Author: "Vichnou Poirier-Colame" - Searchworks@Jio Institute Digital Library Search Results

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1. Upregulation of intratumoral HLA class I and peritumoral Mx1 in ulcerated melanomas

Author: Daniëlle Verver, Vichnou Poirier-Colame, Gorana Tomasic, Khadija Cherif-Rebai, Dirk J. Grunhagen, Cornelis Verhoef, Stefan Suciu, Caroline Robert, Laurence Zitvogel, and Alexander M.M. Eggermont
Subjects: melanoma, ulceration, immunohistochemistry, interferon, immune-editing, Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Before the era of immune checkpoint blockade, a meta-analysis encompassing fifteen trials reported that adjuvant IFN-α significantly reduces the risk of relapse and improves survival of ulcerated melanoma (UM) with no benefit for higher doses compared to lower doses. IFNa2b affects many cell intrinsic features of tumor cells and modulates the host innate and cognate immune responses. To better understand the biological traits associated with ulceration that could explain the efficacy of prophylactic type 1 IFN, we performed immunohistochemical analysis of various molecules (major histocompatibility complex class I and class II, MX Dynamin Like GTPase 1 (MX1), inducible Nitric-Oxide Synthase (iNOS) or CD47) in two retrospective cohorts of melanoma patients, one diagnosed with a primary cutaneous melanoma (1995–2013, N = 172, among whom 49% were ulcerated melanoma (UM)) and a second one diagnosed with metastatic melanoma amenable to lymph node resection (EORTC 18952 and 18991 trials, N = 98, among whom 44% were UM). We found that primary and metastatic UM exhibit higher basal expression of MHC class I molecules, independently of Breslow thickness, histology and lymphocytic infiltration compared with NUM and that primary UM harbored higher constitutive levels of the antiviral protein Mx1 at the border of tumor beds than NUM. These findings suggest that UM expand in a tumor microenvironment where chronic exposure to type 1 IFN could favor a response to exogenous IFNs.
Published: 2019
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2. Supplementary Figure 3 from Regulation of CD4+NKG2D+ Th1 Cells in Patients with Metastatic Melanoma Treated with Sorafenib: Role of IL-15Rα and NKG2D Triggering

Author: Laurence Zitvogel, Caroline Robert, Alexander Eggermont, Danila Valmori, Maha Ayyoub, Christine Mateus, Camillo Porta, Philippe Dessen, Philippe Vielh, Anne Aupérin, Meriem Messaoudene, Anne Caignard, Caroline Flament, Sophie Caillat-Zucman, Yannick Jacques, Erwan Mortier, Kariman Chaba, Nicolas Jacquelot, Sylvie Rusakiewicz, Vichnou Poirier-Colame, Nathalie Chaput, and Ana I. Romero
Abstract: PDF file - 109K, CD4+CD8dim or CD4+NKG2D+ T cells can be found in other malignancies.
Published: 2023
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3. Supplementary Figure 2 from Regulation of CD4+NKG2D+ Th1 Cells in Patients with Metastatic Melanoma Treated with Sorafenib: Role of IL-15Rα and NKG2D Triggering

Author: Laurence Zitvogel, Caroline Robert, Alexander Eggermont, Danila Valmori, Maha Ayyoub, Christine Mateus, Camillo Porta, Philippe Dessen, Philippe Vielh, Anne Aupérin, Meriem Messaoudene, Anne Caignard, Caroline Flament, Sophie Caillat-Zucman, Yannick Jacques, Erwan Mortier, Kariman Chaba, Nicolas Jacquelot, Sylvie Rusakiewicz, Vichnou Poirier-Colame, Nathalie Chaput, and Ana I. Romero
Abstract: PDF file - 84K, The combination therapy induced a profound lymphopenia.
Published: 2023
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4. Supplementary Figure 4 from Regulation of CD4+NKG2D+ Th1 Cells in Patients with Metastatic Melanoma Treated with Sorafenib: Role of IL-15Rα and NKG2D Triggering

Author: Laurence Zitvogel, Caroline Robert, Alexander Eggermont, Danila Valmori, Maha Ayyoub, Christine Mateus, Camillo Porta, Philippe Dessen, Philippe Vielh, Anne Aupérin, Meriem Messaoudene, Anne Caignard, Caroline Flament, Sophie Caillat-Zucman, Yannick Jacques, Erwan Mortier, Kariman Chaba, Nicolas Jacquelot, Sylvie Rusakiewicz, Vichnou Poirier-Colame, Nathalie Chaput, and Ana I. Romero
Abstract: PDF file - 38K, Synergistic effects of TCR or IL-15 stimulation with NKG2D engagement for Th1 polarization in CD4+NKG2D+T cells.
Published: 2023
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5. Supplementary Figure 6 from Regulation of CD4+NKG2D+ Th1 Cells in Patients with Metastatic Melanoma Treated with Sorafenib: Role of IL-15Rα and NKG2D Triggering

Author: Laurence Zitvogel, Caroline Robert, Alexander Eggermont, Danila Valmori, Maha Ayyoub, Christine Mateus, Camillo Porta, Philippe Dessen, Philippe Vielh, Anne Aupérin, Meriem Messaoudene, Anne Caignard, Caroline Flament, Sophie Caillat-Zucman, Yannick Jacques, Erwan Mortier, Kariman Chaba, Nicolas Jacquelot, Sylvie Rusakiewicz, Vichnou Poirier-Colame, Nathalie Chaput, and Ana I. Romero
Abstract: PDF file - 94K, 2D Clustering of LogRatios (D21/D0) of gene expression post- (D21) and pre-therapy (D0) with sorafenib/temozolomide.
Published: 2023
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6. Supplementary Figure 5 from Regulation of CD4+NKG2D+ Th1 Cells in Patients with Metastatic Melanoma Treated with Sorafenib: Role of IL-15Rα and NKG2D Triggering

Author: Laurence Zitvogel, Caroline Robert, Alexander Eggermont, Danila Valmori, Maha Ayyoub, Christine Mateus, Camillo Porta, Philippe Dessen, Philippe Vielh, Anne Aupérin, Meriem Messaoudene, Anne Caignard, Caroline Flament, Sophie Caillat-Zucman, Yannick Jacques, Erwan Mortier, Kariman Chaba, Nicolas Jacquelot, Sylvie Rusakiewicz, Vichnou Poirier-Colame, Nathalie Chaput, and Ana I. Romero
Abstract: PDF file - 1795K, T-cell infiltration and MICA/B expression in metastatic melanoma.
Published: 2023
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7. Supplementary Materials and Methods and Figures 1-3 from Potent Immunomodulatory Effects of the Trifunctional Antibody Catumaxomab

Author: Laurence Zitvogel, Nathalie Chaput, Dominique Elias, Alexander Eggermont, Julien Pesquet, Isabelle Martins, Oliver Kepp, Vichnou Poirier-Colame, Sylvie Rusakiewicz, Caroline Flament, and Diane Goéré
Abstract: PDF - 115K, upplemental Figure 1. Activation of CD4+ T cells by CatmAb in mixed lymphocyte tumor cocultures. Supplemental Figure 2. Activation of CD8+ T cells by CatmAb in mixed lymphocyte tumor cocultures. Supplemental Figure 3. Activation of NK cells by CatmAb in mixed lymphocyte tumor cocultures.
Published: 2023
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8. Supplementary Tables 1 - 3, Figures 1 - 2 from Immune Infiltrates Are Prognostic Factors in Localized Gastrointestinal Stromal Tumors

Author: Laurence Zitvogel, Jean-Yves Blay, Axel Le Cesne, Nathalie Chaput, Guido Kroemer, Jean-Michel Coindre, Jean-François Emile, Paule Opolon, Philippe Terrier, Frédéric Commo, Sylvie Bonvalot, Alexander Eggermont, Dirk Jäger, Niels Halama, Caroline Flament, Kariman Chaba, Vichnou Poirier-Colame, Anne Caignard, Isabelle Cremer, Patrice Dubreuil, Valérie Le Brun-Ly, Loic Chaigneau, Nicolas Isambert, Federico Garrido, Angel Concha, Nadège Vimond, Rosa Mendez, Clara Locher, Mélanie Desbois, Matthieu Sarabi, Michaela Semeraro, and Sylvie Rusakiewicz
Abstract: PDF file - 197K, Supplemental Table 1. Characteristics of GIST patients for the immunohistochemistry study. Supplemental Table 2. Characteristics of GIST and STS patients studied in flow cytometry. Supplemental Table 3: Antibodies for flow cytometry and IHC. Supplemental Figure 1. Correlation between T and NK cell infiltrates and the 3-digit Miettinen score. Supplemental Figure 2. GIST TIls are mainly composed of CD4+ T cells.
Published: 2023
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9. Data from Regulation of CD4+NKG2D+ Th1 Cells in Patients with Metastatic Melanoma Treated with Sorafenib: Role of IL-15Rα and NKG2D Triggering

Author: Laurence Zitvogel, Caroline Robert, Alexander Eggermont, Danila Valmori, Maha Ayyoub, Christine Mateus, Camillo Porta, Philippe Dessen, Philippe Vielh, Anne Aupérin, Meriem Messaoudene, Anne Caignard, Caroline Flament, Sophie Caillat-Zucman, Yannick Jacques, Erwan Mortier, Kariman Chaba, Nicolas Jacquelot, Sylvie Rusakiewicz, Vichnou Poirier-Colame, Nathalie Chaput, and Ana I. Romero
Abstract: Beyond cancer-cell intrinsic factors, the immune status of the host has a prognostic impact on patients with cancer and influences the effects of conventional chemotherapies. Metastatic melanoma is intrinsically immunogenic, thereby facilitating the search for immune biomarkers of clinical responses to cytotoxic agents. Here, we show that a multi-tyrosine kinase inhibitor, sorafenib, upregulates interleukin (IL)-15Rα in vitro and in vivo in patients with melanoma, and in conjunction with natural killer (NK) group 2D (NKG2D) ligands, contributes to the Th1 polarization and accumulation of peripheral CD4+NKG2D+ T cells. Hence, the increase of blood CD4+NKG2D+ T cells after two cycles of sorafenib (combined with temozolomide) was associated with prolonged survival in a prospective phase I/II trial enrolling 63 patients with metastatic melanoma who did not receive vemurafenib nor immune checkpoint–blocking antibodies. In contrast, in metastatic melanoma patients treated with classical treatment modalities, this CD4+NKG2D+ subset failed to correlate with prognosis. These findings indicate that sorafenib may be used as an “adjuvant” molecule capable of inducing or restoring IL-15Rα/IL-15 in tumors expressing MHC class I–related chain A/B (MICA/B) and on circulating monocytes of responding patients, hereby contributing to the bioactivity of NKG2D+ Th1 cells. Cancer Res; 74(1); 68–80. ©2013 AACR.
Published: 2023
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10. Supplementary Figure 1 from Regulation of CD4+NKG2D+ Th1 Cells in Patients with Metastatic Melanoma Treated with Sorafenib: Role of IL-15Rα and NKG2D Triggering

Author: Laurence Zitvogel, Caroline Robert, Alexander Eggermont, Danila Valmori, Maha Ayyoub, Christine Mateus, Camillo Porta, Philippe Dessen, Philippe Vielh, Anne Aupérin, Meriem Messaoudene, Anne Caignard, Caroline Flament, Sophie Caillat-Zucman, Yannick Jacques, Erwan Mortier, Kariman Chaba, Nicolas Jacquelot, Sylvie Rusakiewicz, Vichnou Poirier-Colame, Nathalie Chaput, and Ana I. Romero
Abstract: PDF file - 25K, Schedule of the sorafenib and temozolomide combination regimen.
Published: 2023
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11. Supplementary Figure Legend from Regulation of CD4+NKG2D+ Th1 Cells in Patients with Metastatic Melanoma Treated with Sorafenib: Role of IL-15Rα and NKG2D Triggering

Author: Laurence Zitvogel, Caroline Robert, Alexander Eggermont, Danila Valmori, Maha Ayyoub, Christine Mateus, Camillo Porta, Philippe Dessen, Philippe Vielh, Anne Aupérin, Meriem Messaoudene, Anne Caignard, Caroline Flament, Sophie Caillat-Zucman, Yannick Jacques, Erwan Mortier, Kariman Chaba, Nicolas Jacquelot, Sylvie Rusakiewicz, Vichnou Poirier-Colame, Nathalie Chaput, and Ana I. Romero
Abstract: PDF file - 119K
Published: 2023
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12. T-cell bispecific antibodies in node-positive breast cancer: novel therapeutic avenue for MHC class I loss variants

Author: Mélodie Bonvalet, Anne Caignard, Yu Fu, Thanos P. Mourikis, François Ghiringhelli, Cecile Vicier, Judith Michels, Suzette Delaloge, Fanny Jaulin, Vichnou Poirier-Colame, Guido Kroemer, Bertrand Routy, Semih Dogan, Stephen John Sammut, Sylvie Rusakiewicz, Caroline Flament, Fabrice Andre, M. Lacroix-Trikki, Laurence Zitvogel, Alexander M.M. Eggermont, Meriem Messaoudene, Wei Cope, Aurélien Marabelle, Carlos Caldas, Nicolas Jacquelot, S. Cotteret, Monica Arnedos, Nicholas McGranahan, Aurélie Fluckiger, and Maria Paula Roberti
Subjects: 0301 basic medicine, Receptor, ErbB-2, T cell, Breast Neoplasms, Human leukocyte antigen, Major histocompatibility complex, 03 medical and health sciences, 0302 clinical medicine, Carcinoembryonic antigen, Immune system, Lymphocytes, Tumor-Infiltrating, MHC class I, Antibodies, Bispecific, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, Medicine, Humans, Neoplasm Invasiveness, Prospective Studies, biology, business.industry, Histocompatibility Antigens Class I, Genetic Variation, Hematology, Prognosis, Chemotherapy regimen, Neoadjuvant Therapy, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Lymphatic Metastasis, biology.protein, Cancer research, Female, Lymph Nodes, Antibody, business, Follow-Up Studies
Abstract: Background Tumor-infiltrating lymphocytes (TILs) represent a prognostic factor for survival in primary breast cancer (BC). Nonetheless, neoepitope load and TILs cytolytic activity are modest in BC, compromising the efficacy of immune-activating antibodies, which do not yet compete against immunogenic chemotherapy. Patients and methods We analyzed by functional flow cytometry the immune dynamics of primary and metastatic axillary nodes [metastatic lymph nodes (mLN)] in early BC (EBC) after exposure to T-cell bispecific antibodies (TCB) bridging CD3e and human epidermal growth factor receptor 2 (HER2) or Carcinoembryonic Antigen-Related Cell Adhesion Molecule 5 (CEACAM5), before and after chemotherapy. Human leukocyte antigen (HLA) class I loss was assessed by whole exome sequencing and immunohistochemistry. One hundred primary BC, 64 surrounding ‘healthy tissue’ and 24 mLN-related parameters were analyzed. Results HLA loss of heterozygosity was observed in EBC, at a clonal and subclonal level and was associated with regulatory T cells and T-cell immunoglobulin and mucin-domain-3 expression restraining the immuno-stimulatory effects of neoadjuvant chemotherapy. TCB bridging CD3e and HER2 or CEACAM5 could bypass major histocompatibility complex (MHC) class I loss, partially rescuing T-cell functions in mLN. Conclusion TCB should be developed in BC to circumvent low MHC/peptide complexes.
Published: 2019

