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32 results on '"Maha Ayyoub"'

1. Assessing the implications of sentinel lymph node removal in cervical cancer: an immunogenetic perspective – a SENTICOL ancillary study

Author: Alejandra Martinez, Gwenael Ferron, Fabrice Lécuru, Patrice Mathevet, Maha Ayyoub, Anne-Sophie Navarro, Arash Rafii, Anna Salvioni, Marie Michelas, Gaurav Thareja, Françoise Lauzeral-Vizcaino, Najeeb Halabi, Eliane Mery-Lamarche, Noemie Thebault, Clara-Maria Scarlata, and Jonathan Khalifa
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Background Cervical cancer’s lymphatic spread primarily begins from the sentinel lymph nodes (SLNs), underlining their pivotal role in disease metastasis. However, these nodes’ immune gene expression profiles and immunoregulation mechanisms have yet to be explored.Methods Our study aimed to elucidate the immune cell populations and their roles in the immune gene expression profile of negative SLNs compared with positive SLNs and non-SLNs using Nanostring RNA seq analysis. We performed a principal component analysis on the log2 normalized expression of 685 endogenous genes in the nCounter PanCancer Immune Profiling Panel, followed by an assessment of the differential expression of genes and immune cell type abundance.Results We found significant variations in gene expression among the groups, with negative SLNs displaying overexpression of genes related to tumor-infiltrating immune cells, specifically innate cell populations. They also demonstrated the upregulation of genes involved in antigen presentation and T-cell priming. In contrast, positive SLNs were enriched in regulatory networks, suggesting their potential role in immune evasion. A comparison of negative SLNs and non-SLNs revealed increased innate and adaptive immune cell types, underscoring the ongoing T cell response to tumor antigens.Conclusion Our findings underscore a specific immunogenetic phenotype profile in negative SLNs, emphasizing their crucial role in the initial anticancer response, immunosurveillance, and the propagation of immune tolerance from the primary cervical tumor. These results highlight the potential of SLNs as a novel target for immunotherapy strategies and underscore the importance of new imaging methods for accurately identifying SLN status without removal. Future investigations are needed to understand further the immunological interplay within SLNs and their influence on cervical cancer progression.
Published: 2024
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2. Immune changes in hilar tumor draining lymph nodes following node sparing neoadjuvant chemoradiotherapy of localized cN0 non-small cell lung cancer

Author: Jonathan Khalifa, Noémie Thébault, Clara-Maria Scarlata, Emma Norkowski, Carole Massabeau, Laurent Brouchet, Sophie Peries Bataille, Christelle Casaroli, Liza Vaz, Carine Valle, Emeline Sarot, Nathalie Saint-Laurent, Etienne Martin, Pierre-Benoît Pages, Alice Millière, Julien Mazières, Elizabeth Cohen-Jonathan Moyal, Françoise Lauzéral-Vizcaïno, and Maha Ayyoub
Subjects: radiotherapy, tumor draining lymph node (TDLN), immune changes, non small cell lung cancer (NSCLC), lymph nodes sparing irradiation, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: BackgroundWhile much progress has been accomplished in the understanding of radiation-induced immune effects in tumors, little is known regarding the mechanisms involved at the tumor draining lymph node (TDLN) level. The objective of this retrospective study was to assess the immune and biological changes arising in non-involved TDLNs upon node sparing concurrent chemoradiotherapy (CRT) of non-small cell lung cancer (NSCLC) tumors.MethodsPatients with proven localized (cN0M0) NSCLC, treated by radical surgery plus lymph node dissection with (CRT+) or without (CRT-) neoadjuvant chemoradiotherapy, whereby radiotherapy was targeted on the primary tumor with no significant incidental irradiation of the non-involved TDLN station (stations XI), were identified. Bulk RNA sequencing of TDLNs was performed and data were analyzed based on differential gene expression (DGE) and gene sets enrichment.ResultsSixteen patients were included and 25 TDLNs were analyzed: 6 patients in the CRT+ group (12 samples) and 10 patients in the CRT- group (13 samples). Overall, 1001 genes were differentially expressed between the two groups (CRT+ and CRT-). Analysis with g-profiler revealed that gene sets associated with antitumor immune response, inflammatory response, hypoxia, angiogenesis, epithelial mesenchymal transition and extra-cellular matrix remodeling were enriched in the CRT+ group, whereas only gene sets associated with B cells and B-cell receptor signaling were enriched in the CRT- group. Unsupervised dimensionality reduction identified two clusters of TDLNs from CRT+ patients, of which one cluster (cluster 1) exhibited higher expression of pathways identified as enriched in the overall CRT+ group in comparison to the CRT- group. In CRT+ cluster 1, 3 out of 3 patients had pathological complete response (pCR) or major pathological response (MPR) to neoadjuvant CRT, whereas only 1 out of 3 patients in the other CRT+ cluster (cluster 2) experienced MPR and none exhibited pCR.ConclusionNeoadjuvant node sparing concurrent CRT of NSCLC patients is associated with distinct microenvironment and immunological patterns in non-involved TDLNs as compared to non-involved TDLNs from patients with non-irradiated tumors. Our data are in line with studies showing superiority of lymph node sparing irradiation of the primary tumor in the induction of antitumor immunity.
Published: 2023
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3. Anti-TNF, a magic bullet in cancer immunotherapy?

Author: Anne Montfort, Carine Dufau, Céline Colacios, Nathalie Andrieu-Abadie, Thierry Levade, Thomas Filleron, Jean-Pierre Delord, Maha Ayyoub, Nicolas Meyer, and Bruno Ségui
Subjects: Tumor necrosis factor, Melanoma, Anti-PD-1, Anti-CTLA-4, Infliximab, Certolizumab, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Immune checkpoint blockers (ICB) have revolutionized cancer therapy. However, complete response is observed in a minority of patients and most patients develop immune-related adverse events (irAEs). These include colitis, which can be treated with anti-tumor necrosis factor (TNF) antibodies such as Infliximab. In a recent issue of the Journal for ImmunoTherapy of Cancer, Badran et al. reported that co-administering Infliximab together with ICB to five cancer patients prevents colitis recurrence, with four of them exhibiting overall disease stability. The basis for this treatment strategy stemmed from our pre-clinical demonstration that TNF contributes to resistance to anti-PD-1 therapy. In agreement with this concept, we have shown that TNF blockers improve the anti-tumor therapeutic activity of ICB in mice and based on these findings we are currently evaluating the combination in melanoma patients enrolled in the TICIMEL clinical trial. Herein, (i) we discuss the scientific rationale for combining anti-TNF and ICB in cancer patients, (ii) comment on the paper published by Badran et al. and (iii) provide the TICIMEL clinical trial design.
Published: 2019
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4. Radiotherapy in the Era of Immunotherapy With a Focus on Non-Small-Cell Lung Cancer: Time to Revisit Ancient Dogmas?

Author: Jonathan Khalifa, Julien Mazieres, Carlos Gomez-Roca, Maha Ayyoub, and Elizabeth Cohen-Jonathan Moyal
Subjects: radiotherapy, immunotherapy, immune check point inhibitors (ICI), abscopal effect, lymphopenia, non-small-cell lung cancer (NSCLC), Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Radiation-induced immune effects have been extensively deciphered over the last few years, leading to the concept of the dual immune effect of radiotherapy with both immunostimulatory and immunosuppressive effects. This explains why radiotherapy alone is not able to drive a strong anti-tumor immune response in most cases, hence underlining the rationale for combining both radiotherapy and immunotherapy. This association has generated considerable interest and hundreds of trials are currently ongoing to assess such an association in oncology. However, while some trials have provided unprecedented results or shown much promise, many hopes have been dashed. Questions remain, therefore, as to how to optimize the combination of these treatment modalities. This narrative review aims at revisiting the old, well-established concepts of radiotherapy relating to dose, fractionation, target volumes and organs at risk in the era of immunotherapy. We then propose potential innovative approaches to be further assessed when considering a radio-immunotherapy association, especially in the field of non-small-cell lung cancer (NSCLC). We finally propose a framework to optimize the association, with pragmatic approaches depending on the stage of the disease.
Published: 2021
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5. PD-1 blockade restores helper activity of tumor-infiltrating, exhausted PD-1hiCD39+ CD4 T cells

Author: Camille-Charlotte Balança, Anna Salvioni, Clara-Maria Scarlata, Marie Michelas, Carlos Martinez-Gomez, Carlos Gomez-Roca, Victor Sarradin, Marie Tosolini, Carine Valle, Frédéric Pont, Gwénaël Ferron, Laurence Gladieff, Sébastien Vergez, Agnès Dupret-Bories, Eliane Mery, Philippe Rochaix, Jean-Jacques Fournié, Jean-Pierre Delord, Christel Devaud, Alejandra Martinez, and Maha Ayyoub
Subjects: Immunology, Medicine
Abstract: Tumor antigen–specific CD4 T cells accumulate at tumor sites, evoking their involvement in antitumor effector functions in situ. Contrary to CD8 cytotoxic T lymphocyte exhaustion, that of CD4 T cells remains poorly appreciated. Here, using phenotypic, transcriptomic, and functional approaches, we characterized CD4 T cell exhaustion in patients with head and neck, cervical, and ovarian cancer. We identified a CD4 tumor-infiltrating lymphocyte (TIL) population, defined by high PD-1 and CD39 expression, which contained high proportions of cytokine-producing cells, although the quantity of cytokines produced by these cells was low, evoking an exhausted state. Terminal exhaustion of CD4 TILs was instated regardless of TIM-3 expression, suggesting divergence with CD8 T cell exhaustion. scRNA-Seq and further phenotypic analyses uncovered similarities with the CD8 T cell exhaustion program. In particular, PD-1hiCD39+ CD4 TILs expressed the exhaustion transcription factor TOX and the chemokine CXCL13 and were tumor antigen specific. In vitro, PD-1 blockade enhanced CD4 TIL activation, as evidenced by increased CD154 expression and cytokine secretion, leading to improved dendritic cell maturation and consequently higher tumor-specific CD8 T cell proliferation. Our data identify exhausted CD4 TILs as players in responsiveness to immune checkpoint blockade.
Published: 2021
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6. Phased differentiation of γδ T and T CD8 tumor-infiltrating lymphocytes revealed by single-cell transcriptomics of human cancers

