and Sanofi, is member of the Clinical Trial Steering Committee for NCT02528357 (GlaxoSmithKline [GSK]), NCT03334617 (AstraZeneca), is a member of the Data Safety and Monitoring Board for NCT02423863 (sponsor: Oncovir) and NCT03818685 (sponsor: Centre Léon Bérard), has participated on the scientific advisory boards of the following companies: Merck Serono, eTheRNA, Lytix Biopharma, Kyowa Kirin Pharma, Novartis, BMS, Symphogen, Genmab, Amgen, Biothera, Nektar, Tesaro/GSK, Oncosec, Pfizer, Seattle Genetics, AstraZeneca/Medimmune, Servier, Gritstone, Molecular Partners, Bayer, Partner Therapeutics, Sanofi, Pierre Fabre, RedX Pharma, OSE Immunotherapeutics, Medicxi, HiFiBio, IMCheck, MSD, Innate Pharma, and HotSpot Therapeutics, has received teaching/speaker honoraria from Roche/Genentech, BMS, Merck (MSD), Merck Serono, AstraZeneca/Medimmune, Amgen, Sanofi, and Servier, has received fees for scientific and medical consulting from Roche, Pierre Fabre, Onxeo, EISAI, Bayer, Genticel, Rigontec, Daichii Sankyo, Imaxio, Sanofi/BioNTech, Molecular Partners, Pillar Partners, Benta Pharma Industries (BPI), and Faron, has received nonfinancial support (travel expenses) from AstraZeneca, BMS, Merck (MSD), and Roche, and is co-founder and shareholder of Centessa, holds a patent titled 'Humanized and chimeric monoclonal antibodies to CD81' (US patent application serial no. 62/351,054). LZ is founder of EverImmune, a cancer/microbiome biotechnology company, is a member of the board of directors of Transgene, is a member of the scientific advisory board of Transgene, EpiVax, Lytix Biopharma, has received past research contracts with Merus, Roche, and Tusk and honoraria from Transgene, has current research contracts with Innovate Pharma, Kaleido, Pileje, Incyte, BMS, GSK, and Transgene, and is an employee of Gustave Roussy and the Faculté de Médecine Paris XI. GK is on the board of directors of the BMS Foundation (France), receives grants and research support form Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Samsara, Sotio, and Vasculox/Tioma, is founder and shareholder of EverImmune, Osasuna Therapeutics, Samsara Therapeutics, and Therafast Bio, and is an employee of the University of Paris, AP-HP, Gustave Roussy. OK receives grant and research support from Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Samsara, Sotio, and Vasculox/Tioma, is founder and shareholder of Samsara Therapeutics, and is an employee of INSERM, Gustave Roussy. JPT is the scientific founder and chairman of BioCheetah Pte Ltd (Singapore), a company involved in urine-based bladder cancer diagnostics. LT has received research grants from the BMS Foundation and Terumo and honoraria or consulting fees from Boston Scientific, General Electric, and Ipsen., The authors thank Alice Perchenet and Laetitia Grynszpan for technical support and William Y. Kim (University of North Carolina) for providing the UPPL1541 murine bladder cancer cell line. MR is supported by the Fondation Foch and the Association Française d’Urologie (AFU). AM is supported by the Fondation MSD Avenir, Fondation Gustave Roussy, SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE) and INSERM CIC1428. AGG is supported by the Fondation pour la Recherche Médicale (FRM). NA is supported by the National Cancer Institute (NCI), NIH grant U01CA247573. GK is supported by the Ligue con-tre le Cancer (équipe labellisée), the Agence National de la Recherche (ANR) – Projets blancs, the AMMICa US23/CNRS UMS3655, the Association pour la recherche sur le cancer (ARC), Cancéropôle Ile-de-France, the FRM, a donation by Elior, Equipex Onco-Pheno-Screen, the European Joint Programme on Rare Diseases (EJPRD), Gustave Roussy Odyssea, the European Union Horizon 2020 Projects Oncobiome and Crimson, the Fondation Carrefour, the Institut National du Cancer (INCa), the Institut Universitaire de France, LabEx Immuno – Oncology (ANR-18-IDEX-0001), the Leducq Foundation, a Cancer Research ASPIRE Award from the Mark Foundation, the RHU Torino Lumière, the Seerave Foundation, SIRIC (SOCRATE), and SIRIC Cancer Research and Personalized Medicine (CARPEM). This study contributes to the IDEX Université de Paris ANR-18-IDEX-0001. AB and MD are supported by ANR-10-IAHU-01., ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), HAL UVSQ, Équipe, École normale supérieure - Lyon (ENS Lyon), and École pratique des hautes études (EPHE)
Subjects: nonmuscle-invasive bladder cancer, Immunity, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, General Medicine, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Mycobacterium bovis, immunology, Administration, Intravesical, [SDV.CAN] Life Sciences [q-bio]/Cancer, Urinary Bladder Neoplasms, oncology, BCG Vaccine, Tumor Microenvironment, Humans, Immunotherapy, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, bacillus Calmette-Guérin (BCG), Neoplasm Recurrence, Local
Abstract: International audience; Patients with high-risk, nonmuscle-invasive bladder cancer (NMIBC) frequently relapse after standard intravesical bacillus Calmette-Guérin (BCG) therapy and may have a dismal outcome. The mechanisms of resistance to such immunotherapy remain poorly understood. Here, using cancer cell lines, freshly resected human bladder tumors, and samples from cohorts of patients with bladder cancer before and after BCG therapy, we demonstrate 2 distinct patterns of immune subversion upon BCG relapse. In the first pattern, intracellular BCG infection of cancer cells induced a posttranscriptional downregulation of HLA-I membrane expression via inhibition of autophagy flux. Patients with HLA-I–deficient cancer cells following BCG therapy had a myeloid immunosuppressive tumor microenvironment (TME) with epithelial-mesenchymal transition (EMT) characteristics and dismal outcomes. Conversely, patients with HLA-I–proficient cancer cells after BCG therapy presented with CD8+ T cell tumor infiltrates, upregulation of inflammatory cytokines, and immune checkpoint–inhibitory molecules. The latter patients had a very favorable outcome. We surmise that HLA-I expression in bladder cancers at relapse following BCG does not result from immunoediting but rather from an immune subversion process directly induced by BCG on cancer cells, which predicts a dismal prognosis. HLA-I scoring of cancer cells by IHC staining can be easily implemented by pathologists in routine practice to stratify future treatment strategies for patients with urothelial cancer. Copyright
Published: 2020