13. Upregulation of intratumoral HLA class I and peritumoral Mx1 in ulcerated melanomas

Author: Laurence Zitvogel, D. Verver, Vichnou Poirier-Colame, Caroline Robert, Khadija Cherif-Rebai, Gorana Tomasic, Alexander M.M. Eggermont, Stefan Suciu, Dirk J. Grünhagen, Cornelis Verhoef, and Surgery
Subjects: 0301 basic medicine, immune-editing, lcsh:Immunologic diseases. Allergy, medicine.medical_treatment, Immunology, Human leukocyte antigen, lcsh:RC254-282, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, Interferon, melanoma, Immunology and Allergy, Medicine, Original Research, business.industry, Melanoma, interferon, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Immune checkpoint, Blockade, ulceration, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, immunohistochemistry, Cancer research, Immunohistochemistry, business, lcsh:RC581-607, Adjuvant, medicine.drug
Abstract: Before the era of immune checkpoint blockade, a meta-analysis encompassing fifteen trials reported that adjuvant IFN-α significantly reduces the risk of relapse and improves survival of ulcerated melanoma (UM) with no benefit for higher doses compared to lower doses. IFNa2b affects many cell intrinsic features of tumor cells and modulates the host innate and cognate immune responses. To better understand the biological traits associated with ulceration that could explain the efficacy of prophylactic type 1 IFN, we performed immunohistochemical analysis of various molecules (major histocompatibility complex class I and class II, MX Dynamin Like GTPase 1 (MX1), inducible Nitric-Oxide Synthase (iNOS) or CD47) in two retrospective cohorts of melanoma patients, one diagnosed with a primary cutaneous melanoma (1995-2013, N = 172, among whom 49% were ulcerated melanoma (UM)) and a second one diagnosed with metastatic melanoma amenable to lymph node resection (EORTC 18952 and 18991 trials, N = 98, among whom 44% were UM). We found that primary and metastatic UM exhibit higher basal expression of MHC class I molecules, independently of Breslow thickness, histology and lymphocytic infiltration compared with NUM and that primary UM harbored higher constitutive levels of the antiviral protein Mx1 at the border of tumor beds than NUM. These findings suggest that UM expand in a tumor microenvironment where chronic exposure to type 1 IFN could favor a response to exogenous IFNs.
Published: 2019

14. Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors

Author: Caroline Flament, Christophe Klein, Gladys Ferrere, Laura Mondragón, Coureche Kaderbhai, Meriem Messaoudene, Bertrand Routy, B. Escudier, Hira Rizvi, Jordi Remon Masip, Lisa Derosa, Gérard Zalcman, Nicolas Jacquelot, Conrad Rauber, Kristina Iribarren, François Ghiringhelli, Nathalie Galleron, Nicolas Pons, Romain Daillère, Jean-Charles Soria, Matthew D. Hellmann, Marine Fidelle, Eric Deutsch, Vichnou Poirier-Colame, Laura Mezquita, Benoit Quinquis, Corentin Richard, Bo Qu, Aurélie Fluckiger, Patrick Gonin, Céline Clémenson, Yohann Loriot, Paule Opolon, Connie P.M. Duong, Laurence Zitvogel, Maria Paula Roberti, C. Naltet, Bernhard Ryffel, Guido Kroemer, Laurence Albiges, Veronique Minard-Colin, Alexander M.M. Eggermont, Maryam Tidjani Alou, Florence Levenez, Didier Raoult, François Goldwasser, Solenn Brosseau, 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), MetaGenoPolis, Institut National de la Recherche Agronomique (INRA), Institut Gustave Roussy (IGR), Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes (URMITE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR48, INSB-INSB-Centre National de la Recherche Scientifique (CNRS), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Role des Cellules Dendritiques Dans la Regulation des Effecteurs de l'Immunite Antitumorale, Université Paris-Sud - Paris 11 (UP11)-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 de Paris (UP), Université de Paris - UFR Médecine Paris Centre [Santé] (UP Médecine Paris Centre), Université de Paris (UP), Université Sorbonne Paris Cité (USPC), Sorbonne Université (SU), Laboratoire de Mecanique des Fluides et d'Acoustique (LMFA), École Centrale de Lyon (ECL), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), UMR 996 - DHU Hépatinov, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biologie et de Technologies de Saclay (IBITECS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Oncologie thoracique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Service d'Oncologie Thoracique [ Bichat], Hôpital Bichat - Claude Bernard-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Département d'oncologie médicale [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Plateforme de transfert en biologie cancérologique [Dijon], Centre d'épidémiologie des populations (CEP), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), Université Paris-Saclay, Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO), Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Migrations internationales, espaces et sociétés (MIGRINTER UMR 7301), Centre National de la Recherche Scientifique (CNRS)-Université de Poitiers, Radiothérapie moléculaire (UMR 1030), Département de radiothérapie [Gustave Roussy], 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), Oncologie génito-urinaire, Service de pneumologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], 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), Dpt of Women's and Children's Health [Stockholm], Karolinska University Hospital [Stockholm], Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11), Gustave Roussy Course of Excellence in Oncology-Fondation Philanthropia, McGill University Townsend hematology research fellowship award, Ligue contre le Cancer (equipe labelisee), Agence Nationale de la Recherche (ANR)-Projets blancs, ANR under the frame of E-Rare-2 (ERA-Net for Research on Rare Diseases), Association pour la recherche sur le cancer (ARC), Canceropole Ile-de-France, Institut National du Cancer (INCa), Institut Universitaire de France, Fondation pour la Recherche Medicale (FRM), European Research Council (ERC), LeDucq Foundation, LabEx Immuno-Oncology, SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE), SIRIC Cancer Research and Personalized Medicine (CARPEM), Paris Alliance of Cancer Research Institutes (PACRI), philanthropia, European Project: 257144,EC:FP7:HEALTH,FP7-HEALTH-2010-two-stage,ARTFORCE(2011), Institut des sciences biologiques (INSB-CNRS)-Institut des sciences biologiques (INSB-CNRS)-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), UFR Médecine [Santé] - Université Paris Cité (UFR Médecine UPCité), Université Paris Cité (UPCité), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Université de Lorraine (UL), Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Hôpital Bichat - Claude Bernard-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL)-Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), Université de Poitiers-Centre National de la Recherche Scientifique (CNRS), CHU Cochin [AP-HP], Université Paris-Sud 11 - Faculté de médecine (UP11 UFR Médecine), Plateforme histo-cyto-pathologies (PHCP), 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), INRA US1367 MetaGenoPolis, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Immunologie et embryologie moléculaires (IEM), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Université Paris Descartes - Paris 5 (UPD5), Apoptose, cancer et immunité (Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138), Institut Gustave Roussy (IGR)-Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 ), MetaGénoPolis, Institut National de Recherche Agronomique, Centre d'Investigation Clinique en Biotherapie des cancers ( CIC 1428 , CBT 507 ), Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Plateforme histo-cyto-pathologies ( PHCP ), 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 ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Unité de radiothérapie moléculaire ( UMR 1030 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Gustave Roussy ( IGR ) -Université Paris-Sud - Paris 11 ( UP11 ), Centre de Recherche des Cordeliers ( CRC ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ), Karolinska University Hospital Solna, Department of Women’s and Children’s Health, Childhood Cancer Research Unit, Karolinska Institute, Centre de Recherche des Cordeliers (CRC), and Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Receptors, CXCR3, medicine.drug_class, T-Lymphocytes, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Programmed Cell Death 1 Receptor, Antibiotics, CCR9, [SDV.CAN]Life Sciences [q-bio]/Cancer, CXCR3, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Feces, Mice, Receptors, CCR, 03 medical and health sciences, 0302 clinical medicine, Verrucomicrobia, Neoplasms, medicine, Animals, Humans, ComputingMilieux_MISCELLANEOUS, Multidisciplinary, biology, Antibodies, Monoclonal, Cancer, Immunotherapy, Fecal Microbiota Transplantation, medicine.disease, biology.organism_classification, Interleukin-12, Anti-Bacterial Agents, Gastrointestinal Microbiome, 3. Good health, Blockade, 030104 developmental biology, 030220 oncology & carcinogenesis, CD4 Antigens, Immunology, biology.protein, Metagenome, [SDV.IMM]Life Sciences [q-bio]/Immunology, Antibody, Akkermansia muciniphila
Abstract: Good bacteria help fight cancer Resident gut bacteria can affect patient responses to cancer immunotherapy (see the Perspective by Jobin). Routy et al. show that antibiotic consumption is associated with poor response to immunotherapeutic PD-1 blockade. They profiled samples from patients with lung and kidney cancers and found that nonresponding patients had low levels of the bacterium Akkermansia muciniphila . Oral supplementation of the bacteria to antibiotic-treated mice restored the response to immunotherapy. Matson et al. and Gopalakrishnan et al. studied melanoma patients receiving PD-1 blockade and found a greater abundance of “good” bacteria in the guts of responding patients. Nonresponders had an imbalance in gut flora composition, which correlated with impaired immune cell activity. Thus, maintaining healthy gut flora could help patients combat cancer. Science , this issue p. 91 , p. 104 , p. 97 ; see also p. 32
Published: 2018
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15. Combined evaluation of LC3B puncta and HMGB1 expression predicts residual risk of relapse after adjuvant chemotherapy in breast cancer

Author: Laurent Arnould, Sylvain Ladoire, David Enot, Laura Senovilla, Marie Laure Poillot, Aicha Goubar, Patrick Arveux, Laurence Zitvogel, Suzette Delaloge, C. Dalban, François Ghiringhelli, Frédérique Penault-Llorca, Nicole Prada, Fabrice Andre, Guido Kroemer, Vichnou Poirier-Colame, Clara Locher, Pierre Fumoleau, Marc Spielmann, and Kariman Chaba
Subjects: Oncology, medicine.medical_specialty, Anthracycline, medicine.medical_treatment, Breast Neoplasms, Biology, Breast cancer, Recurrence, Risk Factors, Internal medicine, Autophagy, Biomarkers, Tumor, medicine, Humans, HMGB1 Protein, Molecular Biology, Chemotherapy, Hazard ratio, Cell Biology, medicine.disease, Confidence interval, Gene Expression Regulation, Neoplastic, Chemotherapy, Adjuvant, Immunology, Cohort, Cancer cell, Immunohistochemistry, Female, Clinical Research Paper, Microtubule-Associated Proteins
Abstract: In spite of adjuvant chemotherapy, a significant fraction of patients with localized breast cancer (BC) relapse after optimal treatment. We determined the occurrence of cytoplasmic MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3B)-positive puncta, as well as the presence of nuclear HMGB1 (high mobility group box 1) in cancer cells within surgical BC specimens by immunohistochemistry, first in a test cohort (152 patients) and then in a validation cohort of localized BC patients who all received adjuvant anthracycline-based chemotherapy (1646 patients). Cytoplasmic LC3B(+) puncta inversely correlated with the intensity of SQSTM1 staining, suggesting that a high percentage cells of LC3B(+) puncta reflects increased autophagic flux. After setting optimal thresholds in the test cohort, cytoplasmic LC3B(+) puncta and nuclear HMGB1 were scored as positive in 27.2% and 28.6% of the tumors, respectively, in the validation cohort, while 8.7% were considered as double positive. LC3B(+) puncta or HMGB1 expression alone did not constitute independent prognostic factors for metastasis-free survival (MFS) in multivariate analyses. However, the combined positivity for LC3B(+) puncta and nuclear HMGB1 constituted an independent prognostic factor significantly associated with prolonged MFS (hazard ratio: 0.49 95% confidence interval [0.26-0.89]; P = 0.02), and improved breast cancer specific survival (hazard ratio: 0.21 95% confidence interval [0.05-0.85]; P = 0.029). Subgroup analyses revealed that within patients with poor-prognosis BC, HMGB1(+) LC3B(+) double-positive tumors had a better prognosis than BC that lacked one or both of these markers. Altogether, these results suggest that the combined positivity for LC3B(+) puncta and nuclear HMGB1 is a positive predictor for longer BC survival.
Published: 2015
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16. Negative prognostic impact of regulatory T cell infiltration in surgically resected esophageal cancer post-radiochemotherapy

Author: Aurélie Perier, Michaela Semeraro, C. Gronnier, Peggy Dartigues, David Enot, Kariman Chaba, Irène Villa, Laurence Zitvogel, Vichnou Poirier Colame, Sylvie Rusakiewicz, Erika Vacchelli, Christophe Mariette, Guido Kroemer, and Diane Goéré
Subjects: Male, Pathology, medicine.medical_specialty, autophagy, Esophageal Neoplasms, Genotype, Colorectal cancer, Regulatory T cell, pattern recognition receptor, ATG16L1, Biology, CD8-Positive T-Lymphocytes, T-Lymphocytes, Regulatory, Cohort Studies, Lymphocytes, Tumor-Infiltrating, immunogenic cell death, medicine, Cytotoxic T cell, Humans, Alleles, apoptosis, FOXP3, Forkhead Transcription Factors, Chemoradiotherapy, Esophageal cancer, medicine.disease, Prognosis, Immunohistochemistry, Immunosurveillance, Gene Expression Regulation, Neoplastic, Toll-Like Receptor 4, medicine.anatomical_structure, Treatment Outcome, Oncology, Cancer research, Female, Receptors, Purinergic P2X7, CD8, Priority Research Paper
Abstract: Ever accumulating evidence indicates that the long-term effects of radiotherapy and chemotherapy largely depend on the induction (or restoration) of an anticancer immune response. Here, we investigated this paradigm in the context of esophageal carcinomas treated by neo-adjuvant radiochemotherapy, in a cohort encompassing 196 patients. We found that the density of the FOXP3+ regulatory T cell (Treg) infiltrate present in the residual tumor (or its scar) correlated with the pathological response (the less Tregs the more pronounced was the histological response) and predicted cancer-specific survival. In contrast, there was no significant clinical impact of the frequency of CD8+ cytotoxic T cells. At difference with breast or colorectal cancer, a loss-of-function allele of toll like receptor 4 (TLR4) improved cancer-specific survival of patients with esophageal cancer. While a loss-of-function allele of purinergic receptor P2X, ligand-gated ion channel, 7 (P2RX7) failed to affect cancer-specific survival, its presence did correlate with an increase in Treg infiltration. Altogether, these results corroborate the notion that the immunosurveillance seals the fate of patients with esophageal carcinomas treated with conventional radiochemotherapy.
Published: 2015

17. NKp30 isoforms and NKp30 ligands are predictive biomarkers of response to imatinib mesylate in metastatic GIST patients