Author: Juan-Pablo Cerapio, Marion Perrier, Camille-Charlotte Balança, Pauline Gravelle, Fréderic Pont, Christel Devaud, Don-Marc Franchini, Virginie Féliu, Marie Tosolini, Carine Valle, Fréderic Lopez, Anne Quillet-Mary, Loic Ysebaert, Alejandra Martinez, Jean Pierre Delord, Maha Ayyoub, Camille Laurent, and Jean-Jacques Fournie
Subjects: gamma-delta lymphocyte, scrnaseq, differentiation, Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: γδ T lymphocytes diverge from conventional T CD8 lymphocytes for ontogeny, homing, and antigen specificity, but whether their differentiation in tumors also deviates was unknown. Using innovative analyses of our original and ~150 published single-cell RNA sequencing datasets validated by phenotyping of human tumors and murine models, here we present the first high-resolution view of human γδ T cell differentiation in cancer. While γδ T lymphocytes prominently encompass TCRVγ9 cells more differentiated than T CD8 in healthy donor’s blood, a different scenario is unveiled in tumors. Solid tumors and lymphomas are infiltrated by a majority of TCRVγnon9 γδ T cells which are quantitatively correlated and remarkably aligned with T CD8 for differentiation, exhaustion, gene expression profile, and response to immune checkpoint therapy. This cancer-wide association is critical for developing cancer immunotherapies.
Published: 2021
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7. Circulating CD14high CD16low intermediate blood monocytes as a biomarker of ascites immune status and ovarian cancer progression

Author: Hélène Authier, Agnès Coste, Alejandra Martinez, Gwenael Ferron, Laurence Gladieff, Mélissa Prat, Augustin Le Naour, Kimberley Coulson, Fanny Lemée, Hélène Leray, Godefroy Jacquemin, Mouna Chirine Rahabi, Léa Lemaitre, Jean-Marc Barret, Maha Ayyoub, Jean-Pierre Delord, Isabelle Tabah-Fisch, Jean-François Prost, and Bettina Couderc
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Background Besides the interest of an early detection of ovarian cancer, there is an urgent need for new predictive and prognostic biomarkers of tumor development and cancer treatment. In healthy patients, circulating blood monocytes are typically subdivided into classical (85%), intermediate (5%) and non-classical (10%) populations. Although these circulating monocyte subsets have been suggested as biomarkers in several diseases, few studies have investigate their potential as a predictive signature for tumor immune status,tumor growth and treatment adaptation.Methods In this study, we used a homogeneous cohort of 28 chemotherapy-naïve patients with ovarian cancer to evaluate monocyte subsets as biomarkers of the ascites immunological status. We evaluated the correlations between circulating monocyte subsets and immune cells and tumor burden in peritoneal ascites. Moreover, to validate the use of circulating monocyte subsets tofollow tumor progression and treatment response, we characterized blood monocytes from ovarian cancer patients included in a phase 1 clinical trial at baseline and following murlentamab treatment.Results We demonstrate here a robust expansion of the intermediate blood monocytes (IBMs) in ovarian cancer patients. We establish a significant positive correlation between IBM percentage and tumor–associate macrophages with a CCR2high/CD163high/CD206high/CD86lowprofile. Moreover, IBM expansion is associated with a decreased effector/regulatory T-cell ratio in ascites and with the presence of soluble immunosuppressive mediators. We also establish that IBM proportion positively correlates with the peritoneum tumor burden. Finally, the study of IBMs in patients with ovarian cancer under immunotherapy during the phase clinical trial supports IBMs to follow the evolution of tumor development and the treatment adaptation.Conclusions This study, which links IBM level with immunosuppression and tumor burden in peritoneum, identifies IBMs as apotential predictive signature of ascites immune status and as a biomarker ofovarian cancer development and treatment response.Trial registration number EudraCT: 2015-004252-22 NCT02978755.
Published: 2020
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8. Colon-specific immune microenvironment regulates cancer progression versus rejection

Author: Giulia Trimaglio, Anne-Françoise Tilkin-Mariamé, Virginie Feliu, Françoise Lauzéral-Vizcaino, Marie Tosolini, Carine Valle, Maha Ayyoub, Olivier Neyrolles, Nathalie Vergnolle, Yoann Rombouts, and Christel Devaud
Subjects: colorectal cancer, immune response polarization, orthotopic model, Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Immunotherapies have achieved clinical benefit in many types of cancer but remain limited to a subset of patients in colorectal cancer (CRC). Resistance to immunotherapy can be attributed in part to tissue-specific factors constraining antitumor immunity. Thus, a better understanding of how the colon microenvironment shapes the immune response to CRC is needed to identify mechanisms of resistance to immunotherapies and guide the development of novel therapeutics. In an orthotopic mouse model of MC38-CRC, tumor progression was monitored by bioluminescence imaging and the immune signatures were assessed at a transcriptional level using NanoString and at a cellular level by flow cytometry. Despite initial tumor growth in all mice, only 25% to 35% of mice developed a progressive lethal CRC while the remaining animals spontaneously rejected their solid tumor. No tumor rejection was observed in the absence of adaptive immunity, nor when MC38 cells were injected in non-orthotopic locations, subcutaneously or into the liver. We observed that progressive CRC tumors exhibited a protumor immune response, characterized by a regulatory T-lymphocyte pattern, discernible shortly post-tumor implantation, as well as suppressive myeloid cells. In contrast, tumor-rejecting mice presented an early inflammatory response and an antitumor microenvironment enriched in CD8+ T cells. Taken together, our data demonstrate the role of the colon microenvironment in regulating the balance between anti or protumor immune responses. While emphasizing the relevance of the CRC orthotopic model, they set the basis for exploring the impact of the identified signatures in colon cancer response to immunotherapy.
Published: 2020
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9. Modulation of Cytokine Secretion Allows CD4 T Cells Secreting IL-10 and IL-17 to Simultaneously Participate in Maintaining Tolerance and Immunity.

Author: Kanako Saito, Pascale Pignon, Maha Ayyoub, and Danila Valmori
Subjects: Medicine, Science
Abstract: CD4 T cells secreting IL-10 or IL-17 are frequent at mucosal sites, where their equilibrium is important for simultaneously maintaining tolerance and immunity to the resident microbiota. The mode of action of these cells, however, is as yet incompletely understood. In this study, we have combined ex vivo analysis of CD4 T cells producing IL-10 or/and IL-17 with assessment of clonal populations isolated ex vivo using a cytokine catch assay. We found that circulating CD4 T cells secreting IL-10 or/and IL-17 ex vivo include both conventional FOXP3- CD4 T cells and FOXP3+ Helios- Treg. Upon assessment of clonal populations derived from single ex vivo isolated cytokine secreting cells, we found that IL-10 or/and IL-17 secreting cells prevalently secrete one or the other cytokine depending on the type of stimulation, the time after stimulation and the presence of microbial products. Namely, IL-10 secretion by clonal cells was prevalent at early time points after TCR mediated stimulation, was independent of co-stimulation and was increased in the presence of the microbial fermentation product butyrate. In contrast, IL-17 secretion was higher at later time points after TCR mediated stimulation and in the presence of co-stimulatory signals. Taken together, these results provide insights into the mechanisms that, through modulation of cytokine secretion depending on conditions, allow IL-10 and IL-17 producing CD4 T cells to contribute to maintain tolerance to microbes locally, while retaining the ability to participate in protective immune responses at distant sites.
Published: 2015
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10. MHC class II/ESO tetramer-based generation of in vitro primed anti-tumor T-helper lines for adoptive cell therapy of cancer

Author: Caroline Poli, Caroline Raffin, Danijel Dojcinovic, Immanuel Luescher, Maha Ayyoub, and Danila Valmori
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Abstract: Generation of tumor-antigen specific CD4+ T-helper (TH) lines through in vitro priming is of interest for adoptive cell therapy of cancer, but the development of this approach has been limited by the lack of appropriate tools to identify and isolate low frequency tumor antigen-specific CD4+ T cells. Here, we have used recently developed MHC class II/peptide tetramers incorporating an immunodominant peptide from NY-ESO-1 (ESO), a tumor antigen frequently expressed in different human solid and hematologic cancers, to implement an in vitro priming platform allowing the generation of ESO-specific TH lines. We isolated phenotypically defined CD4+ T-cell subpopulations from circulating lymphocytes of DR52b+ healthy donors by flow cytometry cell sorting and stimulated them in vitro with peptide ESO119-143, autologous APC and IL-2. We assessed the frequency of ESO-specific cells in the cultures by staining with DR52b/ESO119-143 tetramers (ESO-tetramers) and TCR repertoire of ESO-tetramer+ cells by co-staining with TCR variable β chain (BV) specific antibodies. We isolated ESO-tetramer+ cells by flow cytometry cell sorting and expanded them with PHA, APC and IL-2 to generate ESO-specific TH lines. We characterized the lines for antigen recognition, by stimulation with ESO peptide or recombinant protein, cytokine production, by intracellular staining using specific antibodies, and alloreactivity, by stimulation with allo-APC. Using this approach, we could consistently generate ESO-tetramer+ TH lines from conventional CD4+CD25− naïve and central memory populations, but not from effector memory populations or CD4+CD25+ Treg. In vitro primed TH lines recognized ESO with affinities comparable to ESO-tetramer+ cells from patients immunized with an ESO vaccine and used a similar TCR repertoire. In this study, using MHC class II/ESO tetramers, we have implemented an in vitro priming platform allowing the generation of ESO-monospecific polyclonal TH lines from non-immune individuals. This is an approach that is of potential interest for adoptive cell therapy of patients bearing ESO-expressing cancers.
Published: 2013
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11. NY-ESO-1-specific circulating CD4+ T cells in ovarian cancer patients are prevalently T(H)1 type cells undetectable in the CD25+ FOXP3+ Treg compartment.