23. Cross-reactivity between tumor MHC class I-restricted antigens and an enterococcal bacteriophage

Author: Fathia Mami-Chouaib, Vincent Cattoir, Guido Kroemer, Mohamed Sassi, Krisztián Papp, Nathalie Labarrière, Valerio Iebba, Valentin Quiniou, Romain Boidot, Zsofia Sztupinszki, Nicola Segata, Ivo G. Boneca, Friedemann Loos, Sylvain Simon, Jacques Bou-Khalil, Richard J. Wheeler, Carlos López-Otín, Andréanne Gagné, Luisa De Sordi, Barbara S. Sixt, Philippe Joubert, Clara-Maria Scarlata, Fabien Lemaitre, Peng Liu, Laurent Debarbieux, Alexander M.M. Eggermont, Paola Nisticò, Didier Raoult, David Klatzmann, Connie P.M. Duong, Belinda Palermo, Lisa Derosa, Maha Ayyoub, Maryam Tidjani Alou, Meriem Messaoudene, B. Escudier, François Ghiringhelli, Aurélie Fluckiger, Gladys Ferrere, Saber Khelaifia, Bertrand Routy, Laurence Albiges, Edoardo Pasolli, Anne Gaëlle Goubet, Zoltan Szallasi, Romain Daillère, István Csabai, Laurence Zitvogel, Fabrice Andre, Francesco Facciolo, Corentin Richard, Catherine Rabu, Institut Gustave Roussy (IGR), Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, ARN régulateurs bactériens et médecine (BRM), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Umeå University, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Centre d'oncologie et de radiothérapie du parc [Dijon], Institut de médecine génomique et d’immunothérapie (Genomic and Immunotherapy Medical Institute) (institut GIMI), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Anti-Tumor Immunosurveillance and Immunotherapy (CRCINA-ÉQUIPE 3), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Saclay, Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Université Laval [Québec] (ULaval), Institut Pasteur [Paris] (IP), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), National Cancer Institute Regina Elena [Rome, Italy], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Boston Children's Hospital, Harvard Medical School [Boston] (HMS), Eötvös Loránd University (ELTE), University of Trento [Trento], Universidad de Oviedo [Oviedo], Centre d'investigation clinique Biothérapie [CHU Pitié-Salpêtrière] (CIC-BTi), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Immunologie intégrative des tumeurs et immunothérapie des cancers (INTIM), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Centre National de Référence de la Résistance aux Antibiotiques [CHU Rennes] (CNR), CHU Pontchaillou [Rennes], Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), ANR-16-RHUS-0008,LUMIERE,LUMIERE(2016), ANR-19-CE15-0029,Ileobiome,Régulation des réponses immunitaires iléales dans l'immunosurveillance du cancer du colon: rôle du microbiote et des antigènes des cellules souches.(2019), Bernardo, Elizabeth, École pratique des hautes études (EPHE), UNICANCER-UNICANCER-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-FHU TRANSLAD (CHU de Dijon), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'investigation clinique pluridisciplinaire [CHU Pitié Salpêtrière] (CIC-P 1421), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Genetic and Immunology Medical Institute (GIMI), UNICANCER-UNICANCER-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Institut Pasteur [Paris], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Centre d’Investigation Clinique intégré en Biothérapies et immunologie [AP-HP pitié-salpêtrière, Paris] (CIC-BTi), CHU Pitié-Salpêtrière [AP-HP], Fluckiger, A., Daillere, R., Sassi, M., Sixt, B. S., Liu, P., Loos, F., Richard, C., Rabu, C., Alou, M. T., Goubet, A. -G., Lemaitre, F., Ferrere, G., Derosa, L., Duong, C. P. M., Messaoudene, M., Gagne, A., Joubert, P., De Sordi, L., Debarbieux, L., Simon, S., Scarlata, C. -M., Ayyoub, M., Palermo, B., Facciolo, F., Boidot, R., Wheeler, R., Boneca, I. G., Sztupinszki, Z., Papp, K., Csabai, I., Pasolli, E., Segata, N., Lopez-Otin, C., Szallasi, Z., Andre, F., Iebba, V., Quiniou, V., Klatzmann, D., Boukhalil, J., Khelaifia, S., Raoult, D., Albiges, L., Escudier, B., Eggermont, A., Mami-Chouaib, F., Nistico, P., Ghiringhelli, F., Routy, B., Labarriere, N., Cattoir, V., Kroemer, G., Zitvogel, L., and de Sordi, L.
Subjects: H-2 Antigen, Programmed Cell Death 1 Receptor, CD8-Positive T-Lymphocytes, Epitope, Epitopes, Feces, Mice, 0302 clinical medicine, Enterococcus hirae, Neoplasms, Monoclonal, Bacteriophages, 0303 health sciences, Multidisciplinary, biology, Antibodies, Monoclonal, Viral Tail Proteins, Alkylating, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cross Reaction, Immunotherapy, Human, T cell, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cross Reactions, Major histocompatibility complex, Antibodies, Microbiology, 03 medical and health sciences, Animals, Antigens, Neoplasm, Antineoplastic Agents, Alkylating, Cyclophosphamide, Gastrointestinal Microbiome, H-2 Antigens, Histocompatibility Antigens Class I, Humans, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigen, MHC class I, medicine, Antigens, Bacteriophage, Prophage, 030304 developmental biology, Animal, CD8-Positive T-Lymphocyte, biology.organism_classification, biology.protein, Neoplasm, Fece, CD8
Abstract: International audience; Intestinal microbiota have been proposed to induce commensal-specific memory T cells that cross-react with tumor-associated antigens. We identified major histocompatibility complex (MHC) class I-binding epitopes in the tail length tape measure protein (TMP) of a prophage found in the genome of the bacteriophage Enterococcus hirae Mice bearing E. hirae harboring this prophage mounted a TMP-specific H-2Kb-restricted CD8+ T lymphocyte response upon immunotherapy with cyclophosphamide or anti-PD-1 antibodies. Administration of bacterial strains engineered to express the TMP epitope improved immunotherapy in mice. In renal and lung cancer patients, the presence of the enterococcal prophage in stools and expression of a TMP-cross-reactive antigen by tumors correlated with long-term benefit of PD-1 blockade therapy. In melanoma patients, T cell clones recognizing naturally processed cancer antigens that are cross-reactive with microbial peptides were detected.
Published: 2020