Author: Serge Leyvraz, Katrin S. Reiners, Christos Christidis, Jean-Yves Blay, Jonathan M. Pitt, Marion Lambert, Aurélien Marabelle, Frédéric Vély, Alexandre Ivagnes, Jean-François Emile, Christian Auclair, Benedita Rocha, Axel Le Cesne, Loic Chaigneau, Christelle Piperoglou, Kariman Chaba, Philippe Terrier, Eric Vivier, Nicolas Isambert, Julien Adam, Sylvie Rusakiewicz, Pierre Validire, Bruno Landi, Thierry Perniceni, Laurence Zitvogel, Sarah Jegou, Sylvie Bonvalot, Michaela Semeraro, Sophie Caillat-Zucman, David Enot, Sandrine Aspeslagh, Aurélie Perier, Christophe Borg, Vichnou Poirier-Colame, Anne Berger, Alexander M.M. Eggermont, Antoine Toubert, Niels Halama, Joachim Koch, Elke Pogge von Strandmann, Olivier Mir, Julien Domont, Anne Caignard, Jean-Michel Coindre, 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), CHU Necker - Enfants Malades [AP-HP], Institut Gustave Roussy (IGR), Université Paris-Sud 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Saclay, Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP), Laboratoire d'Immunologie [Hôpital de la Conception - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION )-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Service d'Immunologie [AP-HM], Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ), Microorganismes, Molécules Bioactives et Physiopathologie Intestinale (LBM-E4), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de rhumatologie, inflammation-immunopathologie- biothérapie [CHU Saint-Antoine] (DHU i2B ), CHU Saint-Antoine [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service d'oncologie Médicale, Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, Departement d'Anatomopathologie, Institut Mutualiste de Montsouris (IMM), Hellenic Open University [Patras], Département de chirurgie digestive, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer (LabEx LipSTIC), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC)-Université de Montpellier (UM), Département d'oncologie médicale [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), Centre Jean-bernard, Département de biologie et pathologie médicales [Gustave Roussy], Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Service de Pathologie, Institut Bergonié, Service de pathologie [CHU Ambroise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Ambroise Paré, Immunologie et Cancérologie Intégratives (CRC - Inserm U1138), Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Différenciation et physiologie des lymphocytes T (U1020), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Alloimmunité-Autoimmunité-Transplantation (A2T), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Virologie et Immunologie Moléculaires, Université Francois Rabelais [Tours], Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'immunologie, AP-HP Hôpital universitaire Robert-Debré [Paris], Laboratoire de Biologie et de Pharmacologie Appliquée (LBPA), École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS), Service d'Oncologie Médicale [CHRU Besançon], Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC), Equipe 11, Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de médecine oncologique [Gustave Roussy], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 ), Institut Gustave Roussy ( IGR ), Université Paris-Sud 11 - Faculté de médecine ( UP11 UFR Médecine ), Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] ( DITEP ), Assistance Publique - Hôpitaux de Marseille ( APHM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital de la Conception [CHU - APHM] ( LA CONCEPTION ) -Centre National de la Recherche Scientifique ( CNRS ), 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 ), Hôpital de la Conception [CHU - APHM] ( LA CONCEPTION ), Microorganismes, Molécules Bioactives et Physiopathologie Intestinale ( LBM-E4 ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de rhumatologie, inflammation-immunopathologie- biothérapie [CHU Saint-Antoine] ( DHU i2B ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz, Institut Mutualiste de Montsouris ( IMM ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer ( LabEx LipSTIC ), Institut National de la Recherche Agronomique ( INRA ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Université Paris-Sud - Paris 11 ( UP11 ) -École pratique des hautes études ( EPHE ) -Institut Gustave Roussy ( IGR ) -Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ) -Université de Bourgogne ( UB ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université de Franche-Comté ( UFC ), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse ( U981 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, Immunologie et Cancérologie Intégratives ( CRC - Inserm U1138 ), Centre de Recherche des Cordeliers ( CRC ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ), Différenciation et physiologie des lymphocytes T ( U1020 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Necker Enfants-Malades ( INEM - UM 111 (UMR 8253 / U1151) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Alloimmunité-Autoimmunité-Transplantation ( A2T ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Universitaire d'Hématologie ( IUH ), Université Paris Diderot - Paris 7 ( UPD7 ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Centre de recherche sur l'Inflammation ( CRI ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Biologie et de Pharmacologie Appliquée ( LBPA ), École normale supérieure - Cachan ( ENS Cachan ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université de Franche-Comté ( UFC ), Centre de Recherche en Cancérologie de Lyon ( 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 ) -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 ), Centre d'Investigation Clinique en Biotherapie des cancers ( CIC 1428 , CBT 507 ), Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11), Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Service de rhumatologie [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Bourgogne (UB)-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-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Institut Bergonié [Bordeaux], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), University Medical Centre of the Johannes Gutenberg University Mainz, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-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-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Montpellier (UM), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Cachan (ENS Cachan), Medical Oncology, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École Pratique des Hautes Études (EPHE), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), and Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU)
Subjects: 0301 basic medicine, medicine.medical_treatment, Immunology, PDGFRA, Targeted therapy, 03 medical and health sciences, 0302 clinical medicine, medicine, Immunology and Allergy, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, neoplasms, Original Research, Tumor microenvironment, GiST, business.industry, Cancer, medicine.disease, digestive system diseases, 3. Good health, Immunosurveillance, 030104 developmental biology, Imatinib mesylate, Oncology, 030220 oncology & carcinogenesis, Cancer research, [SDV.IMM]Life Sciences [q-bio]/Immunology, business, Tyrosine kinase
Abstract: International audience; Despite effective targeted therapy acting on KIT and PDGFRA tyrosine kinases, gastrointestinal stromal tumors (GIST) escape treatment by acquiring mutations conveying resistance to imatinib mesylate (IM). Following the identification of NKp30-based immunosurveillance of GIST and the off-target effects of IM on NK cell functions, we investigated the predictive value of NKp30 isoforms and NKp30 soluble ligands in blood for the clinical response to IM. The relative expression and the proportions of NKp30 isoforms markedly impacted both event-free and overall survival, in two independent cohorts of metastatic GIST. Phenotypes based on disbalanced NKp30B/NKp30C ratio (Delta BClow) and low expression levels of NKp30A were identified in one third of patients with dismal prognosis across molecular subtypes. This Delta BClow blood phenotype was associated with a pro-inflammatory and immunosuppressive tumor microenvironment. In addition, detectable levels of the NKp30 ligand sB7-H6 predicted a worse prognosis in metastatic GIST. Soluble BAG6, an alternate ligand for NKp30 was associated with low NKp30 transcription and had additional predictive value in GIST patients with high NKp30 expression. Such GIST microenvironments could be rescued by therapy based on rIFN-alpha and anti-TRAIL mAb which reinstated innate immunity.
Published: 2017
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18. Potent Immunomodulatory Effects of the Trifunctional Antibody Catumaxomab

Author: Caroline Flament, Dominique Elias, Laurence Zitvogel, Isabelle Martins, Sylvie Rusakiewicz, Diane Goéré, Oliver Kepp, Nathalie Chaput, Julien Pesquet, Vichnou Poirier-Colame, and Alexander M.M. Eggermont
Subjects: Adult, Cancer Research, T-Lymphocytes, Catumaxomab, Lymphocyte Activation, chemistry.chemical_compound, Antigen, Antibodies, Bispecific, medicine, Humans, Aged, Ovarian Neoplasms, CD40, biology, Ascites, Epithelial cell adhesion molecule, Middle Aged, Flow Cytometry, Trifunctional antibody, Coculture Techniques, Oncology, chemistry, Cancer research, biology.protein, Cytokines, Immunogenic cell death, Female, CD8, CD80, Signal Transduction, medicine.drug
Abstract: Catumaxomab (CatmAb), a trifunctional bispecific antibody directed against the epithelial cell adhesion molecule (EpCAM) and the T-cell antigen CD3, is approved as intraperitoneal therapy for the treatment of malignant ascites in patients with EpCAM-positive carcinomas. The immunomonitoring results of a phase II/III study using CatmAb revealed a tumoricidal effect associated with reduced VEGF levels, CD69-expressing T cells, and the release of T-helper cell (TH)-1 cytokines. We comprehensively dissected the immunomodulatory effects of the CatmAb on the major subsets of malignant ascites-infiltrating leukocytes and the molecular fingerprint of tumor cell death. Herein we show that in the presence of EpCAM-positive tumor targets, CatmAb markedly enhanced T-cell activation [CD69, CD107A (LAMP1), HLA-DR and PD-1(PDCD1) expression] and stimulated inflammatory CD4+ TH1 and CD8+ TH1 to release IFN-γ but failed to trigger TH17 cells. Engagement of CD16-expressing cells caused upregulation of TRAIL (TNFSF10) and costimulatory CD40 and CD80 molecules. CatmAb promoted tumor cell death associated with ATP release and strongly synergized with oxaliplatin for the exposure of the three hallmarks of immunogenic cell death (calreticulin, HMGB1, and ATP). These findings warrant validation as potential biomarkers of efficacy of CatmAb. Cancer Res; 73(15); 4663–73. ©2013 AACR.
Published: 2013
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19. Immune Infiltrates Are Prognostic Factors in Localized Gastrointestinal Stromal Tumors

Author: Jean-François Emile, Frédéric Commo, Nadege Vimond, Guido Kroemer, Axel Le Cesne, Dirk Jäger, Sylvie Rusakiewicz, Philippe Terrier, Federico Garrido, Laurence Zitvogel, Alexander M.M. Eggermont, Jean-Yves Blay, Paule Opolon, Nicolas Isambert, Valérie Le Brun-Ly, Mélanie Desbois, Patrice Dubreuil, Vichnou Poirier-Colame, Isabelle Cremer, Nathalie Chaput, Michaela Semeraro, Niels Halama, Rosa Mendez, Loic Chaigneau, Kariman Chaba, Caroline Flament, Clara Locher, Ángel Concha, Sylvie Bonvalot, Jean-Michel Coindre, Matthieu Sarabi, and Anne Caignard
Subjects: Adult, Male, Cancer Research, Stromal cell, CD3 Complex, Gastrointestinal Stromal Tumors, T-Lymphocytes, Kaplan-Meier Estimate, Biology, Piperazines, Cohort Studies, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, 0302 clinical medicine, Immune system, medicine, Humans, Protein Kinase Inhibitors, neoplasms, Aged, 030304 developmental biology, Aged, 80 and over, 0303 health sciences, GiST, Natural Cytotoxicity Triggering Receptor 1, FOXP3, Cancer, Forkhead Transcription Factors, Middle Aged, Flow Cytometry, Prognosis, medicine.disease, Immunohistochemistry, CD56 Antigen, 3. Good health, Killer Cells, Natural, Immunosurveillance, Pyrimidines, Treatment Outcome, Imatinib mesylate, Oncology, 030220 oncology & carcinogenesis, Benzamides, Multivariate Analysis, Immunology, Imatinib Mesylate, Cancer research, Female, CD8
Abstract: Cancer immunosurveillance relies on effector/memory tumor-infiltrating CD8+ T cells with a T-helper cell 1 (TH1) profile. Evidence for a natural killer (NK) cell-based control of human malignancies is still largely missing. The KIT tyrosine kinase inhibitor imatinib mesylate markedly prolongs the survival of patients with gastrointestinal stromal tumors (GIST) by direct effects on tumor cells as well as by indirect immunostimulatory effects on T and NK cells. Here, we investigated the prognostic value of tumor-infiltrating lymphocytes (TIL) expressing CD3, Foxp3, or NKp46 (NCR1) in a cohort of patients with localized GIST. We found that CD3+ TIL were highly activated in GIST and were especially enriched in areas of the tumor that conserve class I MHC expression despite imatinib mesylate treatment. High densities of CD3+ TIL predicted progression-free survival (PFS) in multivariate analyses. Moreover, GIST were infiltrated by a homogeneous subset of cytokine-secreting CD56bright (NCAM1) NK cells that accumulated in tumor foci after imatinib mesylate treatment. The density of the NK infiltrate independently predicted PFS and added prognostic information to the Miettinen score, as well as to the KIT mutational status. NK and T lymphocytes preferentially distributed to distinct areas of tumor sections and probably contributed independently to GIST immunosurveillance. These findings encourage the prospective validation of immune biomarkers for optimal risk stratification of patients with GIST. Cancer Res; 73(12); 3499–510. ©2013 AACR.
Published: 2013
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20. The ratio of CD8

Author: Michaela, Semeraro, Julien, Adam, Gautier, Stoll, Emilie, Louvet, Kariman, Chaba, Vichnou, Poirier-Colame, Allan, Sauvat, Laura, Senovilla, Erika, Vacchelli, Norma, Bloy, Juliette, Humeau, Aitziber, Buque, Oliver, Kepp, Laurence, Zitvogel, Fabrice, André, Marie-Christine, Mathieu, Suzette, Delaloge, and Guido, Kroemer
Subjects: Original Research
Abstract: In a series of 248 tumor samples obtained from image-guided biopsies from patients diagnosed with ductal carcinoma in situ of the breast, we attempted to identify biomarkers that predict microinfiltration at definitive surgery or relapse during follow-up. For this, we used immunohistochemical methods, followed by automated image analyses, to measure the mean diameter of nuclei (which correlates with ploidy), the phosphorylation of eukaryotic initiation factor 2α (eIF2α, which reflects endoplasmic reticulum stress) as well as the density and ratio of CD8+ cytotoxic T lymphocytes and FOXP3+ regulatory T cells. The median nuclear diameter of malignant cells correlated with eIF2α phosphorylation (in cancerous tissue), which in turn correlated with the density of the CD8+ infiltrate and the CD8+/FOXP3 ratio (both in cancerous and the adjacent non-cancerous parenchyma). Neither microinfiltration nor lymph node involvement was associated with the probability of relapse. Both correlated positively with the CD8+/FOXP3 ratio in the malignant area. In contrast, relapse was associated with a paucity of the CD8+ infiltrate as well as an unfavorable CD8+/FOXP3 ratio, both in malignant and non-malignant parenchyma. The combined analysis of the CD8+/FOXP3 ratio in cancerous and non-cancerous tissues revealed a significant impact of their interaction on the probability of relapse, but not on the presence of microinfiltration or lymph node metastasis. Altogether, these results support the idea of an immunosurveillance system that determines the risk of relapse in ductal carcinoma in situ of the breast.
Published: 2016

21. Biomarkers of immunogenic stress in metastases from melanoma patients: Correlations with the immune infiltrate

Author: Jochen T. Schaefer, Kariman Chaba, Sylvain Ladoire, David Enot, Laurence Zitvogel, Gulsun Erdag, Vichnou Poirier-Colame, Donna H. Deacon, François Ghiringhelli, Guido Kroemer, Craig L. Slingluff, Laura Senovilla, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, 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), Immunologie et Cancérologie Intégratives (CRC - Inserm U1138), Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Lipides - Nutrition - Cancer (U866) (LNC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Department of Surgery, Division of Surgical Oncology-University of Virginia School of Medicine, Department of pathology [Virginia], University of Virginia [Charlottesville], Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Karolinska Institutet [Stockholm], 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), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), University of Virginia, Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), 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 ), Immunologie et Cancérologie Intégratives ( CRC - Inserm U1138 ), Centre de Recherche des Cordeliers ( CRC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Centre d'Investigation Clinique en Biotherapie des cancers ( CIC 1428 , CBT 507 ), Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: 0301 basic medicine, Hmgb1 Expression, CD3, Immunology, T-Cells, chemical and pharmacologic phenomena, Immunogenic Cell Death, [SDV.CAN]Life Sciences [q-bio]/Cancer, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Immune system, medicine, Autophagy, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Immunology and Allergy, Cytotoxic T cell, Cell-Death, Breast-Cancer, Melanoma, Lc3b Puncta, Original Research, Hmgb1, biology, Anticancer Chemotherapy, Immune Infiltrates, Immunosurveillance, FOXP3, medicine.disease, 3. Good health, 030104 developmental biology, Oncology, Cancer research, biology.protein, Lc3, Immunogenic cell death, [SDV.IMM]Life Sciences [q-bio]/Immunology, Mechanism, Therapy, Calreticulin, CD8
Abstract: International audience; Melanoma is known to be under latent immunosurveillance. Here, we studied four biomarkers of immunogenic cell stress and death (microtubule-associated proteins 1A/1B light chain 3B (MAP-LC3B, best known as LC3B)-positive puncta in the cytoplasm as a sign of autophagy; presence of nuclear HMGB1; phosphorylation of eIF2 alpha; increase in ploidy) in melanoma cells, in tissue microarrays (TMA) from metastases from 147 melanoma patients. These biomarkers of immunogenicity were correlated with the density of immune cells infiltrating the metastases and expressing CD3, CD4(+), CD8(+), CD20, CD45, CD56, CD138, CD163, DC-LAMP or FOXP3. LC3B puncta positively correlated with the infiltration of metastases by CD163(+) macrophages, while expression of HMGB1 correlated with infiltration by FOXP3(+) regulatory T cells and CD56(+) lymphocytes. eIF2 alpha phosphorylation was associated with an augmentation of nuclear diameters, reflecting an increase in ploidy. Interestingly, therapeutic vaccination led to a reduction of eIF2 alpha phosphorylation suggestive of immunoselection against cells bearing this sign of endoplasmic reticulum (ER) stress. None of the stress/death-related biomarkers had a significant prognostic impact, contrasting with the major prognostic effect of the ratio of cytotoxic T lymphocytes (CTL) over immunosuppressive FOXP3(+) and CD163(+) cells. Altogether, these results support the idea of a mutual dialog between, on one hand, melanoma cells with their cell-intrinsic stress pathways and, on the other hand, immune effectors. Future work is required to understand the detailed mechanisms of this interaction.Keywords
Published: 2016
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22. The presence of LC3B puncta and HMGB1 expression in malignant cells correlate with the immune infiltrate in breast cancer