Author: Nassima Redjimi, Karine Duperrier-Amouriaux, Isabelle Raimbaud, Immanuel Luescher, Danijel Dojcinovic, Jean-Marc Classe, Dominique Berton-Rigaud, Jean-Sébastien Frenel, Emmanuelle Bourbouloux, Danila Valmori, and Maha Ayyoub
Subjects: Medicine, Science
Abstract: Spontaneous CD4(+) T-cell responses to the tumor-specific antigen NY-ESO-1 (ESO) are frequently found in patients with epithelial ovarian cancer (EOC). If these responses are of effector or/and Treg type, however, has remained unclear. Here, we have used functional approaches together with recently developed MHC class II/ESO tetramers to assess the frequency, phenotype and function of ESO-specific cells in circulating lymphocytes from EOC patients. We found that circulating ESO-specific CD4(+) T cells in EOC patients with spontaneous immune responses to the antigen are prevalently T(H)1 type cells secreting IFN-γ but no IL-17 or IL-10 and are not suppressive. We detected tetramer(+) cells ex vivo, at an average frequency of 1:25,000 memory cells, that is, significantly lower than in patients immunized with an ESO vaccine. ESO tetramer(+) cells were mostly effector memory cells at advanced stages of differentiation and were not detected in circulating CD25(+)FOXP3(+)Treg. Thus, spontaneous CD4(+) T-cell responses to ESO in cancer patients are prevalently of T(H)1 type and not Treg. Their relatively low frequency and advanced differentiation stage, however, may limit their efficacy, that may be boosted by immunogenic ESO vaccines.
Published: 2011
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12. Antibody responses to NY-ESO-1 in primary breast cancer identify a subtype target for immunotherapy.

Author: Ahmed Hamaï, Karine Duperrier-Amouriaux, Pascale Pignon, Isabelle Raimbaud, Lorenzo Memeo, Cristina Colarossi, Vincenzo Canzonieri, Tiziana Perin, Jean-Marc Classe, Mario Campone, Pascal Jézéquel, Loïc Campion, Maha Ayyoub, and Danila Valmori
Subjects: Medicine, Science
Abstract: The highly immunogenic human tumor antigen NY-ESO-1 (ESO) is a target of choice for anti-cancer immune therapy. In this study, we assessed spontaneous antibody (Ab) responses to ESO in a large cohort of patients with primary breast cancer (BC) and addressed the correlation between the presence of anti-ESO Ab, the expression of ESO in the tumors and their characteristics. We found detectable Ab responses to ESO in 1% of the patients. Tumors from patients with circulating Ab to ESO exhibited common characteristics, being mainly hormone receptor (HR)⁻ invasive ductal carcinomas of high grade, including both HER2⁻ and HER2⁺ tumors. In line with these results, we detected ESO expression in 20% of primary HR⁻ BC, including both ESO Ab⁺ and Ab⁻ patients, but not in HR⁺ BC. Interestingly, whereas expression levels in ESO⁺ BC were not significantly different between ESO Ab⁺ and Ab⁻ patients, the former had, in average, significantly higher numbers of tumor-infiltrated lymph nodes, indicating that lymph node invasion may be required for the development of spontaneous anti-tumor immune responses. Thus, the presence of ESO Ab identifies a tumor subtype of HR⁻ (HER2⁻ or HER2⁺) primary BC with frequent ESO expression and, together with the assessment of antigen expression in the tumor, may be instrumental for the selection of patients for whom ESO-based immunotherapy may complement standard therapy.
Published: 2011
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13. Using modified antigenic sequences to develop cancer vaccines: are we losing the focus?

Author: Danila Valmori and Maha Ayyoub
Subjects: Medicine
Published: 2004
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14. PD-1 blockade restores helper activity of tumor-infiltrating, exhausted PD-1hiCD39+ CD4 T cells

Author: Victor Sarradin, Carine Valle, Frédéric Pont, Sébastien Vergez, Philippe Rochaix, Marie Michelas, Carlos Martínez-Gómez, Camille-Charlotte Balança, Marie Tosolini, Laurence Gladieff, Carlos Gomez-Roca, Jean-Pierre Delord, Christel Devaud, Agnès Dupret-Bories, Alejandra Martinez, Clara-Maria Scarlata, Gwenael Ferron, Eliane Mery, Anna Salvioni, Maha Ayyoub, Jean-Jacques Fournié, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Fédérale Toulouse Midi-Pyrénées, Fournié, jean-jacques, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse], CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, 0301 basic medicine, Lymphocyte, [SDV]Life Sciences [q-bio], Lymphocyte Cooperation, Programmed Cell Death 1 Receptor, Immunology, T cells, Gene Expression, Uterine Cervical Neoplasms, Cancer immunotherapy, CD8-Positive T-Lymphocytes, In Vitro Techniques, Biology, Lymphocyte Activation, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, 0302 clinical medicine, Antigens, Neoplasm, Immune Tolerance, medicine, Humans, Cytotoxic T cell, RNA, Messenger, CD154, Ovarian Neoplasms, Immunity, Cellular, Apyrase, T-Lymphocytes, Helper-Inducer, General Medicine, Dendritic cell, Immune checkpoint, Tumor antigen, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, Cancer research, Medicine, Female, Tumor Escape, Cytokine secretion, CD8, Research Article
Abstract: International audience; Tumor antigen-specific CD4 T cells accumulate at tumor sites, evoking their involvement in antitumor effector functions in situ. Contrary to CD8 cytotoxic T lymphocyte exhaustion, that of CD4 T cells remains poorly appreciated. Here, using phenotypic, transcriptomic, and functional approaches, we characterized CD4 T cell exhaustion in patients with head and neck, cervical, and ovarian cancer. We identified a CD4 tumor-infiltrating lymphocyte (TIL) population, defined by high PD-1 and CD39 expression, which contained high proportions of cytokine-producing cells, although the quantity of cytokines produced by these cells was low, evoking an exhausted state. Terminal exhaustion of CD4 TILs was instated regardless of TIM-3 expression, suggesting divergence with CD8 T cell exhaustion. scRNA-Seq and further phenotypic analyses uncovered similarities with the CD8 T cell exhaustion program. In particular, PD-1hiCD39+ CD4 TILs expressed the exhaustion transcription factor TOX and the chemokine CXCL13 and were tumor antigen specific. In vitro, PD-1 blockade enhanced CD4 TIL activation, as evidenced by increased CD154 expression and cytokine secretion, leading to improved dendritic cell maturation and consequently higher tumor-specific CD8 T cell proliferation. Our data identify exhausted CD4 TILs as players in responsiveness to immune checkpoint blockade.
Published: 2021
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15. Phased differentiation of γδ T and T CD8 tumorinfiltrating lymphocytes revealed by single-cell transcriptomics of human cancers

Author: Pauline Gravelle, Marie Tosolini, Juan-Pablo Cerapio, Frédéric Pont, Maha Ayyoub, Camille Laurent, Virginie Féliu, Carine Valle, Anne Quillet-Mary, Alejandra Martinez, Loic Ysebaert, Camille-Charlotte Balança, Christel Devaud, Jean-Jacques Fournié, Don-Marc Franchini, Frédéric Lopez, Marion Perrier, Jean Pierre Delord, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d’Excellence ‘TOUCAN’ [Toulouse], Institut Carnot CALYM [Pierre-Benite], CHU Toulouse [Toulouse], Institut Claudius Regaud, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), QUILLET-MARY, Anne, Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie [IUCT Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Carnot Lymphome (CALYM), and Fournié, jean-jacques
Subjects: [SDV.IMM] Life Sciences [q-bio]/Immunology, Ontogeny, Single cell transcriptomics, [SDV]Life Sciences [q-bio], Immunology, Antigen specificity, [SDV.CAN]Life Sciences [q-bio]/Cancer, CD8-Positive T-Lymphocytes, Biology, Mice, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, T-Lymphocyte Subsets, Neoplasms, Animals, Humans, Immunology and Allergy, RC254-282, ComputingMilieux_MISCELLANEOUS, Gamma-delta lymphocyte, Original Research, 030304 developmental biology, 0303 health sciences, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Tumor-infiltrating lymphocytes, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Cell Differentiation, Receptors, Antigen, T-Cell, gamma-delta, scRNAseq, differentiation, RC581-607, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, [SDV] Life Sciences [q-bio], Oncology, 030220 oncology & carcinogenesis, Cancer research, [SDV.IMM]Life Sciences [q-bio]/Immunology, Immunologic diseases. Allergy, Transcriptome, CD8, CD8/Lymphocytes, Research Article, Homing (hematopoietic)
Abstract: International audience; γδ T lymphocytes diverge from conventional T CD8 lymphocytes for ontogeny, homing, and antigen specificity, but whether their differentiation in tumors also deviates was unknown. Using innovative analyses of our original and ~150 published single-cell RNA sequencing datasets validated by phenotyping of human tumors and murine models, here we present the first high-resolution view of human γδ T cell differentiation in cancer. While γδ T lymphocytes prominently encompass TCRVγ9 cells more differentiated than T CD8 in healthy donor's blood, a different scenario is unveiled in tumors. Solid tumors and lymphomas are infiltrated by a majority of TCRVγnon9 γδ T cells which are quantitatively correlated and remarkably aligned with T CD8 for differentiation, exhaustion, gene expression profile, and response to immune checkpoint therapy. This cancer-wide association is critical for developing cancer immunotherapies.
Published: 2021
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16. Eomes-Dependent Loss of the Co-activating Receptor CD226 Restrains CD8+ T Cell Anti-tumor Functions and Limits the Efficacy of Cancer Immunotherapy