24. Performance of CT Compared with F-FDG PET in Predicting the Efficacy of Nivolumab in Relapsed or Refractory Hodgkin Lymphoma

Author: Mokrane, Fatima-Zohra, Chen, Aiping, Schwartz, Lawrence H, Morschhauser, Franck, Stamatoullas, Apasia, Schiano de Colella, Jean-Marc, Vercellino, Laetitia, Casasnovas, Olivier, Chauchet, Adrien, Delmer, Alain, Nicolas-Virelizier, Emmanuelle, Ghesquières, Hervé, Moles-Moreau, Marie-Pierre, Schmitt, Anna, Duléry, Rémy, Bouabdallah, Krimo, Borel, Cecile, Touati, Mohamed, Deau-Fischer, Bénédicte, Peyrade, Frédéric, Seban, Romain-David, Manson, Guillaume, Houot, Roch, Dercle, Laurent, New York Presbyterian Hospital, Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 (GRITA), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Hôpital du Bocage, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Universitaire de Reims (CHU Reims), Centre Léon Bérard [Lyon], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Institut Bergonié [Bordeaux], UNICANCER, Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), CHU Bordeaux [Bordeaux], Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie biologique [CHU Limoges], CHU Limoges, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Institut Curie [Paris], CHU Pontchaillou [Rennes], Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: [SDV.CAN]Life Sciences [q-bio]/Cancer
Abstract: International audience; Background CT and fluorine 18 (F) fluorodeoxyglucose (FDG) PET/CT performances following immune therapy are not well known in patients with relapsed or refractory Hodgkin lymphoma (RRHL). Purpose To compare CT and PET/CT for prognostic value of early response evaluation following nivolumab therapy. Materials and Methods This retrospective study included patients from 34 institutions who underwent early imaging response evaluation from July 2013 to April 2017. Three experienced readers classified imaging response by using Cheson et al and 2016 Lymphoma Response to Immunomodulatory Therapy Criteria as follows complete (metabolic) response, partial (metabolic) response, stable disease or no metabolic response, or progressive (metabolic) disease. Primary CT and PET assessments were performed at a median of 2.0 months (interquartile range, 1.7-3.7 months) after nivolumab initiation. Kaplan-Meier analysis was used to determine the relationship of primary CT and PET assessment response categories to overall survival (OS). Agreements between primary and secondary imaging assessments were assessed by using κ analysis. Results A total of 45 patients (median age, 37 years; range, 18-77 years; 25 men) underwent a primary assessment using CT and PET/CT; 36 patients also underwent a subsequent assessment. Eleven patients (24%) died after a median follow-up of 21.2 months. CT and PET response categories were associated with OS (P = .03 for primary CT assessment; P = .02 for primary PET assessment). There was no pseudoprogression at primary CT and PET assessments. At the primary assessment, response categories by using CT were reclassified by using PET in 44% (20 of 45) of patients. Among these, 55% (11 of 20) were reclassified to complete metabolic response (complete metabolic response rate 29% [13 of 45 patients] vs complete response rate 4% [two of 45 patients]), with a 2-year OS probability of 100%. At the secondary assessment, complete response rate using CT increased to 17% (six of 36 patients), hence a better agreement with PET (κ = 0.78; P < .001). Conclusion Early CT and PET/CT at a median of 2 months after initiation of nivolumab predicted overall survival in relapsed or refractory Hodgkin lymphoma. Early PET detected additional patients with complete metabolic response. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Scott and Wang in this issue.
Published: 2020

25. Efficacy of anti-PD1 re-treatment in patients with Hodgkin lymphoma who relapsed after anti-PD1 discontinuation

Author: Roch Houot, Florence Poizeau, Pauline Brice, Guillaume Manson, Charles Herbaux, Laurent Dercle, Kamal Bouabdallah, Chloe Antier, CHU Pontchaillou [Rennes], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Bordeaux [Bordeaux], Centre hospitalier universitaire de Nantes (CHU Nantes), Recherche en Pharmaco-épidémiologie et Recours aux Soins (REPERES), Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP), Columbia University Medical Center (CUMC), Columbia University [New York], Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Jonchère, Laurent
Subjects: [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Oncology, medicine.medical_specialty, Programmed Cell Death 1 Receptor, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Antineoplastic Agents, Immunological, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Humans, Medicine, In patient, Hodgkin's Lymphoma, anti-PD1, Letters to the Editor, Anti pd1, 030304 developmental biology, 0303 health sciences, business.industry, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Hodgkin's lymphoma, medicine.disease, Hodgkin Disease, Cell Therapy and Immunotherapy, 3. Good health, Discontinuation, 030220 oncology & carcinogenesis, Hodgkin lymphoma, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, business
Abstract: International audience; Patients with relapsed/refractory Hodgkin lymphoma (R/R HL) experience high response rates upon anti-PD1 therapy. In these patients, there is limited data about the optimal duration of treatment and the risk of relapse after anti-PD1 discontinuation. We have previously reported the outcome of 11 patients with R/R HL who discontinued anti-PD1 therapy after achieving a complete response (CR) upon nivolumab1 . These patients experienced favorable outcome as only 2 of them had relapsed after a median follow-up of 21.2 months from discontinuation. Despite the low relapse rate observed in that study, physicians may be worried about the possibility to further rescue these heavily pre-treated patients in case of relapse after anti-PD1 discontinuation. Notably, it is still unknown whether these patients will remain sensitive to a 2nd course of anti-PD1.
Published: 2020

26. Defective lytic transglycosylase disrupts cell morphogenesis by hindering cell wall de-O-acetylation in Neisseria meningitidis