Author: Laura Senovilla, Marie Laure Poillot, Guido Kroemer, Marie Chaix, Patrick Arveux, Fabrice Andre, Laurent Arnould, Vichnou Poirier-Colame, Laurence Zitvogel, Sylvain Ladoire, David Enot, Suzette Delaloge, François Ghiringhelli, Frédérique Penault-Llorca, Kariman Chaba, Michaela Semeraro, 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 Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Institut Gustave Roussy (IGR), Immunologie et Cancérologie Intégratives (CRC - Inserm U1138), Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Equipe de recherche sur les traitements individualisés des cancers (ERTICa), Université d'Auvergne - Clermont-Ferrand I (UdA), Centre d'épidémiologie des populations (CEP), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Département de médecine oncologique [Gustave Roussy], Karolinska University Hospital [Stockholm], 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Institut Gustave Roussy ( IGR ), Immunologie et Cancérologie Intégratives ( CRC - Inserm U1138 ), Centre de Recherche des Cordeliers ( CRC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre d'Investigation Clinique en Biotherapie des cancers ( CIC 1428 , CBT 507 ), Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Equipe de recherche sur les traitements individualisés des cancers ( ERTICa ), Université d'Auvergne - Clermont-Ferrand I ( UdA ), Centre d'épidémiologie des populations ( CEP ), Université de Bourgogne ( UB ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ) -Assistance publique - Hôpitaux de Paris (AP-HP), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE)
Subjects: 0301 basic medicine, Pathological Complete Response, 0302 clinical medicine, Pathology, Cytotoxic T cell, Lymphocytes, HMGB1 Protein, FOXP3, Forkhead Transcription Factors, Mammary Tumorigenesis, 3. Good health, Immunosurveillance, Death, 030220 oncology & carcinogenesis, Female, Beclin-1, Microtubule-Associated Proteins, Infiltration (medical), Histology, Predictive-Value, Breast Neoplasms, chemical and pharmacologic phenomena, Cd8, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Prognostic, 03 medical and health sciences, Immune system, Breast Cancer, medicine, Autophagy, Humans, Prognostic Value, Treg Cells, Molecular Biology, Hmgb1, Anticancer Chemotherapy, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, Macrophages, Neoadjuvant Chemotherapy, Cell Biology, medicine.disease, 030104 developmental biology, Tumor progression, Cancer cell, Immunology, Cancer research, Lc3, Clinical Research Paper, CD8, T-Lymphocytes, Cytotoxic
Abstract: International audience; Several cell-intrinsic alterations have poor prognostic features in human breast cancer, as exemplified by the absence of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 )-positive puncta in the cytoplasm (which indicates reduced autophagic flux) or the loss of nuclear HMGB1 expression by malignant cells. It is well established that breast cancer is under strong immunosurveillance, as reflected by the fact that scarce infiltration of the malignant lesion by CD8(+) cytotoxic T lymphocytes or comparatively dense infiltration by immunosuppressive cell types (such as FOXP3(+) regulatory T cells or CD68(+) tumor-associated macrophages), resulting in low CD8(+):FOXP3(+) or CD8(+):CD68(+) ratios, has a negative prognostic impact. Here, we reveal the surprising finding that cell-intrinsic features may influence the composition of the immune infiltrate in human breast cancer. Thus, the absence of LC3B puncta is correlated with intratumoral (but not peritumoral) infiltration by fewer CD8(+) cells and more FOXP3(+) or CD68(+) cells, resulting in a major drop in the CD8(+):FOXP3(+) or CD8(+):CD68(+) ratios. Moreover, absence of HMGB1 expression in nuclei correlated with a general drop in all immune effectors, in particular FOXP3(+) and CD68(+) cells, both within the tumor and close to it. Combined analysis of LC3B puncta and HMGB1 expression allowed for improved stratification of patients with respect to the characteristics of their immune infiltrate as well as overall and metastasis-free survival. It can be speculated that blocked autophagy in, or HMGB1 loss from, cancer cells may favor tumor progression due to their negative impact on anticancer immunosurveillance.
Published: 2016
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23. Melanoma and immunotherapy bridge 2015 : Naples, Italy. 1-5 December 2015

Author: Erik Wennerberg, Gabriele Madonna, Gennaro Ciliberto, Michele Minopoli, Caroline Dutriaux, Matthew Wongchenko, Elisabetta Gambale, David F. Stroncek, Céleste Lebbé, Ani S. Balmanoukian, Gianluca Di Monta, Vincenzo Ingangi, Soldano Ferrone, Ivan Marquez-Rodas, Giuseppe Masucci, Janis M. Taube, Simona Mastroeni, Gerardo Bott, Franck Pagès, Jonathan M. Pitt, Judit Olasz, Elisabetta Panza, Paola Michelozzi, Daniil Stoyakovskiy, Stéphane Dalle, Mario Sznol, John M. Kirkwood, Keith T. Flaherty, Maria Capuano, Amalia Azzariti, Edward Cha, Peter Boasberg, Maria Godeny, Angela Gismondi, Ornella Franzese, Giusy Gentilcore, Jean-Jacques Grob, Olivier Michielin, Adina Elena Stanciu, Giuseppe Cirino, Julien Fourcade, Nelofer Syed, Giuseppe Ercolano, Caroline Robert, Ascierto Paolo Antonio, Christine K. Gause, Silviu Voinea, Adeeb Rahman, Anne Caignard, Camila Flores, Cristina Fortes, Yuya Yoshimoto, Angela Sandru, Andras Szollar, Monica Cantile, Frederic Lehmann, Maria Libera Ascierto, Sacha Gnjatic, Marco Tucci, Rosa Russo, Giuseppina Liguori, Valeria De Biasio, David Ross Kaufman, Mary Ruisi, Ewa Kalinka-Warzocha, Phillip Wong, Rosaria Falcon, Vincenzo Faiola, Nicole Richie, Lars Ny, Miri Blank, Paola De Cicco, Anna Passarelli, Jean-François Baurain, Guido Kroemer, Claudio Jommi, Francesca Capone, Maria Teresa Fierro, Tracee L. McMiller, Lev V. Demidov, Alessandro Testori, Omid Hamid, Marone Ugo, Annamaria Anniciello, Andrew J. Park, Fara De Murtas, RuthAnn Gordan, Emil Farkas, David Hogg, Alessandra Di Paolo, Mark Maurer, Yangyang Wang, Mario Mandalà, Rodabe N. Amaria, Massimiliano Di Marzo, Stefania Guida, Luigi Fattore, Veronica Huber, Ludmila Danilova, Luigi Aurisicchio, Gabriella Aquino, Domenico Mallardo, Catriona M. McNeil, Stephanie Anne Kronenberg, Consiglia Carella, Theresa S. Pritchard, Katia Bifulco, Michaela Semeraro, Carlo M. Croce, David P. Enot, Laurence Zitvogel, Marcella Occelli, Benjamin Weide, Magdalena Thurin, Margherita Cerrone, Naiyer A. Rizvi, Blessing Agunwamba, Stella D'Oronzo, Sarah Jegou, Stucci Stefania, Drew M. Pardoll, Vito Michele Garrisi, Haidong Tang, Szabolcs Horvath, Hong Wang, Benjamin Brady, Antonio Doronzo, Claudia Marino, Xian He, Michael A. Davies, Hexiao Wang, Isabelle Rooney, Orsolya Csuka, Maurizio Nudo, Lance Leopold, Jeffrey S. Wasser, Sabino Strippoli, Silvia Ch Formenti, MariaLaura Foddai, Michael A. Postow, Robert H.I. Andtbacka, Paul Lorigan, Tommy Andersson, Naoko Imai, Ari VanderWalde, Mariaelena Capone, Ilsung Chang, Laura Lattanzio, Carmen Loquai, Arantxa Sancho, Christine Horak, Federica Sallusto, Timea Balatoni, Maha Ayyoub, Angela Santoni, Alessio Caggiati, Anna Lisa De Presbiteris, Henrik Schmidt, Paola Savoia, Pontus Berglund, Igor Puzanov, Aurélien Marabelle, Ana Carrizossa Anderson, Hassane M. Zarour, Maria Wolodarski, Patrick Hwu, Joel Jiang, Pio Zeppa, Jeffrey A. Sosman, Eugenio Fernandez, Susan Costantini, Marcus Ballinger, Luc Thomas, Leslie Cope, Rolf Kiessling, Christophe Borg, Francesca Platini, Florian Stratica, Tilman T. Rau, Craig L. Slingluff, Paolo A. Ascierto, Angela Ianaro, Harriet M. Kluger, Stephen Hodi, Tara C. Gangadhar, Claire Vanpouille-Box, Caroline Flament, Hearn J. Cho, Mannavola Francesco, Takahiro Yamazaki, Charles G. Drake, Jason J. Luke, Miklos Kasler, Linda Pan, Caracò Corrado, Alfonso Berrocal, Angel Rivera, Vera Hirsh, Eduardo J. Patriarca, Giovanni Di Giulio, Antonello Pessi, Helena Stabile, Helene Hardy, Tucci Marco, Ralph Venhaus, Maria Luisa Di Cecilia, Catherine A. Harwood, Jonathan Cebon, Anna Maria Anniciello, Grant A. McArthur, Carlo Baldi, Ahmad A. Tarhini, Shelley Coleman, Gil Bar-Sela, Axel Hauschild, Byoung S. Kwon, Maria Paula Roberti, Sabin Cinca, Tiziana Cocco, Valeria Sorrentino, Jeffrey Wallin, Rosa Camerlingo, Sandra Demaria, Jedd D. Wolchok, Isabel Poschke, Alessandro Lugli, Michael B. Atkins, Andrea Cavalcanti, Laura Marra, Rosamaria Pinto, Adam D. Cohen, Michele Maio, Weiyi Peng, Rosario Guarrasi, David Enot, Antoni Ribas, Oscar Alabiso, Chiara Armogida, Silvestris Franco, Jessica C. Hassel, Rita Mancini, Michele Guida, Silvia C. Formenti, Andrea P. Sponghini, Imma Maida, Alba Zappalà, Charlotte M. Proby, Alan J. Korman, Yibing Yan, Matias Chacon, Haiying Xu, Carolin Blattner, Maria-Paula Roberti, Lisa Chen, James Larkin, Ryan J. Sullivan, Madonna Gabriele, Nadege Vimond, Cosmo Di Donna, Farnaz Moradi, Manish R. Patel, Sylvie Rusakiewicz, Francesca Passarelli, Luis de la Cruz-Merino, Nicolas Jacquelot, Roberta Miceli, Viktor Umansky, Akos Savolt, David Rondonotti, Gabriella Liszkay, Jianda Yuan, Stefani Spranger, Yufan Zhao, Yehuda Shoenfeld, Todd M. Bauer, Claus Garbe, Joe-Marc Chauvin, Achim A. Jungbluth, Cristiana Lo Nigro, Alexander M. Lesokhin, Gabriella Guida, Brigitte Dréno, Cindy Sanders, Jeffrey S. Weber, Janet Maleski, Chris Cheadle, Romain Daillère, Isabella Sperduti, Michaele Maio, Claudia Felici, Parneet K. Cheema, Concetta Ragone, Johan Hansson, Klara Eles, Victoria Atkinson, Speiser Daniel, Daniel O. Koralek, Zhaojun Sun, Debora Malpicci, Elena Marra, Rickard Linnskog, Jeffrey Chou, Yang Wang, Eugenia Panaitescu, F. Stephen Hodi, Anthony J. Olszanski, Chiara Botti, Nicola Mozzillo, Anna Ferretta, Paul B. Chapman, Michaë la Semeraro, Belinda Palermo, Francesco Sabbatino, Neil H. Segal, Yago Pico de Coaña, Tseng-hui Timothy Chen, Ornella Pagliano, John B. A. G. Haanen, Huibin Yue, Emilia Caputo, Alan E. Berger, Simona De Summa, Nikoletta Lendvai, Paola Queirolo, Francesco Mannavola, Thomas F. Gajewski, Michele De Tursi, Paola Nisticò, Karen Briscoe, Karmele Mujika Eizmendi, Maria Vincenza Carrier, Passarelli Anna, Laurent Mortier, Crescenzo D'Alterio, Jorge Camarero, Licia Rivoltini, Pietro Quaglino, Davide Quaresmini, Marie Vétizou, Anna Maria Di Giacomo, Chandra Prakash Prasad, Riccardo Bono, Vichnou Poirier-Colame, David Smith, Capone Mariaelena, Giosuè Scognamiglio, Margaret K. Callahan, Vashisht Gopal Yennu Nanda, Fabiola Gilda Cordaro, George J. Netto, Madalina Bolovan, Federica Fratangelo, Josep Malvehy, Robert A. Anders, Karsten A. Pilones, Vincenzo C. Battarra, Karin Leandersson, Maria Letizia Motti, Yang Xin Fu, Tim Crook, Sarah Nataraj, Alastair M. Thompson, Franco Silvestris, Carolina Cauchi, Georgina V. Long, Holbrook E Kohrt, Giuseppe Pirozzi, Celeste Fusciello, Marco Carlo Merlano, François Aubin, Mozzillo Nicola, Giuseppe Cirin, Stefania Scala, Suzanne L. Topalian, Alexander M.M. Eggermont, Antonio Marra, Jinshui Fan, Reinhard Dummer, Federica Zito Marino, Amanda Ralabate, Matthew M. Burke, Piotr Rutkowski, Gerardo Botti, Stefano Pepe, Ivor Caro, and Stefania Tommasi
Subjects: 0301 basic medicine, business.industry, MEDLINE, General Medicine, medicine.disease, Bridge (interpersonal), General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, Medicine, Medical emergency, business
Published: 2016