Author: Stanislas Goriely, Marie-Véronique Joubert, Tobias Bald, Mark J. Smyth, Ludovic Martinet, Elena Morandi, Loïc Dupré, Laure Buisson, Nadège Carrié, Marianne Weulersse, Guillaume Gaud, Marie Le Moine, Thomas Gossye, Anne Dejean, Hervé Avet-Loiseau, Ashmitha Sundarrajan, Assia Asrir, Andrea C. Pichler, Michaël Pérès, Abdelhadi Saoudi, Alejandra Martinez, Julien Mazieres, Sahar Kassem, Elisa Brauns, Els Verhoeyen, Indrajit Das, Sabrina Maheo, Matthias Braun, Vera Pancaldi, Clara Maria Scarlata, Marine Cuisinier, Maha Ayyoub, Laura Do Souto, Lea Lemaitre, Arantxa Agesta, Camille Guillerey, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), QIMR Berghofer Medical Research Institute, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université libre de Bruxelles (ULB), Centre de Physiopathologie Toulouse Purpan (CPTP), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD), Barcelona Supercomputing Center - Centro Nacional de Supercomputacion (BSC - CNS), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (1965 - 2019) (UNS), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP)
Subjects: 0301 basic medicine, MESH: Neoplasms / immunology, 8 Supplementary Figures, Lymphocyte, medicine.medical_treatment, [SDV]Life Sciences [q-bio], MESH: Programmed Cell Death 1 Receptor / immunology, CD226 (DNAM-1), MESH: Receptors, Antigen, T-Cell / immunology, MESH: Neoplasms / therapy, TCR signaling, 0302 clinical medicine, Cancer immunotherapy, MESH: Tumor Necrosis Factor Receptor Superfamily, Member 9 / immunology, Immunology and Allergy, Cytotoxic T cell, MESH: Animals, ComputingMilieux_MISCELLANEOUS, T cell exhaustion, MESH: Signal Transduction / immunology, MESH: CD8-Positive T-Lymphocytes / immunology, 3. Good health, Infectious Diseases, medicine.anatomical_structure, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, 030220 oncology & carcinogenesis, Immunotherapy, MESH: Transcriptome / immunology, Immunology, Eomesodermin, 8 Figures, Biology, MESH: Antigens, Differentiation, T-Lymphocyte / immunology, Co-stimulation, 03 medical and health sciences, tumor immune escape, MESH: Mice, Inbred C57BL, MESH: Immune Checkpoint Inhibitors / immunology, medicine, MESH: Tumor Microenvironment / immunology, MESH: Mice, 96 References CD8 + T lymphocytes, Tumor microenvironment, MESH: Humans, immune checkpoint blockade, MESH: T-Box Domain Proteins / immunology, Immune checkpoint, MESH: Immunotherapy / methods, Sciences biomédicales, 030104 developmental biology, Cancer research, CD8
Abstract: Through complementary approaches, involving cancer patients’ samples and relevant mouse tumor models, Weulersse et al. reveal that CD8 T cells in the tumor microenvironment lose expression of the activating receptor CD226 (DNAM-1) in a manner that is Eomes dependent. CD226 loss restrains CD8 T cell function and limits the efficacy of cancer immunotherapy.CD8 T cells within the tumor microenvironment (TME) are exposed to various signals that ultimately determine functional outcomes. Here, we examined the role of the co-activating receptor CD226 (DNAM-1) in CD8 T cell function. The absence of CD226 expression identified a subset of dysfunctional CD8 T cells present in peripheral blood of healthy individuals. These cells exhibited reduced LFA-1 activation, altered TCR signaling, and a distinct transcriptomic program upon stimulation. CD226 CD8 T cells accumulated in human and mouse tumors of diverse origin through an antigen-specific mechanism involving the transcriptional regulator Eomesodermin (Eomes). Despite similar expression of co-inhibitory receptors, CD8 tumor-infiltrating lymphocyte failed to respond to anti-PD-1 in the absence of CD226. Immune checkpoint blockade efficacy was hampered in Cd226 mice. Anti-CD137 (4-1BB) agonists also stimulated Eomes-dependent CD226 loss that limited the anti-tumor efficacy of this treatment. Thus, CD226 loss restrains CD8 T cell function and limits the efficacy of cancer immunotherapy.
Published: 2020
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17. Cross-reactivity between tumor MHC class I-restricted antigens and an enterococcal bacteriophage

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

Author: Alejandra Martinez, Camille-Charlotte Balança, Jean-Jacques Fournié, Carlos Martinez Gomez, Laurence Gladieff, Philippe Rochaix, Jérôme Sarini, Maha Ayyoub, Carlos Gomez-Roca, Carine Valle, Agnès Dupret-Bories, Christel Devaud, Victor Sarradin, Benjamin Vairel, Virginie Feliu, Aurore Siegfried-Vergnon, Jean-Pierre Delord, Camille Franchet, Yann Tanguy Le Gac, Lucile Mir-Mesnier, Diana Heaugwane, Clara-Maria Scarlata, Frédéric Pont, Stéphanie Motton, Marie Michelas, Eliane Mery, Françoise Lauzeral-Vizcaino, Sébastien Vergez, Marie Tosolini, Claire Illac, Gwenael Ferron, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse], Université Fédérale Toulouse Midi-Pyrénées, Centre National de la Recherche Scientifique - CNRS (FRANCE), Institut National de la Santé et de la Recherche Médicale - INSERM (FRANCE), Université Toulouse III - Paul Sabatier - UT3 (FRANCE), Institut Claudius Regaud - ICR (FRANCE), Centre Hospitalier Universitaire de Toulouse - CHU Toulouse (FRANCE), Institut Universitaire du Cancer de Toulouse - Oncopole - IUCT (Toulouse, France), (OATAO), Open Archive Toulouse Archive Ouverte, and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Cancer Research, [SDV]Life Sciences [q-bio], Immunology, Population, Programmed Cell Death 1 Receptor, [SDV.CAN]Life Sciences [q-bio]/Cancer, CD8-Positive T-Lymphocytes, Lymphocyte Activation, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, 03 medical and health sciences, Mice, 0302 clinical medicine, Immune system, Antineoplastic Agents, Immunological, CD28 Antigens, [SDV.CAN] Life Sciences [q-bio]/Cancer, Bystander effect, Medicine, Animals, Humans, Neoplasms, Glandular and Epithelial, education, Receptor, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, Cell Proliferation, Cancer, education.field_of_study, Lymphocytes T, business.industry, CD28, Immune checkpoint, 3. Good health, Blockade, Mice, Inbred C57BL, Survival Rate, 030104 developmental biology, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, 030220 oncology & carcinogenesis, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, Cancer research, Female, Single-Cell Analysis, business, Transcriptome, CD8
Abstract: Although understanding of T-cell exhaustion is widely based on mouse models, its analysis in patients with cancer could provide clues indicating tumor sensitivity to immune checkpoint blockade (ICB). Data suggest a role for costimulatory pathways, particularly CD28, in exhausted T-cell responsiveness to PD-1/PD-L1 blockade. Here, we used single-cell transcriptomic, phenotypic, and functional approaches to dissect the relation between CD8+ T-cell exhaustion, CD28 costimulation, and tumor specificity in head and neck, cervical, and ovarian cancers. We found that memory tumor–specific CD8+ T cells, but not bystander cells, sequentially express immune checkpoints once they infiltrate tumors, leading, in situ, to a functionally exhausted population. Exhausted T cells were nonetheless endowed with effector and tumor residency potential but exhibited loss of the costimulatory receptor CD28 in comparison with their circulating memory counterparts. Accordingly, PD-1 inhibition improved proliferation of circulating tumor–specific CD8+ T cells and reversed functional exhaustion of specific T cells at tumor sites. In agreement with their tumor specificity, high infiltration of tumors by exhausted cells was predictive of response to therapy and survival in ICB-treated patients with head and neck cancer. Our results showed that PD-1 blockade–mediated proliferation/reinvigoration of circulating memory T cells and local reversion of exhaustion occur concurrently to control tumors.
Published: 2020
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19. Circulating CD14high CD16low intermediate blood monocytes as a biomarker of ascites immune status and ovarian cancer progression

Author: Godefroy Jacquemin, Bettina Couderc, Augustin Le Naour, Gwenael Ferron, Kimberley Coulson, Jean-Marc Barret, Hélène Leray, Hélène Authier, Maha Ayyoub, Jean-Pierre Delord, Lea Lemaitre, Isabelle Tabah-Fisch, Jean-François Prost, Mouna Rahabi, Alejandra Martinez, Agnès Coste, Mélissa Prat, Fanny Lemée, and Laurence Gladieff
Subjects: Oncology, Male, Cancer Research, medicine.medical_specialty, medicine.medical_treatment, Immunology, Short Report, Lipopolysaccharide Receptors, Monocytes, Immune system, biomarkers, tumor, Internal medicine, Ascites, medicine, Tumor Microenvironment, Immunology and Allergy, Humans, RC254-282, Pharmacology, Tumor microenvironment, business.industry, Receptors, IgG, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Immunosuppression, Immunotherapy, medicine.disease, immunity, macrophages, Tumor progression, Disease Progression, Molecular Medicine, Biomarker (medicine), Female, medicine.symptom, business, Ovarian cancer
Abstract: BackgroundBesides the interest of an early detection of ovarian cancer, there is an urgent need for new predictive and prognostic biomarkers of tumor development and cancer treatment. In healthy patients, circulating blood monocytes are typically subdivided into classical (85%), intermediate (5%) and non-classical (10%) populations. Although these circulating monocyte subsets have been suggested as biomarkers in several diseases, few studies have investigate their potential as a predictive signature for tumor immune status,tumor growth and treatment adaptation.MethodsIn this study, we used a homogeneous cohort of 28 chemotherapy-naïve patients with ovarian cancer to evaluate monocyte subsets as biomarkers of the ascites immunological status. We evaluated the correlations between circulating monocyte subsets and immune cells and tumor burden in peritoneal ascites. Moreover, to validate the use of circulating monocyte subsets tofollow tumor progression and treatment response, we characterized blood monocytes from ovarian cancer patients included in a phase 1 clinical trial at baseline and following murlentamab treatment.ResultsWe demonstrate here a robust expansion of the intermediate blood monocytes (IBMs) in ovarian cancer patients. We establish a significant positive correlation between IBM percentage and tumor–associate macrophages with a CCR2high/CD163high/CD206high/CD86lowprofile. Moreover, IBM expansion is associated with a decreased effector/regulatory T-cell ratio in ascites and with the presence of soluble immunosuppressive mediators. We also establish that IBM proportion positively correlates with the peritoneum tumor burden. Finally, the study of IBMs in patients with ovarian cancer under immunotherapy during the phase clinical trial supports IBMs to follow the evolution of tumor development and the treatment adaptation.ConclusionsThis study, which links IBM level with immunosuppression and tumor burden in peritoneum, identifies IBMs as apotential predictive signature of ascites immune status and as a biomarker ofovarian cancer development and treatment response.Trial registration numberEudraCT: 2015-004252-22NCT02978755.
Published: 2020