Author: Joseph P. Dillard, Ahmed Haouz, Muhamed-Kheir Taha, William P. Robins, Christian Malosse, Ala-Eddine Deghmane, Julia Chamot-Rooke, Maryse Moya Nilges, Ryan E. Schaub, Ivo G. Boneca, Ignacio Santecchia, Richard J. Wheeler, Allison H. Williams, Samia Hicham, Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Infections Bactériennes Invasives, Institut Pasteur [Paris], Université Paris Descartes - Paris 5 (UPD5), Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Plateforme BioImagerie Ultrastructurale – Ultrastructural BioImaging Platform (UTechS UBI), Spectrométrie de Masse pour la Biologie – Mass Spectrometry for Biology (UTechS MSBio), Institut Pasteur [Paris]-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Cristallographie (Plateforme) - Crystallography (Platform), Harvard Medical School [Boston] (HMS), European Molecular Biology Organization (ALTF 732-2010), European Research Council (PGN from SHAPE to VIR 202283), Fondation pour la Recherche Médicale (DBF20160635726), Institut Carnot-Pasteur (Maladies Infectious fellowship), Institut Carnot Pasteur Microbes and Santé, Fondation pour la Recherche Médicale (FDT201805005258)AHW was supported by an EMBO long-term fellowship (ALTF 732–2010) and an Institut Carnot-Pasteur Maladies Infectious fellowship. This work was supported by an ERC starting grant (PGN from SHAPE to VIR 202283) and a Fondation pour la recherche médicale (FRM) grant Programme d’Urgence (DBF20160635726) to IGB. This study received funding from the French Government′s Investissement d′Avenir program, Laboratoire d′Excellence ‘Integrative Biology of Emerging Infectious Diseases’ (grant no. ANR- 10-LABX-62-IBEID). IS was supported by the Institut Carnot Pasteur Microbes and Santé given to the Pasteur-Paris University PhD program and the ‘Fin de these de science’ number FDT201805005258 granted by 'Fondation pour la recherche médicale (FRM). The UtechS Photonic BioImaging (Imagopole), C2RT, Institut Pasteur was supported by the French National Research Agency (France BioImaging, ANR-10–INSB–04, Investments for the Future)., We acknowledge the synchrotron beamline staff (PROXIMA-1 at SOLEIL and X06DA at SLS) for their assistance. We are extremely grateful to Frederick Saul, Patrick Weber and Marco Bellinzoni for their constant helpful guidance, advice and assistance. We thank Dr. Antoine Forget for the advice on and help with figure presentations., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), and Institut Pasteur [Paris] (IP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, cell division, Cell division, QH301-705.5, Science, infectious disease, 030106 microbiology, Neisseria meningitidis, peptidoglycan, General Biochemistry, Genetics and Molecular Biology, Bacterial cell structure, Cell wall, Lytic transglycosylase, 03 medical and health sciences, chemistry.chemical_compound, Cell Wall, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Catalytic Domain, Morphogenesis, Amino Acid Sequence, Biology (General), X-ray crystallography, chemistry.chemical_classification, Microbiology and Infectious Disease, General Immunology and Microbiology, biology, Cell morphogenesis, General Neuroscience, microbiology, E. coli, Active site, Glycosyltransferases, General Medicine, Cell biology, 030104 developmental biology, Enzyme, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, chemistry, Lytic cycle, cell separation, biology.protein, Medicine, Peptidoglycan, Research Article, Protein Binding
Abstract: Lytic transglycosylases (LT) are enzymes involved in peptidoglycan (PG) remodeling. However, their contribution to cell-wall-modifying complexes and their potential as antimicrobial drug targets remains unclear. Here, we determined a high-resolution structure of the LT, an outer membrane lipoprotein from Neisseria species with a disordered active site helix (alpha helix 30). We show that deletion of the conserved alpha-helix 30 interferes with the integrity of the cell wall, disrupts cell division, cell separation, and impairs the fitness of the human pathogen Neisseria meningitidis during infection. Additionally, deletion of alpha-helix 30 results in hyperacetylated PG, suggesting this LtgA variant affects the function of the PG de-O-acetylase (Ape 1). Our study revealed that Ape 1 requires LtgA for optimal function, demonstrating that LTs can modulate the activity of their protein-binding partner. We show that targeting specific domains in LTs can be lethal, which opens the possibility that LTs are useful drug-targets., eLife digest Bacteria are surrounded by a tough yet flexible wall that protects the cell and serves as an anchor for several of the cell’s structures. This cell wall contains a large mesh-like molecule called peptidoglycan made of many repeated building blocks. When a bacterial cell divides in two, it needs to make more of this material. Making peptidoglycan involves two different sets of enzymes working together: “polymerases” are the enzymes that link the individual building blocks to peptidoglycan, one after the other; while “lytic transglycosylases” are enzymes that modify the peptidoglycan to create space for the addition of new building blocks and for assemblies of proteins that must span the cell wall. Lytic transglycosylases are known to assemble with other proteins and enzymes to form the cell’s peptidoglycan-modifying machinery, but it was not clear exactly what purpose they serve within these “enzyme complexes”. It was also unclear whether these enzymes would be good targets for new antibiotics. To help answer these questions, Williams et al. looked at a lytic transglycoslyase called LtgA. This enzyme is originally from Neisseria meningitidis, a bacterium that can cause meningitis and life-threatening sepsis in humans. Williams et al. discovered that part of the enzyme’s active site – the region of an enzyme where the chemical reaction takes – can switch from an ordered helix to a disordered, flexible loop. Bacteria were then genetically engineered to make a version of the enzyme that lacked this helix. These bacteria had weaker cell walls and were deformed; they were also less able to grow and divide, both in the laboratory and in a mouse model of infection. Further analysis showed that the deletion of the helix from the enzyme resulted in the peptidoglycan being modified much more than normal, which could likely explain their reduced virulence. Williams et al. also found that deleting the helix from LtgA interfered with the activity of a protein that interacts with this enzyme, called Ape1, which also contributed to the fragility of the cell wall. This shows that lytic transglycosylases assembled into enzyme complexes can alter the activities of other proteins in the complex. Together these findings show that researchers could target one enzyme in a complex in bacteria, and disrupt the activity of other proteins in that complex. This highlights the possibility of considering enzyme complexes as useful targets for new drugs, which is important considering the current problem of antibiotic resistance.
Published: 2020