24. An Immunosurveillance Mechanism Controls Cancer Cell Ploidy

Author: Guillermo Mariño, Frank Madeo, Lorenzo Galluzzi, Shensi Shen, Isabelle Martins, Alexander Valent, Bastien Job, Mark J. Smyth, Maria Castedo, Gian Maria Fimia, Mickaël Michaud, Francesco Berardinelli, Claire Pailleret, Alfredo Criollo, Vladimir Lazar, Santiago Rello-Varona, Guillaume Pourcher, Mauro Piacentini, Antonella Sistigu, Vichnou Poirier-Colame, Laura Senovilla, Sylvain Ladoire, Ming Li, Sandy Adjemian, Clara Locher, Ilio Vitale, Takahiro Yamazaki, Christoph Ruckenstuhl, Josef M. Penninger, Monique Talbot, Nicole L Messina, Antonio Antoccia, François Ghiringhelli, Verena Sigl, Fabiola Ciccosanti, Guido Kroemer, Mireia Niso-Santano, Maximilien Tailler, Oliver Kepp, Laurence Zitvogel, Alice Boilève, Carlos López-Otín, Didac Carmona-Gutierrez, Christopher J. Chan, Antonio Fueyo, Senovilla, L, Vitale, I, Martins, I, Tailler, M, Pailleret, C, Michaud, M, Galluzzi, L, Adjemian, S, Kepp, O, NISO SANTANO, M, Shen, S, Mariño, G, Criollo, A, Boilève, A, Job, B, Ladoire, S, Ghiringhelli, F, Sistigu, A, Yamazaki, T, RELLO VARONA, S, Locher, C, POIRIER COLAME, V, Talbot, M, Valent, A, Berardinelli, Francesco, Antoccia, Antonio, Ciccosanti, F, Fimia, Gm, Piacentini, M, Fueyo, A, Messina, Nl, Li, M, Chan, Cj, Sigl, V, Pourcher, G, Ruckenstuhl, C, CARMONA GUTIERREZ, D, Lazar, V, Penninger, Jm, Madeo, F, LÓPEZ OTÍN, C, Smyth, Mj, Zitvogel, L, Castedo, M, Kroemer, G., Senovilla, Laura, Vitale, Ilio, Martins, Isabelle, Tailler, Maximilien, Pailleret, Claire, Michaud, Mickaël, Galluzzi, Lorenzo, Adjemian, Sandy, Kepp, Oliver, Niso Santano, Mireia, Shen, Shensi, Mariño, Guillermo, Criollo, Alfredo, Boilève, Alice, Job, Bastien, Ladoire, Sylvain, Ghiringhelli, Françoi, Sistigu, Antonella, Yamazaki, Takahiro, Rello Varona, Santiago, Locher, Clara, Poirier Colame, Vichnou, Talbot, Monique, Valent, Alexander, Ciccosanti, Fabiola, Fimia, Gian Maria, Piacentini, Mauro, Fueyo, Antonio, Messina, Nicole L, Li, Ming, Chan, Christopher J, Sigl, Verena, Pourcher, Guillaume, Ruckenstuhl, Christoph, Carmona Gutierrez, Didac, Lazar, Vladimir, Penninger, Josef M, Madeo, Frank, López Otín, Carlo, Smyth, Mark J, Zitvogel, Laurence, Castedo, Maria, and Kroemer, Guido
Subjects: Settore BIO/06, Eukaryotic Initiation Factor-2, medicine.disease_cause, Cell Line, Mice, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, Neoplasms, medicine, Animals, Humans, Epigenetics, Phosphorylation, Endoplasmic Reticulum Stre, Immunologic Surveillance, Inbred BALB C, 030304 developmental biology, Mice, Inbred BALB C, 0303 health sciences, Tumor, Ploidies, Multidisciplinary, biology, Animal, Endoplasmic reticulum, Cancer, DNA, Neoplasm, DNA, Endoplasmic Reticulum Stress, medicine.disease, 3. Good health, Immunosurveillance, Common Variable Immunodeficiency, Cell culture, 030220 oncology & carcinogenesis, Cancer cell, Immunology, biology.protein, Cancer research, Neoplasm, Calreticulin, Carcinogenesis, Immunocompetence, Human
Abstract: Keeping Cancer Cells At Bay Cancer cells are often aneuploid; that is, they have an abnormal number of chromosomes. But to what extent this contributes to the tumorigenic phenotype is not clear. Senovilla et al. (p. 1678 ; see the Perspective by Zanetti and Mahadevan ) found that tetraploidization of cancer cells can cause them to become immunogenic and thus aid in their clearance from the body by the immune system. Cells with excess chromosomes put stress on the endoplasmic reticulum, which leads to movement of the protein calreticulin to the cell surface. Calreticulin exposure in turn caused recognition of cancer cells in mice by the host immune system. Thus, the immune system appears to serve a protective role in eliminating hyperploid cells that must be overcome to allow unrestricted growth of cancer cells.
Published: 2012
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25. Immunohistochemical detection of cytoplasmic LC3 puncta in human cancer specimens

Author: Mickaël Michaud, Vichnou Poirier-Colame, Mathias T. Rosenfeldt, Abdul Qader Sukkurwala, Sandy Adjemian, Lorenzo Galluzzi, Sylvain Ladoire, Felipe Andreiuolo, Kevin M. Ryan, Isabelle Martins, Guido Kroemer, Eileen White, Laurence Zitvogel, and Kariman Chaba
Subjects: Cytoplasm, Pathology, medicine.medical_specialty, ATG5, Cell, Biology, Mice, Cell Line, Tumor, Neoplasms, medicine, Animals, Humans, Molecular Biology, Gene knockdown, Tissue microarray, Staining and Labeling, Cancer, Cell Biology, medicine.disease, Immunohistochemistry, Basic Research Paper, Staining, Cell biology, Mice, Inbred C57BL, Disease Models, Animal, medicine.anatomical_structure, Tissue Array Analysis, Cell culture, embryonic structures, biological phenomena, cell phenomena, and immunity, Microtubule-Associated Proteins
Abstract: Autophagy is an evolutionarily conserved catabolic process that involves the entrapment of cytoplasmic components within characteristic vesicles for their delivery to and degradation within lysosomes. Alterations in autophagic signaling are found in several human diseases including cancer. Here, we describe a validated immunohistochemical protocol for the detection of LC3 puncta in human formalin-fixed, paraffin-embedded cancer specimens that can also be applied to mouse tissues. In response to systemic chemotherapy, autophagy-competent mouse tumors exhibited LC3 puncta, which did not appear in mouse cancers that had been rendered autophagy-deficient by the knockdown of Atg5 or Atg7. As compared with normal tissues, LC3 staining was moderately to highly elevated in the large majority of human cancers studied, albeit tumors of the same histological type tended to be highly heterogeneous in the number and intensity of LC3 puncta per cell. Moreover, tumor-infiltrating immune cells often were highly positive for LC3. Altogether, this protocol for LC3 staining appears suitable for the specific detection of LC3 puncta in human specimens, including tissue microarrays. We surmise that this technique can be employed for retrospective or prospective studies involving large series of human tumor samples.
Published: 2012
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26. Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy

Author: Tiffany Huynh, Mari Mino-Kenudson, Andita Newton, Richard O. Hynes, Christina Pfirschke, Yi Jang Lin, Vichnou Poirier-Colame, Laurence Zitvogel, Gregory R. Wojtkiewicz, Takahiro Yamazaki, Guido Kroemer, Christopher Garris, Steffen Rickelt, Ralph Weissleder, Younes Redouane, Gordon J. Freeman, Mikael J. Pittet, Ferdinando Pucci, Virna Cortez-Retamozo, Camilla Engblom, Yoshiko Iwamoto, Massachusetts Institute of Technology. Department of Biology, Koch Institute for Integrative Cancer Research at MIT, Rickelt, Steffen, and Hynes, Richard O.
Subjects: 0301 basic medicine, Adenocarcinoma/immunology/therapy, Lung Neoplasms, Organoplatinum Compounds, CD8-Positive T-Lymphocytes, medicine.disease_cause, Inbred C57BL, Cyclophosphamide/administration & dosage, Mice, 0302 clinical medicine, Medicine, Immunology and Allergy, Innate, Drug Therapy/methods, Lymphocytes, Inbred BALB C, Mice, Knockout, Central Nervous System Sensitization, Mice, Inbred BALB C, Tumor, CD8-Positive T-Lymphocytes/drug effects, Lung Neoplasms/immunology/therapy, Oxaliplatin, Tumor-Infiltrating/drug effects, Infectious Diseases, 030220 oncology & carcinogenesis, Immunotherapy/methods, Adenocarcinoma, KRAS, Immunotherapy, medicine.drug, Cyclophosphamide, Knockout, Immunology, Central Nervous System Sensitization/drug effects, Article, Cell Line, Cdc/drug effects, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, Drug Therapy, Immunity, Cell Line, Tumor, Genetic model, Animals, Humans, Organoplatinum Compounds/administration & dosage, Innate immune system, business.industry, Animal, medicine.disease, Immunity, Innate, Blockade, Genes, cdc, Mice, Inbred C57BL, Toll-Like Receptor 4, Disease Models, Animal, 030104 developmental biology, Toll-Like Receptor 4/metabolism, Genes, Disease Models, business, CD8
Abstract: Checkpoint blockade immunotherapies can be extraordinarily effective, but might benefit only the minority of patients whose tumors are pre-infiltrated by T cells. Here, using lung adenocarcinoma mouse models, including genetic models, we show that autochthonous tumors that lacked T cell infiltration and resisted current treatment options could be successfully sensitized to host antitumor T cell immunity when appropriately selected immunogenic drugs (e.g., oxaliplatin combined with cyclophosphamide for treatment against tumors expressing oncogenic Kras and lacking Trp53) were used. The antitumor response was triggered by direct drug actions on tumor cells, relied on innate immune sensing through toll-like receptor 4 signaling, and ultimately depended on CD8(+) T cell antitumor immunity. Furthermore, instigating tumor infiltration by T cells sensitized tumors to checkpoint inhibition and controlled cancer durably. These findings indicate that the proportion of cancers responding to checkpoint therapy can be feasibly and substantially expanded by combining checkpoint blockade with immunogenic drugs.
Published: 2015

27. Enterococcus hirae and Barnesiella intestinihominis Facilitate Cyclophosphamide-Induced Therapeutic Immunomodulatory Effects

Author: Vichnou Poirier-Colame, Silvia C. Formenti, Alexander M. M. Eggermont, Christophe Isnard, Elisabeth Chachaty, Didier Raoult, Maria Paula Roberti, Harry Sokol, Patricia Lepage, Encouse B. Golden, David Enot, Ivo G. Boneca, Guido Kroemer, Laurence Zitvogel, Nicolas Jacquelot, Mutsa Tatenda Madondo, Mathias Chamaillard, Jean-Charles Soria, Caroline Flament, Philip Rosenstiel, Marie Vétizou, Takahiro Yamazaki, Romain Daillère, Antoine Roux, Sylvie Rusakiewicz, Sonia Becharef, Vincent Cattoir, Nadine Waldschmitt, Bertrand Routy, Paul Louis Woerther, Magdalena Plebanski, Eric Tartour, Lionel Apetoh, Philippe Langella, Connie P.M. Duong, Ludger Johannes, 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 d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, 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), Unité de Recherche Risques Microbiens (U2RM), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), 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), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Département d'oncologie médicale [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC), Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Apoptose, cancer et immunité (U848), Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Institut Gustave Roussy (IGR), Université Paris Descartes - Paris 5 (UPD5), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), 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)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Chimie biologique des membranes et ciblage thérapeutique (CBMCT - UMR 3666 / U1143), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Microbiologie, Département de biologie et pathologie médicales [Gustave Roussy], Université Paris-Saclay, Department Radiation Oncology (Weill Cornell Medicine), Weill Medical College of Cornell University [New York], Monash University [Clayton], Unabhängiges Landeszentrum für Datenschutz Schleswig-Holstein [Kiel, Germany] (ULD), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes (URMITE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR48, Institut des sciences biologiques (INSB-CNRS)-Institut des sciences biologiques (INSB-CNRS)-Centre National de la Recherche Scientifique (CNRS), CHU Pontchaillou [Rennes], Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall (BGPB), Institut Pasteur [Paris] (IP), La Ligue contre le cancer, Ligue Nationale contre le Cancer (Equipes labellisees), European Research Council Advanced Investigator Grant, Fondation pour la Recherche Medicale (FRM), Institut National du Cancer (INCa), Fondation de France, LabEx Immuno-Oncology, SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE), SIRIC, Paris Alliance of Cancer Research Institutes (PACRI), ISREC, Swiss Bridge Foundation, NIH [R01 CA161879], FRM [DEQ20130326475], INCa [Plbio-2012-106], Agence Nationale de la Recherche [ANR- 13-BSV3-0014-01], Association pour la Recherche contre le cancer [PGA120140200851], Ministere de l'enseignement superieur et de la recherche, Institut de veille sanitaire (InVS), Interreg IVA France (Manche) - Angleterre (Risk Manche), Anti-Cancer Fund, Monash PhD Scholarship, NHMRC SRF Award, DFG CE Inflammation at Interfaces, European Union's FP7 [305564, SFB1182 TP C2], Service de Gastroentérologie et nutrition [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), INSB-INSB-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, 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), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Centre d’Infection et d’Immunité de Lille (CIIL) - U1019 - 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 National de la Recherche Scientifique (CNRS), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie-Université Paris Descartes - Paris 5 (UPD5), Institut Hospitalier Universitaire Méditerranée Infection (IHU AMU), 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 d’Infection et d’Immunité de Lille (CIIL) - U1019 - 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 ) -IFR142-Université de Lille-Centre National de la Recherche Scientifique ( CNRS ), Unité de Recherche Risques Microbiens ( U2RM ), Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Centre d'Investigation Clinique en Biotherapie des cancers ( CIC 1428 , CBT 507 ), Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), MICrobiologie de l'ALImentation au Service de la Santé humaine ( MICALIS ), Institut National de la Recherche Agronomique ( INRA ) -AgroParisTech, Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Université Pierre et Marie Curie - Paris 6 ( UPMC ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Apoptose, cancer et immunité ( U848 ), Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Institut Gustave Roussy ( IGR ), Université Paris Descartes - Paris 5 ( UPD5 ), Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Chimie biologique des membranes et ciblage thérapeutique ( CBMCT - UMR 3666 / U1143 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Unabhängiges Landeszentrum für Datenschutz Schleswig-Holstein [Kiel, Germany] ( ULD ), Institut Hospitalier Universitaire Méditerranée Infection ( IHU AMU ), Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes ( URMITE ), Institut de Recherche pour le Développement ( IRD ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR48, INSB-INSB-Centre National de la Recherche Scientifique ( CNRS ), and Biologie et Génétique de la Paroi bactérienne
Subjects: 0301 basic medicine, Richness, Nod2 Signaling Adaptor Protein, medicine.disease_cause, Mice, 0302 clinical medicine, Enterococcus hirae, NOD2, Neoplasms, Intestine, Small, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Immunology and Allergy, Gut Microbiota, Cancer, biology, 3. Good health, Immunosurveillance, Infectious Diseases, 030220 oncology & carcinogenesis, Barnesiella intestinihominis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Immunotherapy, medicine.symptom, Infection, medicine.drug, Cyclophosphamide, Colon, Immunology, Translocation, Inflammation, 03 medical and health sciences, Interferon-gamma, Immune system, Monitoring, Immunologic, medicine, Animals, Immunologic Factors, Antitumor Immunity, Bacteria, Dendritic Cells, Th1 Cells, medicine.disease, biology.organism_classification, Mice, Inbred C57BL, 030104 developmental biology, Intestinal Microbiota, Ovarian cancer, Immunologic Memory
Abstract: International audience; The efficacy of the anti-cancer immunomodulatory agent cyclophosphamide (CTX) relies on intestinal bacteria. How and which relevant bacterial species are involved in tumor immunosurveillance, and their mechanism of action are unclear. Here, we identified two bacterial species, Enterococcus hirae and Barnesiella intestinihominis that are involved during CTX therapy. Whereas E. hirae translocated from the small intestine to secondary lymphoid organs and increased the intratumoral CD8/ Treg ratio, B. intestinihominis accumulated in the colon and promoted the infiltration of IFN-gamma-producing gamma delta Tau cells in cancer lesions. The immune sensor, NOD2, limited CTX-induced cancer immunosurveillance and the bioactivity of these microbes. Finally, E. hirae and B. intestinihominis specific-memory Th1 cell immune responses selectively predicted longer progression-free survival in advanced lung and ovarian cancer patients treated with chemo-immunotherapy. Altogether, E. hirae and B. intestinihominis represent valuable ''oncomicrobiotics'' ameliorating the efficacy of the most common alkylating immunomodulatory compound.
Published: 2015
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28. Clinical impact of the NKp30/B7-H6 axis in high-risk neuroblastoma patients