20. Colon-specific immune microenvironment regulates cancer progression versus rejection

Author: Françoise Lauzeral-Vizcaino, Marie Tosolini, Giulia Trimaglio, Christel Devaud, Olivier Neyrolles, Anne-Françoise Tilkin-Mariamé, Virginie Feliu, Yoann Rombouts, Maha Ayyoub, Carine Valle, Nathalie Vergnolle, Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut de Recherche en Santé Digestive (IRSD ), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées, Association Entente Cordiale Gaillacoise, H2020 Marie Skłodowska-Curie Actions (European Training Network, 'GlyCoCan' project, grant number 676421), Region Occitanie Pyrénées-Méditerranée, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Rombouts, Yoann
Subjects: [SDV.IMM] Life Sciences [q-bio]/Immunology, Colorectal cancer, immune response polarization, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, CD8-Positive T-Lymphocytes, Mice, 03 medical and health sciences, 0302 clinical medicine, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, MESH: orthotopic model, Tumor Microenvironment, medicine, Animals, Humans, Bioluminescence imaging, RC254-282, Original Research, 030304 developmental biology, 0303 health sciences, orthotopic model, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Cancer, Immunotherapy, RC581-607, medicine.disease, Acquired immune system, 3. Good health, Tumor progression, 030220 oncology & carcinogenesis, Colonic Neoplasms, Cancer research, [SDV.IMM]Life Sciences [q-bio]/Immunology, Immunologic diseases. Allergy, business, CD8, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Research Article
Abstract: BackgroundImmunotherapies have achieved clinical benefit in many types of cancer but remain limited to a subset of patients in colorectal cancer (CRC). Resistance to immunotherapy can be attributed in part to tissue-specific factors constraining antitumor immunity. Thus, a better understanding of how the colon microenvironment shapes the immune response to CRC is needed to identify mechanisms of resistance to immunotherapies and guide the development of novel therapeutics.MethodsIn an orthotopic mouse model of MC38-CRC, tumor progression was monitored by bioluminescence imaging and the immune signatures were assessed at a transcriptional level using NanoString and at a cellular level by flow cytometry.ResultsDespite initial tumor growth in all mice, only 25 to 35% of mice developed a progressive lethal CRC while the remaining animals spontaneously rejected their solid tumor. No tumor rejection was observed in the absence of adaptive immunity, nor when MC38 cells were injected in non-orthotopic locations, subcutaneously or into the liver. We observed that progressive CRC tumors exhibited a protumor immune response, characterized by a regulatory T-lymphocyte pattern, discernible shortly post-tumor implantation, as well as suppressive myeloid cells. In contrast, tumor-rejecting mice presented an early inflammatory response and an antitumor microenvironment enriched in CD8+T cells.ConclusionsTaken together, our data demonstrate the role of the colon microenvironment in regulating the balance between anti or protumor immune responses. While emphasizing the relevance of the CRC orthotopic model, they set the basis for exploring the impact of the identified signatures in colon cancer response to immunotherapy.
Published: 2020
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21. Molecular and immunological evaluation of the expression of cancer/testis gene products in human colorectal cancer

Author: Pedro M. S. Alves, Nermin Halkic, Hanifa Bouzourene, Maha Ayyoub, Jean-Claude Givel, Daniel E. Speiser, Gabriel Bricard, Frédéric Lévy, Henri Vuilleumier, Sebastien Viatte, Nicole Lévy, and Pedro Romero
Subjects: Male, Cancer Research, Pathology, medicine.medical_specialty, Colorectal cancer, T cell, Immunology, Gene Expression, Biology, CD8-Positive T-Lymphocytes, Antigen, Antigens, Neoplasm, medicine, Immunology and Allergy, Humans, neoplasms, Antigens, Neoplasm/biosynthesis, Antigens, Neoplasm/genetics, CD8-Positive T-Lymphocytes/immunology, Colorectal Neoplasms/genetics, Colorectal Neoplasms/immunology, Gene Expression Profiling, Immunohistochemistry, Liver Neoplasms/metabolism, Liver Neoplasms/secondary, Neoplasm Proteins/biosynthesis, Neoplasm Proteins/genetics, Reverse Transcriptase Polymerase Chain Reaction, Melanoma, Liver Neoplasms, Cancer, medicine.disease, Neoplasm Proteins, Gene expression profiling, medicine.anatomical_structure, Oncology, Cancer/testis antigens, Colorectal Neoplasms
Abstract: Tumor-specific gene products, such as cancer/testis (CT) antigens, constitute promising targets for the development of T cell vaccines. Whereas CT antigens are frequently expressed in melanoma, their expression in colorectal cancers (CRC) remains poorly characterized. Here, we have studied the expression of the CT antigens MAGE-A3, MAGE-A4, MAGE-A10, NY-ESO-1 and SSX2 in CRC because of the presence of well-described HLA-A2-restricted epitopes in their sequences. Our analyses of 41 primary CRC and 14 metastatic liver lesions confirmed the low frequency of expression of these CT antigens. No increased expression frequencies were observed in metastatic tumors compared to primary tumors. Histological analyses of CRC samples revealed heterogeneous expression of individual CT antigens. Finally, evidence of a naturally acquired CT antigen-specific CD8(+) T cell response could be demonstrated. These results show that the expression of CT antigens in a subset of CRC patients induces readily detectable T cell responses.
Published: 2018

22. Predictors of responses to immune checkpoint blockade in advanced melanoma

Author: Brigitte Dréno, Caroline Flament, Nicolas Jacquelot, B. Balme, Yaron Meirow, Mitchell P. Levesque, Jeffrey S. Weber, Christophe Borg, Lawrence Fong, Amir Khammari, Guido Kroemer, Sylvie Rusakiewicz, Morten Hartvig Hansen, Ignacio Melero, Gorana Tomasic, Henrik Schmidt, Meriem Messaoudene, Andrea Cavalcanti, Maria Paula Roberti, Sarah Jegou, Yoshinobu Koguchi, Stefan Michiels, Moshe Sade-Feldman, Michal Baniyash, Ana C. Anderson, Byoung S. Kwon, Lieping Chen, Aurélien Marabelle, David Enot, Arun Burra, Inge Marie Svane, Stéphane Dalle, A.M. Di Giacomo, Dirk Schadendorf, Nils Ternès, Laurence Zitvogel, Reinhard Dummer, Andressa L. Sodre, Serena S. Kwek, O Beatrix, Vijay K. Kuchroo, Alexander M.M. Eggermont, David M. Woods, Benjamin Weide, Mark J. Smyth, Michele Maio, Maha Ayyoub, François Aubin, Connie P.M. Duong, Michal Lotem, Immunologie des tumeurs et immunothérapie (UMR 1015), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Université Paris-Saclay, Institut Gustave Roussy (IGR), 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), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Microorganismes et physiopathologie intestinale (ERL INSERM U1157 - CNRS UMR 7203), Laboratoire des biomolécules (LBM UMR 7203), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC), Laura & Isaac Perlmutter Cancer Center [New York, NY, USA], New York University Langone Medical Center (NYU Langone Medical Center), NYU System (NYU)-NYU System (NYU), Department of Hematology and Oncology [Herlev, Denmark], Copenhagen University Hospital, The Lautenberg Center for General and Tumor Immunology [Jerusalem, Israel], The Hebrew University Hadassah Medical School -BioMedical Research institute Israel Canada of the Faculty of Medicine [Jerusalem, Israel], Division of Hematology-Oncology [San Francisco, CA, USA] (Department of Medicine), University of California [San Francisco] (UCSF), University of California-University of California, Department of Immunobiology [New Haven, CT, USA] (Yale School of Medicine), Yale University [New Haven], Eutilex Co., Ltd [Seoul, Korea], Section of Clinical Immunology, Allergy, and Rheumatology [New Orleans, LA, USA] (Department of Medicine), Tulane University Health Sciences Center [New Orleans, LA, USA], Evergrande Center for Immunologic Diseases [Boston, MA, USA] (Ann Romney Center for Neurologic Diseases), Brigham & Women's Hospital, Harvard Medical School, Department of Dermatology [Tubingen, Germany], University Medical Center [Tubingen, Germany], Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), 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), Service d'Oncologie Médicale [CHRU Besançon], Centre d'Investigation Clinique de Besançon (Inserm CIC 1431), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, 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), Département de Pathologie [CHU Lyon-Sud - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Département de biologie et pathologie médicales [Gustave Roussy], Division of Medical Oncology and Immunotherapy [Siena, Italy], University Hospital of Siena, Department of Dermatology [Heidelberg, Germany], University Duisburg-Essen [Germany]-University Hospital [Heidelberg, Germany]-Germany & German Cancer Consortium - DKTZ [Heidelberg, Germany], Division of Hepatology and Gene Therapy (CIMA), Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV)-Universidad de Navarra [Pamplona] (UNAV), Oncology Department [Pamplona, Spain], University Clinic of Navarra - CUN [Pamplona, Spain], Centro de Investigación Biomedica en Red de Oncologia [Pamplona, Spain] (CIBERO), Clinical and Translational Research in Skin Cancer (CRCINA-ÉQUIPE 2), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Department of Dermatology [Zürich, Switzerland], Universität Zürich [Zürich] = University of Zurich (UZH)-University hospital of Zurich [Zurich], Earle A. Chiles Research Institute [Portland, OR, USA], Providence Portland Medical Center-Robert W. Franz Cancer Research Center, Sharett Institute of Oncology [Jerusalem, Israel], Hadassah Medical Organization [Jerusalem, Israel], Department of Oncology [Aarhus, Denmark], Aarhus University Hospital, 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), 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 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 Sorbonne Paris Cité (USPC), 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), Département de chirurgie générale [Gustave Roussy], Service de dermatologie, Département de médecine oncologique [Gustave Roussy], Immunology in Cancer and Infection Laboratory [Herston, QLD, Australia], QIMR Berghofer Medical Research Institute, School of Medicine [Herston, QLD, Australia], University of Southern Queensland (USQ), This work was supported by Institut National du Cancer INCa, ANR, Ligue contre le cancer (équipe labellisée de L.Z.) and Swiss Bridge Foundation, ISREC Foundation, LABEX OncoImmunology, la direction générale de l’offre de soins (DGOS), Université Paris-Sud, SIRIC SOCRATE (INCa/DGOS/INSERM 6043), PACRI network and PIA2 TORINO-LUMIERE. N.J. received a fellowship from Cancéropole Idf. M.J.S. was supported by a National Health and Medical Research Council of Australia Senior Principal Research Fellowship., Bernardo, Elizabeth, 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), Université Pierre et Marie Curie - Paris 6 (UPMC)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (UR 3181) (CEF2P / CARCINO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), 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 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 National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Universität Duisburg-Essen = University of Duisburg-Essen [Essen]-University Hospital [Heidelberg, Germany]-Germany & German Cancer Consortium - DKTZ [Heidelberg, Germany], 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, Oncology, medicine.medical_treatment, Medizin, General Physics and Astronomy, 0302 clinical medicine, METASTATIC MELANOMA, TUMOR-INFILTRATING LYMPHOCYTES, lcsh:Science, Cancer, screening and diagnosis, Multidisciplinary, CD137, 3. Good health, Detection, 030220 oncology & carcinogenesis, Patient Safety, BREAST-CANCER PATIENTS, Nivolumab, Adjuvant, CIRCULATING SOLUBLE FAS, medicine.drug, medicine.medical_specialty, CELL LUNG-CANCER, Science, PROGNOSTIC IMPACT, Clinical Trials and Supportive Activities, Ipilimumab, [SDV.CAN]Life Sciences [q-bio]/Cancer, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, Clinical Research, Internal medicine, Journal Article, STAGE-III MELANOMA, medicine, CLINICAL-SIGNIFICANCE, business.industry, UNTREATED MELANOMA, General Chemistry, Immune checkpoint, Blockade, 4.1 Discovery and preclinical testing of markers and technologies, 030104 developmental biology, COMBINED NIVOLUMAB, Immunology, lcsh:Q, business, CD8
Abstract: Immune checkpoint blockers (ICB) have become pivotal therapies in the clinical armamentarium against metastatic melanoma (MMel). Given the frequency of immune related adverse events and increasing use of ICB, predictors of response to CTLA-4 and/or PD-1 blockade represent unmet clinical needs. Using a systems biology-based approach to an assessment of 779 paired blood and tumor markers in 37 stage III MMel patients, we analyzed association between blood immune parameters and the functional immune reactivity of tumor-infiltrating cells after ex vivo exposure to ICB. Based on this assay, we retrospectively observed, in eight cohorts enrolling 190 MMel patients treated with ipilimumab, that PD-L1 expression on peripheral T cells was prognostic on overall and progression-free survival. Moreover, detectable CD137 on circulating CD8+ T cells was associated with the disease-free status of resected stage III MMel patients after adjuvant ipilimumab + nivolumab (but not nivolumab alone). These biomarkers should be validated in prospective trials in MMel., The clinical management of metastatic melanoma requires predictors of the response to checkpoint blockade. Here, the authors use immunological assays to identify potential prognostic/predictive biomarkers in circulating blood cells and in tumor-infiltrating lymphocytes from patients with resected stage III melanoma.
Published: 2017
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23. Immunophenotyping of Stage III Melanoma Reveals Parameters Associated with Patient Prognosis