27. The immuno-oncological challenge of COVID-19

Author: Cléa Melenotte, Aurélien Marabelle, Lisa Derosa, Franck Griscelli, Bertrand Gachot, Laurence Zitvogel, Guido Kroemer, Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Faculté de médecine de l'Université Paris-Sud [Kremlin Bicêtre, Paris], Université Paris-Saclay, Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Institut Gustave Roussy (IGR), Département de biologie et pathologie médicales [Gustave Roussy], Département de soins aigus [Gustave Roussy] (DSA), Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), COMBE, Isabelle, École Pratique des Hautes Études (EPHE), and ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018)
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), [SDV]Life Sciences [q-bio], Disease, Virus, Cancer prognosis, 03 medical and health sciences, 0302 clinical medicine, Immune system, Internal medicine, medicine, Humans, SARS-CoV-2, business.industry, Therapeutic effect, COVID-19, Cancer, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, business
Abstract: International audience; Coronavirus disease 2019 (COVID-19) and its causative virus, SARS-CoV-2, pose considerable challenges for the management of oncology patients. COVID-19 presents as a particularly severe respiratory and systemic infection in aging and immunosuppressed individuals, including patients with cancer. Moreover, severe COVID-19 is linked to an inflammatory burst and lymphopenia, which may aggravate cancer prognosis. Here we discuss why those with cancer are at higher risk of severe COVID-19, describe immune responses that confer protective or adverse reactions to this disease and indicate which antineoplastic therapies may either increase COVID-19 vulnerability or have a dual therapeutic effect on cancer and COVID-19. Zitvogel and colleagues discuss the interplay between cancer and COVID-19 with respect to patient risk and prognosis, immune responses and potential therapies.
Published: 2020

28. COVID-19: a challenge for oncology services

Author: Lisa Derosa, Laurence Zitvogel, Guido Kroemer, Bertrand Routy, Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Faculté de médecine de l'Université Paris-Sud [Kremlin Bicêtre, Paris], Université Paris-Saclay, Institut Gustave Roussy (IGR), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), COMBE, Isabelle, and École Pratique des Hautes Études (EPHE)
Subjects: 0301 basic medicine, 2019-20 coronavirus outbreak, Time Factors, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), [SDV]Life Sciences [q-bio], Immunology, Time to treatment, medicine.disease_cause, Disease cluster, Time-to-Treatment, 03 medical and health sciences, 0302 clinical medicine, Neoplasms, Oncology Service, Hospital, Ambulatory Care, Medicine, Humans, Immunology and Allergy, China, RC254-282, ComputingMilieux_MISCELLANEOUS, Coronavirus, business.industry, COVID-19, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC581-607, medicine.disease, Telemedicine, 3. Good health, Hospitalization, [SDV] Life Sciences [q-bio], Pneumonia, 030104 developmental biology, Editorial, Oncology, 030220 oncology & carcinogenesis, Medical emergency, Immunologic diseases. Allergy, business, Delivery of Health Care
Abstract: On March 11, 2020, the WHO declared that the cluster of pneumonia cases caused by the novel coronavirus SARS-CoV-2 (COVID-19) from Wuhan, China was a global pandemic.1 As of April 5th 2020, over to...
Published: 2020