Author: Guido Kroemer, Andrei Tchirkov, Frédéric Commo, Vichnou Poirier-Colame, Sophie Cotteret, Nicole Prada, Dominique Valteau-Couanet, Sylvie Rusakiewicz, Benjamin Papoular, Laurence Zitvogel, Jessica Matta, Nathalie Chaput, David Enot, Tala Shekarian, Aurélien Marabelle, Laurence Brugières, Brigitte Bressac, Michaela Semeraro, Valérie Lapierre, Mirco Ponzoni, Frédéric Vély, Christelle Piperoglou, Patrizia Perri, Françoise Farace, Nicolas F. Delahaye, Sandrine Valsesia-Wittmann, and Véronique Minard-Colin
Subjects: Adult, B7 Antigens, Adolescent, Antineoplastic Agents, Biology, Ligands, Jurkat cells, Disease-Free Survival, Jurkat Cells, Neuroblastoma, Young Adult, Risk Factors, Cell Line, Tumor, Antineoplastic Combined Chemotherapy Protocols, medicine, Biomarkers, Tumor, Humans, Prospective Studies, Neoplasm Metastasis, Child, Natural Cytotoxicity Triggering Receptor 3, Brain Neoplasms, Induction chemotherapy, Infant, General Medicine, medicine.disease, Prognosis, Transplantation, Immunosurveillance, Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, Phenotype, Cell culture, Child, Preschool, Immunology, Bone marrow, Stem cell, Protein Binding
Abstract: The immunosurveillance mechanisms governing high-risk neuroblastoma (HR-NB), a major pediatric malignancy, have been elusive. We identify a potential role for natural killer (NK) cells, in particular the interaction between the NK receptor NKp30 and its ligand, B7-H6, in the metastatic progression and survival of HR-NB after myeloablative multimodal chemotherapy and stem cell transplantation. NB cells expressing the NKp30 ligand B7-H6 stimulated NK cells in an NKp30-dependent manner. Serum concentration of soluble B7-H6 correlated with the down-regulation of NKp30, bone marrow metastases, and chemoresistance, and soluble B7-H6 contained in the serum of HR-NB patients inhibited NK cell functions in vitro. The expression of distinct NKp30 isoforms affecting the polarization of NK cell functions correlated with 10-year event-free survival in three independent cohorts of HR-NB in remission from metastases after induction chemotherapy (n = 196, P0.001), adding prognostic value to known risk factors such as N-Myc amplification and age18 months. We conclude that the interaction between NKp30 and B7-H6 may contribute to the fate of NB patients and that both the expression of NKp30 isoforms on circulating NK cells and the concentration of soluble B7-H6 in the serum may be clinically useful as biomarkers for risk stratification.
Published: 2015

29. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota

Author: Elisabeth Chachaty, Alexander M.M. Eggermont, Vichnou Poirier-Colame, Jérôme Nigou, Antoine Roux, Gérard Eberl, Caroline Robert, Nicolas Jacquelot, Caroline Flament, Laurence Zitvogel, Franck Carbonnel, Silvia C. Formenti, Guido Kroemer, Didier Raoult, Paul Louis Woerther, Nadine Waldschmitt, David Enot, Marie Vétizou, Jonathan M. Pitt, Sonia Becharef, Romain Daillère, Christina Mateus, Sascha Cording, Paule Opolon, Sridhar Mani, Connie P.M. Duong, Nathalie Chaput, Bertrand Routy, Takahiro Yamazaki, Patricia Lepage, Ivo G. Boneca, Marion Bérard, Mathias Chamaillard, Florent Ginhoux, Sylvie Rusakiewicz, Maria Paula Roberti, Andreas Schlitzer, Encouse B. Golden, Université Paris-Sud - Paris 11 (UP11), 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), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, 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), 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), Université Sorbonne Paris Cité (USPC), New York University [New York] (NYU), NYU System (NYU), Microenvironnement et Immunité - Microenvironment and Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Singapore Immunology Network (SIgN), Biomedical Sciences Institute (BMSI), Albert Einstein College of Medicine [New York], Animalerie centrale (Plate-forme), Institut Pasteur [Paris] (IP), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR), 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), Université Paris Descartes - Paris 5 (UPD5), 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), 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), Université de la Méditerranée - Aix-Marseille 2, Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Hôpital Bicêtre, La Ligue contre le cancer, ARC, Ligue Nationale contre le Cancer (Equipes labelisees), Agence Nationale pour la Recherche (ANR AUTOPH), Agence Nationale pour la Recherche (ANR, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris], Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, 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), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), ProdInra, Migration, and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Adoptive cell transfer, Skin Neoplasms, medicine.medical_treatment, T-Lymphocytes, [SDV]Life Sciences [q-bio], B7-H1 Antigen, Mice, Cancer immunotherapy, Bacteroides, Innate, CTLA-4 Antigen, Melanoma, Cancer, Aged, 80 and over, Multidisciplinary, Host, Antibodies, Monoclonal, hemic and immune systems, Fecal Microbiota Transplantation, Middle Aged, 3. Good health, Anti-Bacterial Agents, [SDV] Life Sciences [q-bio], Intestines, medicine.anatomical_structure, Female, Immunotherapy, Adult, T cell, T-Cells, chemical and pharmacologic phenomena, Biology, Article, Polysaccharides, medicine, Germ-Free Life, Animals, Humans, Antibody, Aged, Molecule, medicine.disease, Ipilimumab, Blockade, Gastrointestinal Microbiome, Transplantation, Mice, Inbred C57BL, CTLA-4, Immunology, Dysbiosis, Bifidobacterium, Immunologic Memory, Model
Abstract: International audience; Antibodies targeting CTLA-4 have been successfully used as cancer immunotherapy. We find that the antitumor effects of CTLA-4 blockade depend on distinct Bacteroides species. In mice and patients, Tcell responses specific for B. thetaiotaomicron or B. fragilis were associated with the efficacy of CTLA-4 blockade. Tumors in antibiotic-treated or germ-free mice did not respond to CTLA blockade. This defect was overcome by gavage with B. fragilis, by immunization with B. fragilis polysaccharides, or by adoptive transfer of B. fragilis-specific T cells. Fecal microbial transplantation from humans to mice confirmed that treatment of melanoma patients with antibodies against CTLA-4 favored the outgrowth of B. fragilis with anticancer properties. This study reveals a key role for Bacteroidales in the immunostimulatory effects of CTLA-4 blockade.
Published: 2015
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30. The presence of LC3B puncta and HMGB1 expression in malignant cells correlate with the immune infiltrate in breast cancer

Author: Sylvain Ladoire, David Enot, Laura Senovilla, François Ghiringhelli, Vichnou Poirier-Colame, Kariman Chaba, Michaela Semeraro, Marie Chaix, Frédérique Penault-Llorca, Laurent Arnould, Marie Laure Poillot, Patrick Arveux, Suzette Delaloge, Fabrice Andre, Laurence Zitvogel, Guido Kroemer, Sylvain Ladoire, David Enot, Laura Senovilla, François Ghiringhelli, Vichnou Poirier-Colame, Kariman Chaba, Michaela Semeraro, Marie Chaix, Frédérique Penault-Llorca, Laurent Arnould, Marie Laure Poillot, Patrick Arveux, Suzette Delaloge, Fabrice Andre, Laurence Zitvogel, and Guido Kroemer
Abstract: Several cell-intrinsic alterations have poor prognostic features in human breast cancer, as exemplified by the absence of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 β)-positive puncta in the cytoplasm (which indicates reduced autophagic flux) or the loss of nuclear HMGB1 expression by malignant cells. It is well established that breast cancer is under strong immunosurveillance, as reflected by the fact that scarce infiltration of the malignant lesion by CD8+ cytotoxic T lymphocytes or comparatively dense infiltration by immunosuppressive cell types (such as FOXP3+ regulatory T cells or CD68+ tumor-associated macrophages), resulting in low CD8+:FOXP3+ or CD8+:CD68+ ratios, has a negative prognostic impact. Here, we reveal the surprising finding that cell-intrinsic features may influence the composition of the immune infiltrate in human breast cancer. Thus, the absence of LC3B puncta is correlated with intratumoral (but not peritumoral) infiltration by fewer CD8+ cells and more FOXP3+ or CD68+ cells, resulting in a major drop in the CD8+:FOXP3+ or CD8+:CD68+ ratios. Moreover, absence of HMGB1 expression in nuclei correlated with a general drop in all immune effectors, in particular FOXP3+ and CD68+ cells, both within the tumor and close to it. Combined analysis of LC3B puncta and HMGB1 expression allowed for improved stratification of patients with respect to the characteristics of their immune infiltrate as well as overall and metastasis-free survival. It can be speculated that blocked autophagy in, or HMGB1 loss from, cancer cells may favor tumor progression due to their negative impact on anticancer immunosurveillance.
Published: 2016
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31. Combined evaluation of LC3B puncta and HMGB1 expression predicts residual risk of relapse after adjuvant chemotherapy in breast cancer

Author: Sylvain Ladoire, Frédérique Penault-Llorca, Laura Senovilla, Cécile Dalban, David Enot, Clara Locher, Nicole Prada, Vichnou Poirier-Colame, Kariman Chaba, Laurent Arnould, François Ghiringhelli, Pierre Fumoleau, Marc Spielmann, Suzette Delaloge, Marie Laure Poillot, Patrick Arveux, Aicha Goubar, Fabrice Andre, Laurence Zitvogel, Guido Kroemer, Sylvain Ladoire, Frédérique Penault-Llorca, Laura Senovilla, Cécile Dalban, David Enot, Clara Locher, Nicole Prada, Vichnou Poirier-Colame, Kariman Chaba, Laurent Arnould, François Ghiringhelli, Pierre Fumoleau, Marc Spielmann, Suzette Delaloge, Marie Laure Poillot, Patrick Arveux, Aicha Goubar, Fabrice Andre, Laurence Zitvogel, and Guido Kroemer
Published: 2016
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32. Cancer cell–autonomous contribution of type I interferon signaling to the efficacy of chemotherapy

Author: Aicha Goubar, Julien Adam, Joanna Cyrta, Kariman Chaba, Mireia Niso-Santano, Valentina La Sorsa, Laurence Zitvogel, Christina Pfirschke, Guido Kroemer, Gilles Uzé, Oliver Kepp, Magali Lacroix-Triki, Francesca Urbani, Antonella Sistigu, Elisa E. Baracco, Suzette Delaloge, Sylvain Ladoire, David Enot, Camilla Engblom, Marco Bianchi, Laurent Arnould, Virginie Quidville, Mauro Delorenzi, Enrico Proietti, Melvyn T. Chow, Laetitia Aymeric, Fabrice Andre, Giovanna Ziccheddu, Joachim L. Schultze, Alexander M.M. Eggermont, Thomas Tüting, Laetitia Fend, Mark J. Smyth, Catarina Remédios, Takahiro Yamazaki, Robert D. Schreiber, Laura Bracci, Erika Vacchelli, Rosa Conforti, Ilio Vitale, Paola Sestili, Mikael J. Pittet, Marie Charlotte Dessoliers, Filippo Belardelli, Vichnou Poirier-Colame, Frédérique Penault-Llorca, Jean Philippe Spano, Lajos Pusztai, Xavier Préville, Dalil Hannani, Yuting Ma, National Cancer Institute Regina Elena [Rome, Italy], 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), Apoptose, cancer et immunité (Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138), Institut Gustave Roussy (IGR)-Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie et Cancérologie Intégratives (CRC - Inserm U1138), Centre de Recherche des Cordeliers (CRC), Institut Gustave Roussy (IGR), Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Département de biologie et pathologie médicales [Gustave Roussy], Apoptose, cancer et immunité (U848), 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), Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III [Madrid] (ISC), 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)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Life and Medical Sciences Institute for Genomics and Immunoregulation, Universität Bonn = University of Bonn, Dept. of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità (ISS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Department of Breast Medical Oncology [Houston], The University of Texas M.D. Anderson Cancer Center [Houston], Pathologie mammaire, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), Département de Biologie et pathologie des tumeurs [Centre Georges-François Leclerc], UNICANCER-UNICANCER, Harvard Medical School [Boston] (HMS), Dynamique des interactions membranaires normales et pathologiques (DIMNP), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Department of Cell Biology and Neurosciences, Université Paris-Sud - Paris 11 (UP11), Sistigu, A, Yamazaki, T, Vacchelli, E, Chaba, K, Enot, Dp, Adam, J, Vitale, I, Goubar, A, Baracco, Ee, Remédios, C, Fend, L, Hannani, D, Aymeric, L, Ma, Y, Niso Santano, M, Kepp, O, Schultze, Jl, Tüting, T, Belardelli, F, Bracci, L, La Sorsa, V, Ziccheddu, G, Sestili, P, Urbani, F, Delorenzi, M, Lacroix Triki, M, Quidville, V, Conforti, R, Spano, Jp, Pusztai, L, Poirier Colame, V, Delaloge, S, Penault Llorca, F, Ladoire, S, Arnould, L, Cyrta, J, Dessoliers, Mc, Eggermont, A, Bianchi, MARCO EMILIO, Pittet, M, Engblom, C, Pfirschke, C, Préville, X, Uzè, G, Schreiber, Rd, Chow, Mt, Smyth, Mj, Proietti, E, André, F, Kroemer, G, Zitvogel, L., Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), 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)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École pratique des hautes études (EPHE), University of Bonn, Istituto Superiore di Sanità, Service d'Oncologie médicale [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Istituto Superiore di Sanita', and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Myxovirus Resistance Proteins, Messenger, Receptor, Interferon alpha-beta, Inbred C57BL, chemotherapy, Interferon alpha-beta, Mice, Interferon, Receptors, Anthracyclines, Neoplasm Metastasis, RIG-I, Pattern recognition receptor, Adaptor Proteins, General Medicine, Neoadjuvant Therapy, 3. Good health, Gene Expression Regulation, Neoplastic, Treatment Outcome, Receptors, Pattern Recognition, Interferon Type I, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Immunocompetence, medicine.drug, Receptor, Signal Transduction, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Pattern Recognition, Settore BIO/09, General Biochemistry, Genetics and Molecular Biology, Paracrine signalling, Immune system, medicine, CXCL10, Animals, Humans, cancer, RNA, Messenger, Autocrine signalling, Neoplastic, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Toll-Like Receptor 3, Mice, Inbred C57BL, Vesicular Transport, Chemokine CXCL10, Adaptor Proteins, Vesicular Transport, Gene Expression Regulation, Doxorubicin, Immunology, TLR3, RNA
Abstract: International audience; The immune system is routinely confronted with cell death resulting from the physiological turnover of renewable tissues, as well as from pathological insults of several types. We hypothesize the existence of a mechanism that allows the immune system to discriminate between physiological and pathological instances of cell death, but the factors that determine whether cellular demise is perceived as a neutral, tolerogenic or immunogenic event remain unclear 1. Infectious insults are accompanied by so-called microbe-associated molecular patterns (MAMPs), i.e., viral or bacterial products that activate immune cells through a panel of pattern-recognition receptors (PRRs) 2. Moreover, intracellular pathogens generally trigger adaptive mechanisms aimed toward the re-establishment of homeosta-sis, including the unfolded protein response (UPR) and autophagy 3,4. In mammals, MAMPs coupled to the activation of stress responses Some of the anti-neoplastic effects of anthracyclines in mice originate from the induction of innate and T cell-mediated anticancer immune responses. Here we demonstrate that anthracyclines stimulate the rapid production of type I interferons (IFNs) by malignant cells after activation of the endosomal pattern recognition receptor Toll-like receptor 3 (TLR3). By binding to IFN- and IFN- receptors (IFNARs) on neoplastic cells, type I IFNs trigger autocrine and paracrine circuitries that result in the release of chemokine (C-X-C motif) ligand 10 (CXCL10). Tumors lacking Tlr3 or Ifnar failed to respond to chemotherapy unless type I IFN or Cxcl10, respectively, was artificially supplied. Moreover, a type I IFN-related signature predicted clinical responses to anthracycline-based chemotherapy in several independent cohorts of patients with breast carcinoma characterized by poor prognosis. Our data suggest that anthracycline-mediated immune responses mimic those induced by viral pathogens. We surmise that such 'viral mimicry' constitutes a hallmark of successful chemotherapy. npg
Published: 2014
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33. Regulation of CD4+NKG2D+ Th1 Cells in Patients with Metastatic Melanoma Treated with Sorafenib: Role of IL-15Rα and NKG2D Triggering