Author: Lieping Chen, François Aubin, Sylvie Rusakiewicz, Laurence Zitvogel, Guido Kroemer, Sarah Jegou, Alexander M.M. Eggermont, Nicolas Jacquelot, Maria Paula Roberti, Aurélien Marabelle, Benjamin Weide, Maha Ayyoub, Holbrook E Kohrt, Byoung S. Kwon, David Enot, Stéphane Dalle, Camila Flores, Andrea Cavalcanti, Christophe Borg, Michaela Semeraro, HAL UPMC, Gestionnaire, Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Saclay, 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), Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC), Yale University [New Haven], National Cancer Center Korea, Tulane University, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre d'Investigation Clinique de Besançon (Inserm CIC 1431), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Hospices Civils de Lyon (HCL), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, 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), 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 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 Descartes - Paris 5 (UPD5), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut Gustave Roussy (IGR), 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), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), 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 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), 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 ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Tulane University - New Orleans, LA, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Centre d'Investigation Clinique de Besançon ( CICB ), Etablissement Français du Sang Bourgogne Franche-Comté-Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Franche-Comté ( UFC ), Eberhard Karls Universität Tübingen, Hospices Civils de Lyon ( HCL ), Stanford University School of Medicine [Stanford], Stanford University [Stanford], 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 ), 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 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 ), Université Paris Descartes - Paris 5 ( UPD5 ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Institut Gustave Roussy ( IGR ), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), 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, Oncology, Male, Skin Neoplasms, medicine.medical_treatment, Lymphocyte, Biochemistry, Cohort Studies, 0302 clinical medicine, Immunophenotyping, Prospective Studies, Lymph node, Melanoma, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Middle Aged, Prognosis, Combined Modality Therapy, Neoadjuvant Therapy, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Female, Immunotherapy, Adult, medicine.medical_specialty, Dermatology, Risk Assessment, Disease-Free Survival, Article, 03 medical and health sciences, Internal medicine, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, medicine, Humans, Clinical significance, Neoplasm Invasiveness, Progression-free survival, Molecular Biology, Survival analysis, business.industry, Cell Biology, medicine.disease, Survival Analysis, 030104 developmental biology, Immunology, Lymph Nodes, Neoplasm Recurrence, Local, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Stage III metastatic melanomas require adequate adjuvant immunotherapy to prevent relapses. Prognostic factors are awaited to optimize the clinical management of these patients. The magnitude of metastatic lymph node invasion and the BRAF V600 activating mutation have clinical significance. Based on a comprehensive immunophenotyping of 252 parameters per patient in paired blood and metastatic lymph nodes performed in 39 metastatic melanomas, we found that blood markers were as contributive as tumor-infiltrated lymphocyte immunotypes, and parameters associated with lymphocyte exhaustion/suppression showed higher clinical significance than those related to activation or lineage. High frequencies of CD45RA þ CD4 þ and CD3 e CD56 e tumor-infiltrated lymphocytes appear to be independent prognostic factors of short progression-free survival. High NKG2D expression on CD8 þ tumor-infiltrated lymphocytes, low level of regulatory T-cell tumor-infiltrated lymphocytes, and low PD-L1 expression on circulating T cells were retained in the multivariate Cox analysis model to predict prolonged overall survival. Prospective studies are needed to determine whether such immunological markers may guide adjuvant therapies in stage III metastatic melanomas.
Published: 2016
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24. 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

25. Modulation of Cytokine Secretion Allows CD4 T Cells Secreting IL-10 and IL-17 to Simultaneously Participate in Maintaining Tolerance and Immunity

Author: Maha Ayyoub, Pascale Pignon, Kanako Saito, and Danila Valmori
Subjects: CD4-Positive T-Lymphocytes, medicine.medical_treatment, lcsh:Medicine, Biology, In Vitro Techniques, T-Lymphocytes, Regulatory, Immune tolerance, Ikaros Transcription Factor, Immune system, medicine, Immune Tolerance, Humans, IL-2 receptor, lcsh:Science, Multidisciplinary, lcsh:R, Interleukin-17, FOXP3, Forkhead Transcription Factors, Gastrointestinal Microbiome, Interleukin-10, Interleukin 10, Cytokine, Immunology, Butyric Acid, Cytokines, lcsh:Q, Cytokine secretion, Immunologic Memory, Ex vivo, Research Article
Abstract: CD4 T cells secreting IL-10 or IL-17 are frequent at mucosal sites, where their equilibrium is important for simultaneously maintaining tolerance and immunity to the resident microbiota. The mode of action of these cells, however, is as yet incompletely understood. In this study, we have combined ex vivo analysis of CD4 T cells producing IL-10 or/and IL-17 with assessment of clonal populations isolated ex vivo using a cytokine catch assay. We found that circulating CD4 T cells secreting IL-10 or/and IL-17 ex vivo include both conventional FOXP3- CD4 T cells and FOXP3+ Helios- Treg. Upon assessment of clonal populations derived from single ex vivo isolated cytokine secreting cells, we found that IL-10 or/and IL-17 secreting cells prevalently secrete one or the other cytokine depending on the type of stimulation, the time after stimulation and the presence of microbial products. Namely, IL-10 secretion by clonal cells was prevalent at early time points after TCR mediated stimulation, was independent of co-stimulation and was increased in the presence of the microbial fermentation product butyrate. In contrast, IL-17 secretion was higher at later time points after TCR mediated stimulation and in the presence of co-stimulatory signals. Taken together, these results provide insights into the mechanisms that, through modulation of cytokine secretion depending on conditions, allow IL-10 and IL-17 producing CD4 T cells to contribute to maintain tolerance to microbes locally, while retaining the ability to participate in protective immune responses at distant sites.
Published: 2015