29. Gut Bacteria Composition Drives Primary Resistance to Cancer Immunotherapy in Renal Cell Carcinoma Patients

Author: Conrad Rauber, Gladys Ferrere, Jean-Eudes Fahrner, Valerio Iebba, Nicolas Pons, Romain Daillère, Emmanuelle Le Chatellier, Hugo Roume, Filippo Pietrantonio, Nicola Segata, Marine Fidelle, Anne-Gaëlle Goubet, Carolina Alves Costa Silva, Bertrand Routy, Connie P.M. Duong, Karim Fizazi, Edoardo Pasolli, Safae Terrisse, Beatrice Casu, Laurence Albiges, Bernard Escudier, Mélodie Bonvalet, Maryam Tidjani Alou, Laurie Alla, Kristina Iribarren, Didier Raoult, Aude Desnoyer, Guido Kroemer, Lisa Derosa, Laura Mondragón, Nathalie Galleron, Anna Reni, Fabien Lemaitre, Laurence Zitvogel, Derosa, L., Routy, B., Fidelle, M., Iebba, V., Alla, L., Pasolli, E., Segata, N., Desnoyer, A., Pietrantonio, F., Ferrere, G., Fahrner, J. -E., Le Chatellier, E., Pons, N., Galleron, N., Roume, H., Duong, C. P. M., Mondragon, L., Iribarren, K., Bonvalet, M., Terrisse, S., Rauber, C., Goubet, A. -G., Daillere, R., Lemaitre, F., Reni, A., Casu, B., Alou, M. T., Alves Costa Silva, C., Raoult, D., Fizazi, K., Escudier, B., Kroemer, G., Albiges, L., Zitvogel, L., Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Faculté de médecine de l'Université Paris-Sud [Kremlin Bicêtre, Paris], Université Paris-Saclay, Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), MetaGenoPolis (MGP (US 1367)), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of Naples Federico II = Università degli studi di Napoli Federico II, Centre for Integrative Biology (CIBIO), University of Trento (CIBIO), University of Trento [Trento], Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR), IRCCS Istituto Nazionale dei Tumori [Milano], Université Paris-Sud - Paris 11 (UP11), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Suzhou Institute of Systems Medicine [Jiangsu, P.R. China], Karolinska University Hospital [Stockholm], Philanthropia Foundation ESMO translational research fellowship Fonds de la Recherche en Sante du Quebec Kidney Cancer Research Network of Canada Ligue nationale contre le cancerFrench National Research Agency (ANR)French National Research Agency (ANR)ERA-Net for Research on Rare Diseases Fondation ARC pour la Recherche sur le CancerRegion Ile-de-France Fondation de FranceFondation pour la Recherche MedicaleEuropean Commission Joint Research CentreEuropean Research Council (ERC)Fondation Carrefour, High-end Foreign Expert Program in China GDW20171100085 GDW20181100051Institut National du Cancer (INCA) FranceInserm (HTE) Institut Universitaire de France Leducq FoundationSearave and Carrefour Foundation SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE 2.0) BMS Foundation SIRIC Cancer Research and Personalized Medicine (CARPEM) Paris Alliance of Cancer Research Institutes (PACRI) Mediterranee Infection 10-IAHU-03Region Provence-Alpes-Cote d'AzurNational Research, Development and Innovation Fund of Hungary FIEK_16-1-20160005Research and Technology Innovation Fund NAP2-2017-1.2.1-NKP-0002Breast Cancer Research Foundation BCRF-17-156Novo Nordisk Foundation Interdisciplinary Synergy Program Grant NNF15OC0016584, ANR-16-RHUS-0008,LUMIERE,LUMIERE(2016), European Project: 825410,ONCOBIOME, University of Naples Federico II, Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Gustave Roussy Cancer Campus (GRCC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Saclay, Université Paris-Sud [Le Kremlin-Bicêtre] (Faculté de Médecine), Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM), Centre d’Investigation Clinique en Biothérapies [CHU Pitié-Salpêtrière] (CIC-BT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Université Paris-Saclay, Faculté de Pharmacie, 92290 Châtenay-Malabry, France, MetaGenoPolis, European Institute of Oncology [Milan] (ESMO), Gustave Roussy Cancer Campus, Partenaires INRAE, Chinese Academy of Medical Sciences, Philanthropia Foundation ESMO translational research fellowship.Fonds de la Recherche en Sante du Quebec Kidney Cancer Research Network of CanadaLigue nationale contre le cancerFrench National Research Agency (ANR) ERA-Net for Research on Rare DiseasesFondation ARC pour la Recherche sur le CancerRegion Ile-de-FranceFondation de FranceFondation pour la Recherche MedicaleEuropean Commission Joint ResearchCentre European Research Council (ERC)Fondation Carrefour, and High-end Foreign Expert Program in China GDW20171100085 GDW20181100051Institut National du Cancer (INCA) France Inserm (HTE) Institut Universitaire de FranceLeducq FoundationSearave and Carrefour Foundation SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE 2.0) BMS Foundation SIRIC Cancer Research and Personalized Medicine (CARPEM) Paris Alliance of Cancer Research Institutes (PACRI)Mediterranee Infection 10-IAHU-03Region Provence-Alpes-Cote d'AzurNational Research, Development and Innovation Fund of Hungary FIEK_16-1-20160005Research and Technology Innovation Fund NAP2-2017-1.2.1-NKP-0002Breast Cancer Research Foundation BCRF-17-156Novo Nordisk Foundation Interdisciplinary Synergy Program Grant NNF15OC0016584
Subjects: Oncology, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Antibiotics, 030232 urology & nephrology, Tyrosine kinase inhibitor, Immune checkpoint inhibitor, Tyrosine-kinase inhibitor, Feces, Mice, 0302 clinical medicine, Cancer immunotherapy, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Renal cell carcinoma, Prospective Studies, Immune Checkpoint Inhibitors, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Microbiota, Kidney cancer, Kidney Neoplasms, 3. Good health, Nivolumab, 030220 oncology & carcinogenesis, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, medicine.medical_specialty, medicine.drug_class, Urology, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Predictive Value of Tests, Internal medicine, medicine, Animals, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Carcinoma, Renal Cell, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, business.industry, Antibiotic, Immunotherapy, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Immune checkpoint, Gastrointestinal Microbiome, Drug Resistance, Neoplasm, business
Abstract: Background: The development of immune checkpoint blockade (ICB) has revolutionized the clinical outcome of renal cell carcinoma (RCC). Nevertheless, improvement of durability and prediction of responses remain unmet medical needs. While it has been recognized that antibiotics (ATBs) decrease the clinical activity of ICB across various malignancies, little is known about the direct impact of distinct intestinal nonpathogenic bacteria (commensals) on therapeutic outcomes of ICB in RCC. Objective: To evaluate the predictive value of stool bacteria composition for ICB efficacy in a cohort of advanced RCC patients. Design, setting, and participants: We prospectively collected fecal samples from 69 advanced RCC patients treated with nivolumab and enrolled in the GETUG-AFU 26 NIVOREN microbiota translational substudy phase 2 trial (NCT03013335) at Gustave Roussy. We recorded patient characteristics including ATB use, prior systemic therapies, and response criteria. We analyzed 2994 samples of feces from healthy volunteers (HVs). In parallel, preclinical studies performed in RCC-bearing mice that received fecal transplant (FMT) from RCC patients resistant to ICB (NR-FMT) allowed us to draw a cause-effect relationship between gut bacteria composition and clinical outcomes for ICB. The influence of tyrosine kinase inhibitors (TKIs) taken before starting nivolumab on the microbiota composition has also been assessed. Outcome measurements and statistical analysis: Metagenomic data (MG) from whole genome sequencing (WGS) were analyzed by multivariate and pairwise comparisons/fold ratio to identify bacterial fingerprints related to ATB or prior TKI exposure and patients’ therapeutic response (overall response and progression-free survival), and compared with the data from cancer-free donors. Results and limitations: Recent ATB use (n = 11; 16%) reduced objective response rates (from 28% to 9%, p < 0.03) and markedly affected the composition of the microbiota, facilitating the dominance of distinct species such as Clostridium hathewayi, which were also preferentially over-represented in stools from RCC patients compared with HVs. Importantly, TKIs taken prior to nivolumab had implications in shifting the microbiota composition. To establish a cause-effect relationship between gut bacteria composition and ICB efficacy, NR-FMT mice were successfully compensated with either FMT from responding RCC patients or beneficial commensals identified by WGS-MG (Akkermansia muciniphila and Bacteroides salyersiae). Conclusions: The composition of the microbiota is influenced by TKIs and ATBs, and impacts the success of immunotherapy. Future studies will help sharpen the role of these specific bacteria and their potential as new biomarkers. Patient summary: We used quantitative shotgun DNA sequencing of fecal microbes as well as preclinical models of fecal or bacterial transfer to study the association between stool composition and (pre)clinical outcome to immune checkpoint blockade. Novel insights into the pathophysiological relevance of intestinal dysbiosis in the prognosis of kidney cancer may lead to innovative therapeutic solutions, such as supplementation with probiotics to prevent primary resistance to therapy. Antibiotics prior to immune checkpoint inhibitors have a deleterious clinical impact, reduce the microbiome diversity, and increase Clostridium hathewayi bacteria associated with resistance. Higher baseline microbiome diversity and Akkermansia muciniphila are associated with longer progression-free survival. In murine fecal microbiome transplantation experiments, A. muciniphila can restore the anticancer activity of the combination of anti–PD-1 and CTLA-4.
Published: 2020