Author: Sylvie Rusakiewicz, Sophie Caillat-Zucman, Christine Mateus, Yannick Jacques, Caroline Flament, Caroline Robert, Vichnou Poirier-Colame, Nathalie Chaput, Danila Valmori, Philippe Dessen, Philippe Vielh, Erwan Mortier, Nicolas Jacquelot, Maha Ayyoub, Camillo Porta, Laurence Zitvogel, Alexander M.M. Eggermont, Ana I. Romero, Anne Auperin, Anne Caignard, Meriem Messaoudene, Kariman Chaba, 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 d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Laboratoire de recherche translationnelle, Direction de la recherche [Gustave Roussy], Hématopoïèse normale et pathologique (U1170 Inserm), Stabilité Génétique et Oncogenèse (UMR 8200), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), IRCCS San Matteo Hospital Foundation & University of Pavia, Service de dermatologie, Département de médecine oncologique [Gustave Roussy], Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Université Paris-Sud - Paris 11 (UP11), This work was supported by Schering-Plough legacy, Bayer Schering Pharma, Institut National du Cancer INCa, ANR, Ligue contre le cancer (équipe labellisée de LZ) and INFLACARE EU grant, ISREC Foundation, SIRIC SOCRATES, LABEX OncoImmunology, PACRI network. S. Rusakiewicz and V. Poirier-Colame were supported by the Fondation pour la Recherche Medicale (FRM) and the Fondation de France respectively. A.I. Romero was supported by the Swedish Research Council., Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Università degli Studi di Pavia = University of Pavia (UNIPV), and Mortier, Erwan
Subjects: Male, Cancer Research, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Ligands, 0302 clinical medicine, Enzymes -- Regulation, Vemurafenib, Melanoma, Interleukin-15, 0303 health sciences, Interleukin, Middle Aged, Sorafenib, 3. Good health, [SDV] Life Sciences [q-bio], Oncology, NK Cell Lectin-Like Receptor Subfamily K, 030220 oncology & carcinogenesis, CD4 Antigens, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, CD4 antigen, Adjuvant, medicine.drug, Adult, Niacinamide, [SDV.IMM] Life Sciences [q-bio]/Immunology, Killer cells, Cells -- Growth, chemical and pharmacologic phenomena, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Growth Processes, Young Adult, 03 medical and health sciences, Immune system, Interleukin-15 Receptor alpha Subunit, Antigen, [SDV.CAN] Life Sciences [q-bio]/Cancer, Th1 cells, medicine, Humans, Antigens, Aged, 030304 developmental biology, business.industry, Phenylurea Compounds, Th1 Cells, medicine.disease, NKG2D, Cancer research, business
Abstract: Beyond cancer-cell intrinsic factors, the immune status of the host has a prognostic impact on patients with cancer and influences the effects of conventional chemotherapies. Metastatic melanoma is intrinsically immunogenic, thereby facilitating the search for immune biomarkers of clinical responses to cytotoxic agents. Here, we show that a multi-tyrosine kinase inhibitor, sorafenib, upregulates interleukin (IL)-15Rα in vitro and in vivo in patients with melanoma, and in conjunction with natural killer (NK) group 2D (NKG2D) ligands, contributes to the Th1 polarization and accumulation of peripheral CD4+NKG2D+ T cells. Hence, the increase of blood CD4+NKG2D+ T cells after two cycles of sorafenib (combined with temozolomide) was associated with prolonged survival in a prospective phase I/II trial enrolling 63 patients with metastatic melanoma who did not receive vemurafenib nor immune checkpoint-blocking antibodies. In contrast, in metastatic melanoma patients treated with classical treatment modalities, this CD4+NKG2D+ subset failed to correlate with prognosis. These findings indicate that sorafenib may be used as an "adjuvant" molecule capable of inducing or restoring IL-15Rα/IL-15 in tumors expressing MHCclass I-related chain A/B (MICA/B) and on circulating monocytes of responding patients, hereby contributing to the bioactivity of NKG2D+ Th1 cells., peer-reviewed
Published: 2014
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34. Keratoacanthomas and Squamous Cell Carcinomas in Patients Receiving Sorafenib

Author: Jean Philippe Arnault, Christine Mateus, Jean-Didier Grange, Alain Spatz, Janine Wechsler, Vincent Sibaud, Vichnou Poirier-Colame, Bernard Escudier, Selim Aractingi, Jean-Charles Soria, Gorana Tomasic, David Malka, and Caroline Robert
Subjects: Adult, Keratinocytes, Male, Niacinamide, Oncology, Sorafenib, Cancer Research, medicine.medical_specialty, Keratoacanthoma, Skin Neoplasms, Time Factors, Pyridines, Cell, MEDLINE, Antineoplastic Agents, Text mining, Internal medicine, medicine, Carcinoma, Humans, In patient, Protein Kinase Inhibitors, Aged, Skin, Aged, 80 and over, Phenylurea Compounds, business.industry, Benzenesulfonates, Middle Aged, medicine.disease, Cell Transformation, Neoplastic, medicine.anatomical_structure, Carcinoma, Squamous Cell, Female, business, Follow-Up Studies, medicine.drug
Published: 2009
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35. Combined evaluation of LC3B puncta and HMGB1 expression predicts residual risk of relapse after adjuvant chemotherapy in breast cancer

Author: Sylvain Ladoire, Frédérique Penault-Llorca, Laura Senovilla, Cécile Dalban, David Enot, Clara Locher, Nicole Prada, Vichnou Poirier-Colame, Kariman Chaba, Laurent Arnould, François Ghiringhelli, Pierre Fumoleau, Marc Spielmann, Suzette Delaloge, Marie Laure Poillot, Patrick Arveux, Aicha Goubar, Fabrice Andre, Laurence Zitvogel, Guido Kroemer, Sylvain Ladoire, Frédérique Penault-Llorca, Laura Senovilla, Cécile Dalban, David Enot, Clara Locher, Nicole Prada, Vichnou Poirier-Colame, Kariman Chaba, Laurent Arnould, François Ghiringhelli, Pierre Fumoleau, Marc Spielmann, Suzette Delaloge, Marie Laure Poillot, Patrick Arveux, Aicha Goubar, Fabrice Andre, Laurence Zitvogel, and Guido Kroemer
Published: 2015
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36. The ratio of CD8+/FOXP3 T lymphocytes infiltrating breast tissues predicts the relapse of ductal carcinoma in situ

Author: Fabrice Andre, Guido Kroemer, Gautier Stoll, Aitziber Buqué, Juliette Humeau, Oliver Kepp, Michaela Semeraro, Laura Senovilla, Suzette Delaloge, Vichnou Poirier-Colame, Laurence Zitvogel, Kariman Chaba, Julien Adam, Allan Sauvat, Norma Bloy, Erika Vacchelli, Emilie Louvet, and Marie-Christine Mathieu
Subjects: 0301 basic medicine, Pathology, medicine.medical_specialty, Immunology, FOXP3, Biology, Ductal carcinoma, Immunosurveillance, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Parenchyma, medicine, Immunology and Allergy, Immunohistochemistry, Cytotoxic T cell, Lymph node, CD8
Abstract: In a series of 248 tumor samples obtained from image-guided biopsies from patients diagnosed with ductal carcinoma in situ of the breast, we attempted to identify biomarkers that predict microinfiltration at definitive surgery or relapse during follow-up. For this, we used immunohistochemical methods, followed by automated image analyses, to measure the mean diameter of nuclei (which correlates with ploidy), the phosphorylation of eukaryotic initiation factor 2α (eIF2α, which reflects endoplasmic reticulum stress) as well as the density and ratio of CD8+ cytotoxic T lymphocytes and FOXP3+ regulatory T cells. The median nuclear diameter of malignant cells correlated with eIF2α phosphorylation (in cancerous tissue), which in turn correlated with the density of the CD8+ infiltrate and the CD8+/FOXP3 ratio (both in cancerous and the adjacent non-cancerous parenchyma). Neither microinfiltration nor lymph node involvement was associated with the probability of relapse. Both correlated positively with the CD8+/FOXP3 ratio in the malignant area. In contrast, relapse was associated with a paucity of the CD8+ infiltrate as well as an unfavorable CD8+/FOXP3 ratio, both in malignant and non-malignant parenchyma. The combined analysis of the CD8+/FOXP3 ratio in cancerous and non-cancerous tissues revealed a significant impact of their interaction on the probability of relapse, but not on the presence of microinfiltration or lymph node metastasis. Altogether, these results support the idea of an immunosurveillance system that determines the risk of relapse in ductal carcinoma in situ of the breast.
Published: 2016
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37. Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors

Author: Frédéric Commo, Sylvie Rusakiewicz, Jean Franãois Emile, Caroline Flament, Jean-Yves Blay, Nicolas Ibrahim, Véronique Minard-Colin, Saadia Kerdine-Römer, Philippe Terrier, Jacques A. Nunès, Cédric Ménard, Pascale Paul, Benedita Rocha, Laurence Zitvogel, Kariman Chaba, Alessandro Moretta, Dominique Valteau-Couanet, Cristina Bottino, Javier Celis Gutierrez, Luc Lyonnet, A. Lecesne, Nathalie Chaput, Stephan Roux, Hélène Authier, Jean Michel Coindre, Matthieu Sarabi, Pascal Rihet, Véronique Baud, Nicolas F. Delahaye, Laetitia Peaudecerf, Isabelle Martins, Sylvie Bonvalot, Jan Tavernier, Eric Vivier, Nicolas Isambert, Michaela Semeraro, Isabelle Cremer, Marc Pallardy, Paule Opolon, Vichnou Poirier-Colame, Guido Kroemer, 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), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Chirurgie, Assistance Publique - Hôpitaux de Marseille (APHM)-Hospices Civiles de Marseille-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ), Department of Immunology, Duke University Medical Center, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), School of Medicine, Université Paris-Sud - Paris 11 (UP11), Recepteurs et Signalisation des Interleukines (U749), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de Pédiatrie, Institut Gustave Roussy (IGR), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Service d'anatomie pathologique [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Tenon [APHP], Département de biologie et pathologie médicales [Gustave Roussy], Vectorologie et transfert de gènes (VTG / UMR8121), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Università di Genova, Dipartimento di Medicina Sperimentale, Universita degli studi di Genova, Biochemistry, Ghent University [Belgium] (UGENT), Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques (IP-TPT), Service de Santé des Armées-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD), Département de pathologie, Institut Bergonié - CRLCC Bordeaux, Département de Médecine Nucléaire, Centre Léon Bérard [Lyon], Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Laboratory of Human Genetics of Infectious Diseases, Apoptose, cancer et immunité (U848), Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Pôle de biologie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), 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 ), Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Jacques Monod ( IJM ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Centre d'Investigation Clinique en Biotherapie des cancers ( CIC 1428 , CBT 507 ), Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance Publique - Hôpitaux de Marseille ( APHM ) -Hospices Civiles de Marseille-Hôpital de la Conception [CHU - APHM] ( LA CONCEPTION ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Faculté de Médecine ( UPD5 Médecine ), Université Paris Descartes - Paris 5 ( UPD5 ), Université Paris-Sud - Paris 11 ( UP11 ), Recepteurs et Signalisation des Interleukines ( U749 ), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Gustave Roussy ( IGR ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Tenon [APHP], Vectorologie et transfert de gènes ( VTG / UMR8121 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Centre National de la Recherche Scientifique ( CNRS ), University of Genova, Ghent University [Belgium] ( UGENT ), Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques ( IP-TPT ), Institut de Recherche pour le Développement ( IRD ) -Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) -Service de Santé des Armées-Université de Montpellier ( UM ), Université Claude Bernard Lyon 1 ( UCBL ), Apoptose, cancer et immunité ( U848 ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), 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)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance Publique - Hôpitaux de Marseille (APHM)-Hospices Civiles de Marseille-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli studi di Genova = University of Genoa (UniGe), Universiteit Gent = Ghent University (UGENT), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Service de Santé des Armées, Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, 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), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Universiteit Gent = Ghent University [Belgium] (UGENT)
Subjects: MESH: Interleukin-12, MESH : Alternative Splicing, MESH: Protein Isoforms, MESH: Lysosomal-Associated Membrane Protein 1, 0302 clinical medicine, Interferon, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Protein Isoforms, Receptor, MESH : Tumor Necrosis Factor-alpha, 0303 health sciences, MESH : Prognosis, MESH : Gastrointestinal Stromal Tumors, GiST, MESH : Lysosomal-Associated Membrane Protein 1, MESH: Alternative Splicing, MESH: Polymorphism, Single Nucleotide, MESH : Polymorphism, Single Nucleotide, General Medicine, Prognosis, Interleukin-12, MESH: Proto-Oncogene Proteins c-kit, Killer Cells, Natural, Proto-Oncogene Proteins c-kit, [SDV.IMM]Life Sciences [q-bio]/Immunology, Tumor necrosis factor alpha, MESH : Killer Cells, Natural, Sarcoma, MESH: Natural Cytotoxicity Triggering Receptor 3, Tyrosine kinase, MESH: Gastrointestinal Stromal Tumors, medicine.drug, MESH: Killer Cells, Natural, Gene isoform, MESH : Natural Cytotoxicity Triggering Receptor 3, MESH: Cell Line, Tumor, Stromal cell, MESH: Interferon-gamma, Gastrointestinal Stromal Tumors, Biology, Polymorphism, Single Nucleotide, MESH : Proto-Oncogene Proteins c-kit, MESH: Prognosis, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Interferon-gamma, Lysosomal-Associated Membrane Protein 1, Cell Line, Tumor, MESH : Interleukin-12, medicine, Humans, MESH : Interferon-gamma, 030304 developmental biology, MESH: Humans, Natural Cytotoxicity Triggering Receptor 3, MESH : Cell Line, Tumor, Tumor Necrosis Factor-alpha, MESH : Humans, MESH : Protein Isoforms, medicine.disease, Alternative Splicing, MESH: Tumor Necrosis Factor-alpha, Immunology, Cancer research, 030215 immunology
Abstract: International audience; The natural killer (NK) cell receptor NKp30 is involved in the recognition of tumor and dendritic cells (DCs). Here we describe the influence of three NKp30 splice variants on the prognosis of gastrointestinal sarcoma (GIST), a malignancy that expresses NKp30 ligands and that is treated with NK-stimulatory KIT tyrosine kinase inhibitors. Healthy individuals and those with GIST show distinct patterns of transcription of functionally different NKp30 isoforms. In a retrospective analysis of 80 individuals with GIST, predominant expression of the immunosuppressive NKp30c isoform (over the immunostimulatory NKp30a and NKp30b isoforms) was associated with reduced survival of subjects, decreased NKp30-dependent tumor necrosis factor-α (TNF-α) and CD107a release, and defective interferon-γ (IFN-γ) and interleukin-12 (IL-12) secretion in the NK-DC cross-talk that could be restored by blocking of IL-10. Preferential NKp30c expression resulted partly from a single-nucleotide polymorphism at position 3790 in the 3' untranslated region of the gene encoding NKp30. The genetically determined NKp30 status predicts the clinical outcomes of individuals with GIST independently from KIT mutation.
Published: 2010
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38. Low numbers of blood and salivary natural killer cells are associated with a better response to belimumab in primary Sjögren’s syndrome: results of the BELISS study