26. Classification of current anticancer immunotherapies

Author: Chiara Castelli, Axel Hoos, Anna Karolina Palucka, Aitziber Buqué, Kenneth J. Pienta, Aled Clayton, Daniel E. Speiser, Jean-Pierre Mach, Klas Kärre, Richard G. Vile, Maha Ayyoub, Norma Bloy, Theresa L. Whiteside, Eli Gilboa, Naiyer A. Rizvi, Cornelis J. M. Melief, Alexander Knuth, Bruno Silva-Santos, Lisa M. Coussens, James E. Talmadge, Jean-Yves Blay, Rolf Kiessling, Lorenzo Moretta, Alexander M.M. Eggermont, Estaban Celis, Anne Caignard, Mario P. Colombo, Abhishek D. Garg, José Manuel Bravo-San Pedro, Pramod K. Srivastava, Dmitry I. Gabrilovich, Wolf H. Fridman, Catherine Sautès-Fridman, Eric Tartour, Fabrizio Mattei, Patrizia Agostinis, Philipp Beckhove, Laura Bracci, Vincenzo Cerundolo, Giuseppe Giaccone, Fernando Aranda, Angel Porgador, Elisa E. Baracco, Radek Spisek, Jean Pierre Abastado, Michael T. Lotze, Ron N. Apte, Federica Cavallo, Benoît Van den Eynde, Weiping Zou, François Ghiringhelli, Hans Schreiber, Jitka Fucikova, Lorenzo Galluzzi, Adekunke Odunsi, Erika Vacchelli, Roland S. Liblau, Hideho Okada, Hiroshi Shiku, Laurence Zitvogel, Pawel Kalinski, Guido Kroemer, Oliver Kepp, George C. Prendergast, Eva Klein, Francesca Castoldi, Enrico Lugli, Jedd D. Wolchok, Anne Hosmalin, Sjoerd H. van der Burg, Hermann Wagner, Mark J. Smyth, Nicholas P. Restifo, Dirk Jäger, John M. Kirkwood, Gabriel A. Rabinovich, Sacha Gnjatic, Madhav V. Dhodapkar, E. A. Mittendorf, Douglas T. Fearon, Ignacio Melero, Marcus E. Peter, Jérôme Galon, Domenico Mavilio, Laura Senovilla, Claire E. Lewis, Barbara Seliger, Jeffrey S. Weber, UCL - SSS/DDUV - Institut de Duve, 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), Université Paris Descartes - Paris 5 (UPD5), Université Paris-Sud - Paris 11 (UP11), Sotio a.c., Pole d’innovation thérapeutique en oncologie, Institut de Recherches Internationales Servier, Cell Death Research and Therapy (CDRT) Laboratory, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Group of Immune receptors of the Innate and Adaptive System, Institut d’Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Cancer Vaccines and Immune Regulation, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Translational Immunology Division, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), 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), Dept. of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità (ISS), Alloimmunité-Autoimmunité-Transplantation (A2T), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unit of Immunotherapy of Human Tumors, Dept. of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori - National Cancer Institute [Milan], Molecular Biotechnology Center, Dept. of Molecular Biotechnology and Health Sciences, Università degli studi di Torino = University of Turin (UNITO), Cancer Immunology, Inflammation and Tolerance Program, Augusta University, University System of Georgia (USG)-University System of Georgia (USG), MRC Human Immunology Unit, The Weatherall Institute of Molecular Medicine, University of Oxford-University of Oxford, Department of Oncology - Pathology, Cancer Center Karolinska [Karolinska Institutet] (CCK), Karolinska Institutet [Stockholm]-Karolinska Institutet [Stockholm], Institute of Cancer & Genetics, Cardiff University, Velindre Cancer Centre, Knight Cancer Institute, Oregon Health and Science University [Portland] (OHSU), Sect. of Hematology and Immunobiology,Yale Cancer Center, Yale University [New Haven], Institut Gustave Roussy (IGR), Cold Spring Harbor Laboratory, NY, Cold Spring Harbor, Centre de Recherche des Cordeliers (CRC), Dept. of Immunology, 2nd Faculty of Medicine and University Hospital Motol, Charles University [Prague] (CU), Dept. of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Lombardi Comprehensive Cancer Center, Georgetown University [Washington] (GU), Dept. of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, University of Miami [Coral Gables], Glaxo Smith Kline, Cancer Immunotherapy Consortium, 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), National Center for Tumor Diseases, University Medical Center Heidelberg, Hillman Cancer Center, University of Pittsburg, Department of Surgery, Cancer Institute-University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Dept. of Immunology and Infectious Diseases and Microbiology, University of Pittsburgh (PITT), Dept. of Microbiology, Tumor and Cell Biology, Karolinska Institutet [Stockholm], Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Dept. of Oncology, Karolinska Institute Hospital, Cancer Institute Laboratory, Academic Unit of Inflammation and Tumour Targeting, Dept. of Oncology, University of Sheffield Medical School, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Institute, Institut de Biochimie, Université de Lausanne = University of Lausanne (UNIL), Dept. of Medical Biotechnologies and Translational Medicine, Università degli Studi di Milano = University of Milan (UNIMI), Dept. of Immunology, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Clínica Universidad de Navarra [Pamplona], ISA Therapeutics, Dept. of Immunohematology and Blood Transfusion, Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Research Dept. of Surgical Oncology, The University of Texas, Istituto Giannina Gaslini, Center for Immunotherapy [Buffalo], Roswell Park Cancer Institute [Buffalo] (RPCI), Dept. of Neurological Surgery, University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), The Jackson Laboratory [Bar Harbor] (JAX), Div. of Hematology/Oncology, Northwestern University, The James Buchanan Brady Urological Institute, The Johns Hopkins Medical Institutions, Shraga Segal Department of Microbiology and Immunology, Ben-Gurion University of the Negev (BGU)-Faculty of Health Sciences and Cancer Research Center, Cell Biology and Signaling Program, Thomas Jefferson University-Sidney Kimmel Cancer Center, Jefferson (Philadelphia University + Thomas Jefferson University)-Jefferson (Philadelphia University + Thomas Jefferson University), Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental [Buenos Aires] (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET)-Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET), Memorial Sloane Kettering Cancer Center [New York], Dept. of Pathology, The Cancer Research Center, University of Chicago, Institute of Medical Immunology, Martin-Luther-Universität Halle Wittenberg (MLU), Department of Immuno-gene Therapy, Mie University, Instituto de Medicina Molecular, Universidade de Lisboa = University of Lisbon (ULISBOA), Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, School of Medicine, University of Queensland [Brisbane], Ludwig Cancer Research Center, Dept. of Immunology, University of Connecticut (UCONN), Carole and Ray Neag Comprehensive Cancer Center, Laboratory of Transplantation Immunology, Dept. of Pathology and Microbiology, University of Nebraska Medical Center, University of Nebraska System-University of Nebraska System, 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), Service d'immunologie biologique, 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), Dept. of Clinical Oncology, Université Catholique de Louvain = Catholic University of Louvain (UCL), Ludwig Institute for Cancer Research, de Duve Institute, Dept. of Molecular Medicine and Immunology, Mayo Clinic College of Medicine, Institute of Medical Microbiology, Immunology and Hygiene, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Donald A. Adam Comprehensive Melanoma Research Center, H. Lee Moffitt Cancer Center & Research Institute, University of Pittsburgh School of Medicine, Dept. of Medicine and Ludwig Center, Weill Medical College of Cornell University [New York], 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), Medical School, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Pôle de biologie, GK is supported by the Ligue contre le Cancer(équipe labelisée), Agence Nationale de la Recherche(ANR), Association pour la recherche sur le cancer (ARC), Cancéropôle Ile-de-France, Institut National du Cancer(INCa), Fondation Bettencourt-Schueller, Fondation deFrance, Fondation pour la Recherche Médicale (FRM), theEuropean Commission (ArtForce), the European ResearchCouncil (ERC), the LabEx Immuno-Oncology, the SIRICStratified Oncology Cell DNA Repair and Tumor ImmuneElimination (SOCRATE), the SIRIC Cancer Researchand Personalized Medicine (CARPEM), and the ParisAlliance of Cancer Research Institutes (PACRI). MPC issupported by Association for Cancer Research (AIRC). SGis supported by Cancer Vaccine Collaborative and CancerResearch Institute. MJS is supported by the NationalHealth and Medical Research Council of Australia, the QIMR Berghofer Medical Research Institute, andthe Susan G Komen Breast Cancer Foundation. FM issupported by a grant from the Italian Ministry of Health., Repositório da Universidade de Lisboa, 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 de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Istituto Superiore di Sanità, Università degli studi di Torino (UNITO), University of Oxford [Oxford]-University of Oxford [Oxford], University of Pennsylvania [Philadelphia], Georgetown University, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lausanne (UNIL), University of Milan, Roswell Park Cancer Institute [Buffalo], University of California [San Francisco] (UCSF), University of California-University of California, Universidade de Lisboa (ULISBOA), 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)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Bos, Mireille, 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 ), Université Paris Descartes - Paris 5 ( UPD5 ), Université Paris-Sud - Paris 11 ( UP11 ), Catholic University of Leuven ( KU Leuven ), Institut de cancérologie de l'Ouest - Nantes ( ICO Nantes ), CRLCC Paul Papin-CRLCC René Gauducheau, Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), German Cancer Research Center, 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 ), Alloimmunité-Autoimmunité-Transplantation ( A2T ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Università degli studi di Torino ( UNITO ), Georgia Regents University Cancer Center, Cancer Center Karolinska [Karolinska Institutet] ( CCK ), Oregon Health & Science University [Portland] ( OHSU ), 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 ), Charles University, Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), University of Miami, 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 ), Cancer Institute-University of Pittsburgh, University of Pittsburgh, Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Centre de Physiopathologie de Toulouse Purpan ( CPTP ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Lausanne ( UNIL ), Center for Immunotherapy, University of California [San Francisco] ( UCSF ), The Jackson Laboratory for Genomics Medicine, Ben-Gurion University of the Negev ( BGU ) -Faculty of Health Sciences and Cancer Research Center, Instituto de Biología y Medicina Experimental (IBYME), National Cancer Institute (NCI), Memorial Sloan Kettering Cancer Center ( MSKCC ), Martin Luther University Halle-Wittenberg, Mie University Graduate School of Medicine, Universidade de Lisboa ( ULISBOA ), University of Lausanne, University of Connecticut School of Medicine, 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 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Université Catholique de Louvain ( UCL ), Technical University of Munich ( TUM ), 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 ), and Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: immunostimulatory cytokines, medicine.medical_treatment, Review, Bioinformatics, DNA-based vaccines, Efficacy, 0302 clinical medicine, Cancer immunotherapy, Neoplasms, peptide-based vaccines, 0303 health sciences, Patología, purl.org/becyt/ford/3.1 [https], CANCER, 3. Good health, Medicina Básica, Oncology, checkpoint blockers, 030220 oncology & carcinogenesis, QR180, purl.org/becyt/ford/3 [https], Immunotherapy, CIENCIAS MÉDICAS Y DE LA SALUD, medicine.drug_class, Inmunología, adoptive cell transfer, dendritic cell-based interventions, oncolytic viruses, Toll-like receptor agonists, Monoclonal antibody, RC0254, 03 medical and health sciences, Immune system, Antigen, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, IMMUNOTHERAPIES, business.industry, Cancer, medicine.disease, R1, Oncolytic virus, Immunology, business
Abstract: © 2014. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited., During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into "passive" and "active" based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor-associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches.
Published: 2014

27. 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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28. Antibody responses to NY-ESO-1 in primary breast cancer identify a subtype target for immunotherapy