30. Elucidating the gut microbiota composition and the bioactivity of immunostimulatory commensals for the optimization of immune checkpoint inhibitors

Author: Marine Mazzenga, Carolina Alves Costa Silva, Marine Fidelle, Laurence Zitvogel, Yacine Haddad, Alexandria P. Cogdill, Lisa Derosa, Gladys Ferrere, Maria Paula Roberti, Peng Liu, Cassandra Thelemaque, Anne-Gaëlle Goubet, Pierre Ly, Safae Terrisse, Romain Daillère, Cléa Melenotte, Aurélie Fluckiger, Eugenie Pizzato, Bertrand Routy, Guido Kroemer, Oliver Kepp, Institut Gustave Roussy (IGR), Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Saclay, The University of Texas M.D. Anderson Cancer Center [Houston], Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), Faculté de médecine de l'Université Paris-Sud [Kremlin Bicêtre, Paris], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), ANR-16-RHUS-0008,LUMIERE,LUMIERE(2016), European Project: 825410,ONCOBIOME, École pratique des hautes études (EPHE), Sow, Cissé, LUMIERE - - LUMIERE2016 - ANR-16-RHUS-0008 - RHUS - VALID, European Union’s Horizon 2020 research and innovation programme under grant agreement. - ONCOBIOME - 825410 - INCOMING, and ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018)
Subjects: 0301 basic medicine, Immune checkpoint inhibitors, [SDV]Life Sciences [q-bio], Immunology, Review, Anticancer therapeutics, Biology, Gut flora, digestive system, Treatment failure, 03 medical and health sciences, 0302 clinical medicine, Neoplasms, medicine, Immunology and Allergy, Humans, Symbiosis, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, Immune Checkpoint Inhibitors, RC254-282, ComputingMilieux_MISCELLANEOUS, Cancer, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, gut microbiota, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC581-607, medicine.disease, Commensalism, biology.organism_classification, Immune checkpoint, Gastrointestinal Microbiome, [SDV] Life Sciences [q-bio], 030104 developmental biology, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Oncology, 030220 oncology & carcinogenesis, Dysbiosis, Immunologic diseases. Allergy, Microbiota composition, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Accumulating evidence from preclinical studies and human trials demonstrated the crucial role of the gut microbiota in determining the effectiveness of anticancer therapeutics such as immunogenic chemotherapy or immune checkpoint blockade. In summary, it appears that a diverse intestinal microbiota supports therapeutic anticancer responses, while a dysbiotic microbiota composition that lacks immunostimulatory bacteria or contains overabundant immunosuppressive species causes treatment failure. In this review, we explore preclinical and translational studies highlighting how eubiotic and dysbiotic microbiota composition can affect progression-free survival in cancer patients.
Published: 2020
Full Text: View/download PDF

31. Trial watch : the gut microbiota as a tool to boost the clinical efficacy of anticancer immunotherapy

Author: Lucie Heinzerling, Sibylle Loilbl, Lars Engstrand, Lisa Derosa, Romain Daillère, Eva Budinská, I. Jolanda M. de Vries, Nicola Segata, Guido Kroemer, Carlos Caldas, Alessio Naccarati, Manuela Gariboldi, Bertrand Routy, Jacques Fieschi, Laurence Zitvogel, Mélodie Bonvalet, Valérie Zitvogel, Institut Gustave Roussy (IGR), Immunologie intégrative des tumeurs et immunothérapie des cancers (INTIM), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre for Integrative Biology (CIBIO), University of Trento (CIBIO), University of Trento [Trento], Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CR CHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM), IRCCS Istituto Nazionale dei Tumori [Milano], Research Centre for Toxic Compounds in the Environment [Brno] (RECETOX / MUNI), Faculty of Science [Brno] (SCI / MUNI), Masaryk University [Brno] (MUNI)-Masaryk University [Brno] (MUNI), Radboud University Medical Center [Nijmegen], Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Cancer Research UK Cambridge Institute [Cambridge, Royaume-Uni] (CRUK), University of Cambridge [UK] (CAM), Karolinska Institutet [Stockholm], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Service de biologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), University of Science & Technology of China [Suzhou], Karolinska University Hospital [Stockholm], Centre d’Investigation Clinique en Biothérapies [CHU Pitié-Salpêtrière] (CIC-BT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Radboud Institute for Molecular Life Sciences [Nijmegen, the Netherlands], Cancer Research UK Cambridge Research Institute and Department of Oncology, University of Cambridge, German Breast Group (GBG), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), ANR-16-RHUS-0008,LUMIERE,LUMIERE(2016), and European Project: 825410,ONCOBIOME
Subjects: 0301 basic medicine, Gut microbiota, anticancer therapeutics, clinical trials, Dysbiosis, Humans, Immunotherapy, Treatment Outcome, Gastrointestinal Microbiome, Neoplasms, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2], Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Review, Gut flora, Bioinformatics, digestive system, 03 medical and health sciences, 0302 clinical medicine, Immunology and Allergy, Medicine, RC254-282, ComputingMilieux_MISCELLANEOUS, Chemotherapy, biology, business.industry, Cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, RC581-607, medicine.disease, biology.organism_classification, Immune checkpoint, 3. Good health, Blockade, Clinical trial, 030104 developmental biology, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Oncology, Tumor progression, 030220 oncology & carcinogenesis, Immunologic diseases. Allergy, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Contains fulltext : 220857.pdf (Publisher’s version ) (Open Access) Accumulating evidence demonstrates the decisive role of the gut microbiota in determining the effectiveness of anticancer therapeutics such as immunogenic chemotherapy or immune checkpoint blockade in preclinical tumor models, as well as in cancer patients. In synthesis, it appears that a normal intestinal microbiota supports therapeutic anticancer responses, while a dysbiotic microbiota that lacks immunostimulatory bacteria or contains overabundant immunosuppressive species causes treatment failure. These findings have led to the design of clinical trials that evaluate the capacity of modulation of the gut microbiota to synergize with treatment and hence limit tumor progression. Along the lines of this Trial Watch, we discuss the rationale for harnessing the gut microbiome in support of cancer therapy and the progress of recent clinical trials testing this new therapeutic paradigm in cancer patients.
Published: 2020