Author: F. Desmoulins, Houria Hendel-Chavez, Thierry Lazure, Gaetane Nocturne, Philippe Ravaud, Vichnou Poirier-Colame, Raphaèle Seror, Xavier Mariette, Mohcine Benbijja, Yacine Taoufik, and Rakiba Belkhir
Subjects: Adult, T-Lymphocytes, Naive B cell, Immunology, Antibodies, Monoclonal, Humanized, Salivary Glands, Minor, Rheumatology, Interquartile range, B-Cell Activating Factor, Humans, Medicine, Immunology and Allergy, Lymphocyte Count, B-cell activating factor, B-Lymphocytes, biology, business.industry, Middle Aged, Flow Cytometry, medicine.disease, Belimumab, Sialadenitis, Killer Cells, Natural, Sjogren's Syndrome, Treatment Outcome, Monoclonal, biology.protein, Female, Antibody, business, Immunosuppressive Agents, Rheumatism, Research Article, medicine.drug
Abstract: Introduction In this study, we sought to address changes in blood lymphocyte subpopulations and labial salivary gland (LSG) inflammation after belimumab treatment in patients with primary Sjögren’s syndrome (pSS) and to identify predictors of response to treatment. Methods Sequential blood lymphocyte subsets and LSG biopsies were analysed between week 0 (W0) and W28 in 15 patients with pSS treated with belimumab. Systemic response to treatment was defined as a decrease in the European League Against Rheumatism Sjögren’s Syndrome Disease Activity Index score of ≥3 points at W28. Results After belimumab, we observed a decrease in blood B lymphocytes primarily involving CD27-negative/immunoglobulin D–positive naïve B cells (p=0.008). Lymphocytic sialadenitis (focus score >1) that was present in 12 patients (80.0 %) before belimumab treatment became negative in 5 of them after treatment (p=0.03). The median (interquartile range) LSG B-cell/T-cell ratio decreased from 0.58 (0.5–0.67) to 0.50 (0.5–0.5) (p=0.06). B-cell activating factor (BAFF) staining was detected in 11 (78.6 %) of 14 patients before belimumab treatment compared with 7 (50.0 %) of 14 after belimumab therapy (p=0.10). The median percentage of BAFF-positive cells in foci significantly decreased from 27.5 % (10–40) to 5 % (0–20) (p=0.03). A systemic response was achieved in six patients (40 %). The only predictor of response was the presence of a low number of natural killer (NK) cells, both in blood (8.5 % [7–10] vs 11 % [9–21]; p=0.04) and in LSG (20.6/mm3 [20.0–21.4] vs 30.0/mm3 [25.0–100.0], p=0.003). Serum BAFF levels did not influence response to treatment. Conclusions Low blood and salivary NK cell numbers are associated with a better response to belimumab. This suggests that two distinct subsets of pSS may exist: one with a predominant type I interferon (IFN)–BAFF–B-cell axis, representing good responders to belimumab; and one with a predominant type II IFN–NK cell axis, representing non-responders. Trial registration ClinicalTrials.gov identifier: NCT01160666. Registered 9 July 2010.
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39. Chemokine receptor patterns in lymphocytes mirror metastatic spreading in melanoma

Author: Marie Vétizou, Jianda Yuan, Caroline Flament, David Enot, Romain Daillère, Craig L. Slingluff, Phillip Wong, Andrea Cavalcanti, Stéphane Dalle, Alexander M.M. Eggermont, Anne Caignard, Laurence Zitvogel, Nadege Vimond, Benjamin Weide, Michaela Semeraro, Aurélien Marabelle, Sylvie Rusakiewicz, Federica Sallusto, Takahiro Yamazaki, Michele Maio, Holbrook E Kohrt, Anna Maria Di Giacomo, Carolin Blattner, Vichnou Poirier-Colame, Nicolas Jacquelot, Viktor Umansky, Maria Paula Roberti, Jedd D. Wolchok, Guido Kroemer, Jonathan M. Pitt, Institut Gustave Roussy (IGR), 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, Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Mannheim Medical Center, Universität Heidelberg [Heidelberg], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Virginia [Charlottesville], Università della Svizzera italiana = University of Italian Switzerland (USI), Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, 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), Apoptose, cancer et immunité (Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138), Institut Gustave Roussy (IGR)-Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie et Cancérologie Intégratives (CRC - Inserm U1138), Centre de Recherche des Cordeliers (CRC), Université Paris Descartes - Paris 5 (UPD5), Université Pierre et Marie Curie - Paris 6 (UPMC), 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), Università degli Studi di Siena = University of Siena (UNISI), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Universität Heidelberg [Heidelberg] = Heidelberg University, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Virginia, Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), HAL UPMC, Gestionnaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), 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 ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Centre d'Investigation Clinique en Biotherapie des cancers ( CIC 1428 , CBT 507 ), Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), German Cancer Research Center [Heidelberg] ( DKFZ ), Helmholtz-Gemeinschaft, Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Università della Svizzera italiana ( USI ), Eberhard Karls Universität Tübingen, Stanford University School of Medicine [Stanford], Stanford University [Stanford], Centre de Recherche en Cancérologie de Lyon ( 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 ), Apoptose, cancer et immunité ( Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138 ), Institut Gustave Roussy ( IGR ) -Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Immunologie et Cancérologie Intégratives ( CRC - Inserm U1138 ), Centre de Recherche des Cordeliers ( CRC ), Université Paris Descartes - Paris 5 ( UPD5 ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ), and Università degli Studi di Siena ( UNISI )
Subjects: 0301 basic medicine, Adult, Male, Chemokine, Lung Neoplasms, Skin Neoplasms, T cell, Receptor expression, T-Lymphocytes, Antineoplastic Agents, C-C chemokine receptor type 6, Kaplan-Meier Estimate, Biology, CXCR3, CXCR4, CXCR5, 03 medical and health sciences, 0302 clinical medicine, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Cell Line, Tumor, medicine, Biomarkers, Tumor, Animals, Humans, Melanoma, Proportional Hazards Models, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Antibodies, Monoclonal, General Medicine, Middle Aged, Ipilimumab, 3. Good health, Mice, Inbred C57BL, 030104 developmental biology, medicine.anatomical_structure, ROC Curve, 030220 oncology & carcinogenesis, Case-Control Studies, Lymphatic Metastasis, Immunology, Cancer research, biology.protein, Female, Receptors, Chemokine, CD8, Neoplasm Transplantation, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Research Article
Abstract: International audience; Melanoma prognosis is dictated by tumor-infiltrating lymphocytes, the migratory and functional behavior of which is guided by chemokine or cytokine gradients. Here, we retrospectively analyzed the expression patterns of 9 homing receptors (CCR/CXCR) in naive and memory CD4+ and CD8+ T lymphocytes in 57 patients with metastatic melanoma (MMel) with various sites of metastases to evaluate whether T cell CCR/CXCR expression correlates with intratumoral accumulation, metastatic progression, and/or overall survival (OS). Homing receptor expression on lymphocytes strongly correlated with MMel dissemination. Loss of CCR6 or CXCR3, but not cutaneous lymphocyte antigen (CLA), on circulating T cell subsets was associated with skin or lymph node metastases, loss of CXCR4, CXCR5, and CCR9 corresponded with lung involvement, and a rise in CCR10 or CD103 was associated with widespread dissemination. High frequencies of CD8+CCR9+ naive T cells correlated with prolonged OS, while neutralizing the CCR9/CCL25 axis in mice stimulated tumor progression. The expansion of CLA-expressing effector memory CD8+ T cells in response to a single administration of CTLA4 blockade predicted disease control at 3 months in 47 patients with MMel. Thus, specific CCR/CXCR expression patterns on circulating T lymphocytes may guide potential diagnostic and therapeutic approaches.
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40. NCR3/NKp30 contributes to pathogenesis in primary Sjogren's syndrome

Author: Caroline Flament, Lindsey A. Criswell, Kathy L. Sivils, Kariman Chaba, Roland Jonsson, Gaetane Nocturne, Marie Wahren-Herlenius, Maija-Leena Eloranta, Corinne Miceli-Richard, Helena Forsblad-d'Elia, Joanne Nititham, Roald Omdal, Sylvie Rusakiewicz, Michaela Semeraro, Jacques-Eric Gottenberg, Sophie Caillat-Zucman, Lars Rönnblom, Per Eriksson, Xavier Mariette, Eric Vivier, Thierry Lazure, Nicolas Delahaye, Laurence Zitvogel, Vichnou Poirier-Colame, Gunnel Nordmark, Christopher J. Lessard, Kimberly E. Taylor, Elke Theander, Damien Sène, 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), 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), Régulation de la réponse immune, infection VIH-1 et autoimmunité, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), CEA-Direction des Energies (ex-Direction de l'Energie Nucléaire) (CEA-DES (ex-DEN)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Inserm U986, 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), Immunologie et Cancérologie Intégratives (CRC - Inserm U1138), Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Medical Sciences, Department of Rheumatology (Dep Rheumato - Malmo - SUEDE), Skåne University Hospital, Swedish Defence Research Agency [Stockholm] (FOI), Rosalind Russell Medical Research Center for Arthritis, Howard Hughes Medical Institute (HHMI)-University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), University of Oklahoma Health Sciences Center (OUHSC), Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de rhumatologie, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Centre d'Investigation Clinique (CIC - Brest), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lymphocytes B, Autoimmunité et Immunothérapies (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), CHRU Brest - Service de Rhumatologie (CHU - BREST - Rhumato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), CEA-Direction de l'Energie Nucléaire (CEA-DEN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of California [San Francisco] (UCSF), University of California-University of California-Howard Hugues Medical Institute, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, Centre d'Investigation Clinique INSERM 1412 (CIC 1412 - BREST), Lymphocyte B et Auto-immunité (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Howard Hughes Medical Institute (HHMI)-University of California [San Francisco] (UCSF), University of California-University of California, Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Centre d'Investigation Clinique en Biotherapie des cancers ( CIC 1428 , CBT 507 ), Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), 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-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), CEA-Direction de l'Energie Nucléaire ( CEA-DEN ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Institut National de la Santé et de la Recherche Médicale, Centre d'Immunologie de Marseille - Luminy ( CIML ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Immunologie et Cancérologie Intégratives ( CRC - Inserm U1138 ), Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Department of Rheumatology ( Dep Rheumato - Malmo - SUEDE ), Swedish Defence Research Agency [Stockholm] ( FOI ), University of California [San Francisco] ( UCSF ) -Howard Hugues Medical Institute, University of Oklahoma Health Sciences Center ( OUHSC ), Université de Strasbourg ( UNISTRA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, Centre d'Investigation Clinique INSERM 1412 ( CIC 1412 - BREST ), Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Lymphocyte B et Auto-immunité ( LBAI ), Université de Brest ( UBO ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHRU Brest - Service de Rhumatologie ( CHU - BREST - Rhumato ), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), and Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-LabEX IGO Immunothérapie Grand Ouest-Institut Brestois Santé Agro Matière (IBSAM)
Subjects: MESH : Cell Line, Male, MESH : Polymorphism, Genetic, [SDV]Life Sciences [q-bio], MESH : Aged, MESH : Genotype, Medical and Health Sciences, Pathogenesis, MESH: Genotype, Interferon, MESH: Reverse Transcriptase Polymerase Chain Reaction, 2.1 Biological and endogenous factors, MESH : Female, Interferon gamma, Aetiology, Cells, Cultured, MESH: Aged, Cultured, MESH: Middle Aged, Reverse Transcriptase Polymerase Chain Reaction, MESH : Reverse Transcriptase Polymerase Chain Reaction, General Medicine, MESH : Adult, Middle Aged, Biological Sciences, Sjogren's Syndrome, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Female, MESH: Natural Cytotoxicity Triggering Receptor 3, medicine.drug, MESH: Cells, Cultured, Adult, MESH : Natural Cytotoxicity Triggering Receptor 3, Genotype, MESH: Interferon-gamma, MESH : Male, Cells, Biology, Autoimmune Disease, Article, Cell Line, [ SDV.MHEP.RSOA ] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Interferon-gamma, Rare Diseases, Genetic, Clinical Research, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, MESH : Cells, Cultured, MESH: Polymorphism, Genetic, Genetics, medicine, Humans, MESH : Middle Aged, Secretion, Polymorphism, MESH : Interferon-gamma, Aged, Autoimmune disease, Polymorphism, Genetic, Natural Cytotoxicity Triggering Receptor 3, MESH: Humans, [ SDV ] Life Sciences [q-bio], Inflammatory and immune system, MESH : Humans, MESH: Adult, medicine.disease, MESH: Male, Blockade, Lymphoma, MESH: Cell Line, MESH: Sjogren's Syndrome, Cell culture, Immunology, MESH : Sjogren's Syndrome, Digestive Diseases, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease characterized by a lymphocytic exocrinopathy. However, patients often have evidence of systemic autoimmunity, and they are at markedly increased risk for the development of non- Hodgkin's lymphoma. Similar to other autoimmune disorders, a strong interferon (IFN) signature is present among subsets of pSS patients, although the precise etiology remains uncertain. NCR3/NKp30 is a natural killer (NK)-specific activating receptor regulating the cross talk between NK and dendritic cells and type II IFN secretion. We performed a case-control study of genetic polymorphisms of the NCR3/NKp30 gene and found that rs11575837 (G>A) residing in the promoter was associated with reduced gene transcription and function as well as protection to pSS. We also demonstrated that circulating levels of NCR3/NKp30 were significantly increased among pSS patients compared with controls and correlated with higher NCR3/NKp30 but not CD16-dependent IFN-γ secretion by NK cells. Excess accumulation of NK cells in minor salivary glands correlated with the severity of the exocrinopathy. B7H6, the ligand of NKp30, was expressed by salivary epithelial cells. These findings suggest that NK cells may promote an NKp30-dependent inflammatory state in salivary glands and that blockade of the B7H6/NKp30 axis could be clinically relevant in pSS.

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