32. Susceptibilities of CNS Cells towards Rabies Virus Infection Is Linked to Cellular Innate Immune Responses

Author: Lena Feige, Tatsuya Kozaki, Guilherme Dias de Melo, Vincent Guillemot, Florence Larrous, Florent Ginhoux, Hervé Bourhy, Lyssavirus, épidémiologie et neuropathologie - Lyssavirus Epidemiology and Neuropathology, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Agency for science, technology and research [Singapore] (A*STAR), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics, Institut Pasteur [Paris] (IP), Shanghai Jiao Tong University School of Medicine, SingHealth Polyclinics, Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, and Lena Feige was supported by the Pasteur–Paris University (PPU) International PhD Program.
Subjects: Infectious Diseases, Virology, [SDV]Life Sciences [q-bio], astrocytes, microglia, neurons, rabies, viral tropism, immune evasion
Abstract: International audience; Rabies is caused by neurotropic rabies virus (RABV), contributing to 60,000 human deaths annually. Even though rabies leads to major public health concerns worldwide, we still do not fully understand factors determining RABV tropism and why glial cells are unable to clear RABV from the infected brain. Here, we compare susceptibilities and immune responses of CNS cell types to infection with two RABV strains, Tha and its attenuated variant Th2P-4M, mutated on phospho- (P-protein) and matrix protein (M-protein). We demonstrate that RABV replicates in human stem cell-derived neurons and astrocytes but fails to infect human iPSC-derived microglia. Additionally, we observed major differences in transcription profiles and quantification of intracellular protein levels between antiviral immune responses mediated by neurons, astrocytes (IFNB1, CCL5, CXCL10, IL1B, IL6, and LIF), and microglia (CCL5, CXCL10, ISG15, MX1, and IL6) upon Tha infection. We also show that P- and M-proteins of Tha mediate evasion of NF-κB- and JAK-STAT-controlled antiviral host responses in neuronal cell types in contrast to glial cells, potentially explaining the strong neuron-specific tropism of RABV. Further, Tha-infected astrocytes and microglia protect neurons from Tha infection via a filtrable and transferable agent. Overall, our study provides novel insights into RABV tropism, showing the interest in studying the interplay of CNS cell types during RABV infection.
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32 results on '"Immunologie anti-tumorale et immunothérapie des cancers (ITIC)"'

1. Infection of lung megakaryocytes and platelets by SARS-CoV-2 anticipate fatal COVID-19

2. Genomic Instability and Protumoral Inflammation Are Associated with Primary Resistance to Anti–PD-1 + Antiangiogenesis in Malignant Pleural Mesothelioma

3. High serum LDH and liver metastases are the dominant predictors of primary cancer resistance to anti-PD(L)1 immunotherapy

4. Tumor-intrinsic sensitivity to the pro-apoptotic effects of IFN-γ is a major determinant of CD4+ CAR T-cell antitumor activity

5. The European MAPPYACTS Trial: Precision Medicine Program in Pediatric and Adolescent Patients with Recurrent Malignancies

6. Epidemiological Study to Assess the Prevalence of Lung Cancer in patients with smoking-associated atherosclerotic cardiovascular diseases: PREVALUNG study protocol

7. Meningeal macrophages protect against viral neuroinfection

8. Intestinal microbiota influences clinical outcome and side effects of early breast cancer treatment

9. Sustained-hepatic arterial infusion of oxaliplatin: pharmacokinetic advantages over hepatic arterial infusion using a preclinical animal tumour model

10. Dual ontogeny of disease-associated microglia and disease inflammatory macrophages in aging and neurodegeneration

11. Escherichia coli-Specific CXCL13-Producing TFH Are Associated with Clinical Efficacy of Neoadjuvant PD-1 Blockade against Muscle-Invasive Bladder Cancer

12. Plasmacytoid urothelial carcinoma (UC) are luminal tumors with similar CD8+ Tcell density and PD-L1 protein expression on immune cells as compared to conventional UC

13. Local Anti-CTLA4 Cancer Immunotherapy From Bench to Bedside

15. A subset of Kupffer cells regulates metabolism through the expression of CD36

16. Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade

17. Targeting the DNA damage response in immuno-oncology: developments and opportunities

18. Multifaceted modes of action of the anticancer probiotic Enterococcus hirae

19. Metabolomic analyses of COVID-19 patients unravel stage-dependent and prognostic biomarkers

20. Isoginkgetin derivative IP2 enhances the adaptive immune response against tumor antigens

21. A TLR3 Ligand Reestablishes Chemotherapeutic Responses in the Context of FPR1 Deficiency

22. BCG therapy downregulates HLA-I on malignant cells to subvert antitumor immune responses in bladder cancer

23. Cross-reactivity between tumor MHC class I-restricted antigens and an enterococcal bacteriophage

24. Performance of CT Compared with F-FDG PET in Predicting the Efficacy of Nivolumab in Relapsed or Refractory Hodgkin Lymphoma

25. Efficacy of anti-PD1 re-treatment in patients with Hodgkin lymphoma who relapsed after anti-PD1 discontinuation

26. Defective lytic transglycosylase disrupts cell morphogenesis by hindering cell wall de-O-acetylation in Neisseria meningitidis

27. The immuno-oncological challenge of COVID-19

28. COVID-19: a challenge for oncology services

29. Gut Bacteria Composition Drives Primary Resistance to Cancer Immunotherapy in Renal Cell Carcinoma Patients

30. Elucidating the gut microbiota composition and the bioactivity of immunostimulatory commensals for the optimization of immune checkpoint inhibitors

31. Trial watch : the gut microbiota as a tool to boost the clinical efficacy of anticancer immunotherapy

32. Susceptibilities of CNS Cells towards Rabies Virus Infection Is Linked to Cellular Innate Immune Responses

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32 results on '"Immunologie anti-tumorale et immunothérapie des cancers (ITIC)"'

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