Author: Danila Valmori, Mario Campone, Pascal Jézéquel, Maha Ayyoub, Jean Marc Classe, Ahmed Hamaï, Pascale Pignon, Cristina Colarossi, Isabelle Raimbaud, Tiziana Perin, Lorenzo Memeo, Karine Duperrier-Amouriaux, Loïc Campion, Vincenzo Canzonieri, Hamai, A, Duperrier-Amouriaux, K, Pignon, P, Raimbaud, I, Memeo, L, Colarossi, C, Canzonieri, V, Perin, T, Classe, Jm, Campone, M, Jezequel, P, Campion, L, Ayyoub, M, and Valmori, D
Subjects: Anatomy and Physiology, Antibodies, Neoplasm, Receptor, ErbB-2, medicine.medical_treatment, Cancer Treatment, lcsh:Medicine, Antibody Specificity, Immune Physiology, Breast Tumors, lcsh:Science, Lymph node, Multidisciplinary, biology, Obstetrics and Gynecology, Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, Oncology, Receptors, Estrogen, Medicine, Lymph, Immunotherapy, Antibody, NY-ESO-1, Receptors, Progesterone, Research Article, Tumor Immunology, Immunology, Breast Neoplasms, Breast cancer, Immune system, Antigen, Antibody Therapy, Antigens, Neoplasm, Cell Line, Tumor, Breast Cancer, medicine, Humans, Antigens, Biology, Patient Selection, lcsh:R, Cancers and Neoplasms, Membrane Proteins, Immunologic Subspecialties, medicine.disease, biology.protein, Cancer research, Clinical Immunology, lcsh:Q
Abstract: The highly immunogenic human tumor antigen NY-ESO-1 (ESO) is a target of choice for anti-cancer immune therapy. In this study, we assessed spontaneous antibody (Ab) responses to ESO in a large cohort of patients with primary breast cancer (BC) and addressed the correlation between the presence of anti-ESO Ab, the expression of ESO in the tumors and their characteristics. We found detectable Ab responses to ESO in 1% of the patients. Tumors from patients with circulating Ab to ESO exhibited common characteristics, being mainly hormone receptor (HR)(-) invasive ductal carcinomas of high grade, including both HER2(-) and HER2(+) tumors. In line with these results, we detected ESO expression in 20% of primary HR(-) BC, including both ESO Ab(+) and Ab(-) patients, but not in HR(+) BC. Interestingly, whereas expression levels in ESO(+) BC were not significantly different between ESO Ab(+) and Ab(-) patients, the former had, in average, significantly higher numbers of tumor-infiltrated lymph nodes, indicating that lymph node invasion may be required for the development of spontaneous anti-tumor immune responses. Thus, the presence of ESO Ab identifies a tumor subtype of HR(-) (HER2(-) or HER2(+)) primary BC with frequent ESO expression and, together with the assessment of antigen expression in the tumor, may be instrumental for the selection of patients for whom ESO-based immunotherapy may complement standard therapy.
Published: 2011

29. Vaccination with NY-ESO-1 protein and CpG in Montanide induces integrated antibody/Th1 responses and CD8 T cells through cross-priming

Author: Eric Hoffmann, Lloyd J. Old, Linda Pan, Angelica Angiulli, David O'Neill, Maha Ayyoub, Valeria Tosello, Anna C. Pavlick, Gerd Ritter, Crystal M. Cruz, Ralph Venhaus, Gregory Mears, Danila Valmori, Francesca Angiulli, Susan M. Vogel, Achim A. Jungbluth, Nina Bhardwaj, Naira E. Souleimanian, Sylvia Adams, and J. Escalon
Subjects: T cell, Oleic Acids, Biology, CD8-Positive T-Lymphocytes, Cancer Vaccines, Epitope, Antibodies, Interleukin 21, Cross-Priming, Antigen, Antigens, Neoplasm, Neoplasms, medicine, Cytotoxic T cell, Humans, Mannitol, Antigen-presenting cell, Multidisciplinary, Vaccination, Membrane Proteins, Biological Sciences, Th1 Cells, Tumor antigen, Recombinant Proteins, medicine.anatomical_structure, Oligodeoxyribonucleotides, Immunology, Epitopes, B-Lymphocyte, Immunotherapy, CD8
Abstract: The use of recombinant tumor antigen proteins is a realistic approach for the development of generic cancer vaccines, but the potential of this type of vaccines to induce specific CD8 + T cell responses, through in vivo cross-priming, has remained unclear. In this article, we report that repeated vaccination of cancer patients with recombinant NY-ESO-1 protein, Montanide ISA-51, and CpG ODN 7909, a potent stimulator of B cells and T helper type 1 (Th1)-type immunity, resulted in the early induction of specific integrated CD4 + Th cells and antibody responses in most vaccinated patients, followed by the development of later CD8 + T cell responses in a fraction of them. The correlation between antibody and T cell responses, together with the ability of vaccine-induced antibodies to promote in vitro cross-presentation of NY-ESO-1 by dendritic cells to vaccine-induced CD8 + T cells, indicated that elicitation of NY-ESO-1-specific CD8 + T cell responses by cross-priming in vivo was associated with the induction of adequate levels of specific antibodies. Together, our data provide clear evidence of in vivo cross-priming of specific cytotoxic T lymphocytes by a recombinant tumor antigen vaccine, underline the importance of specific antibody induction for the cross-priming to occur, and support the use of this type of formulation for the further development of efficient cancer vaccines.
Published: 2007

30. A peripheral circulating compartment of natural naive CD4+ Tregs

Author: Charles S. Hesdorffer, Danila Valmori, Andrea Merlo, Maha Ayyoub, and Naira E. Souleimanian
Subjects: Adult, CD4-Positive T-Lymphocytes, Receptors, CCR7, DNA, Complementary, Population, Gene Expression, chemical and pharmacologic phenomena, Cell Separation, In Vitro Techniques, Immunophenotyping, Mice, Immune system, Antigen, Antigens, CD, T-Lymphocyte Subsets, Animals, Humans, CTLA-4 Antigen, IL-2 receptor, L-Selectin, education, Cell Proliferation, education.field_of_study, biology, Base Sequence, T-cell receptor, hemic and immune systems, Forkhead Transcription Factors, Receptors, Interleukin-2, General Medicine, Flow Cytometry, Antigens, Differentiation, Immunity, Innate, DNA-Binding Proteins, Self Tolerance, Immunology, biology.protein, Leukocyte Common Antigens, L-selectin, Receptors, Chemokine, Ex vivo, Research Article
Abstract: CD4+CD25+ Tregs play a central role in the maintenance of peripheral self tolerance by keeping autoreactive T cells in check. Whereas the thymic origin of CD4+CD25+ Tregs, as a distinct lineage, has been inferred, understanding of their developmental pathways has remained elusive. In both mice and humans, peripheral CD4+CD25+ Treg populations have been described as composed of antigen-experienced T cells that fail to significantly proliferate following TCR stimulation but suppress proliferation and effector functions of CD25– T cells. Here we show that analysis of CD25 expression in human circulating CD4+ T lymphocytes with respect to their in vivo differentiation stages identifies a distinct subset of CD25+CCR7+CD62L+CTLA-4+FOXP3+ cells contained in the CD45RA+/RO– naive fraction. The subset, which we have named natural naive Tregs (NnTregs), is prominent in young adults and decreases with age together with the total naive CD4+ population. NnTregs are anergic following stimulation in the absence of IL-2 and exert ex vivo cell-cell contact–mediated suppressor functions. In addition, they proliferate in response to stimulation with autologous APCs, which indicates a high enrichment in T cells bearing self-reactive TCRs. The definition of this subset has important implications for the analysis of human naturally occurring Tregs and for their targeting in therapeutic immune interventions.
Published: 2005

31. Using Modified Antigenic Sequences to Develop Cancer Vaccines: Are We Losing the Focus?

Author: Maha Ayyoub and Danila Valmori
Subjects: Focus (computing), lcsh:R, Cancer, lcsh:Medicine, General Medicine, Biology, medicine.disease, Virology, Cancer Vaccines, Major Histocompatibility Complex, Antigen, Oncology, Antigens, Neoplasm, medicine, Antigenic variation, Humans, Antigens neoplasm, Original antigenic sin, Perspectives, Cancer Biology, T-Lymphocytes, Cytotoxic
Abstract: Are short synthetic peptides the key to developing cancer vaccines? And what are the obstacles in the way?
Published: 2004

32. Ex-Vivo Analysis of CD8+ T Cells Infiltrating Colorectal Tumors Identifies a Major Effector-Memory Subset with Low Perforin Content.

Author: SHENG-WEI YE, YU WANG, DANILA VALMORI, MAHA AYYOUB, YAN HAN, XIAO-LAN XU, AI-LIAN ZHAO, LI QU, SACHA GNJATIC, GERD RITTER, LLOYD OLD, and JIN GU
Abstract: Previous studies have indicated that the infiltration of CD8+ T cells in colorectal cancer is an independent predictor of increased survival but clinical observations have suggested that the cytotoxic function of CD8+ T cells infiltrating colorectal cancer may often be limited. In this study, we have assessed the phenotype of colorectal cancer CD8+ tumor-infiltrating lymphocytes (TILs) isolated ex vivo from tumor tissue, and assessed the perforin content of TIL with respect to their location using immunohistochemistry. We found that CD8+ T cells TILs isolated from colorectal cancer are mainly composed of antigen-experienced cells of effector memory type (TEM, CD45RA-CCR7−, and CD27+/CD28− or CD27−/CD28−), and contain only minor proportions of terminally differentiated CD8+ T cells (TEMRA, CD45RA+CCR7−). The perforin content of these TILs, however, is significantly lower than that of antigen-experienced T cells in PBMCs due to the much lower levels of perforin found in the CD27-CD28− subset in TILs compared with CD8+ T cells of similar phenotype in PBMCs. [ABSTRACT FROM AUTHOR]
Published: 2006

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32 results on '"Maha Ayyoub"'

1. Assessing the implications of sentinel lymph node removal in cervical cancer: an immunogenetic perspective – a SENTICOL ancillary study

2. Immune changes in hilar tumor draining lymph nodes following node sparing neoadjuvant chemoradiotherapy of localized cN0 non-small cell lung cancer

3. Anti-TNF, a magic bullet in cancer immunotherapy?

4. Radiotherapy in the Era of Immunotherapy With a Focus on Non-Small-Cell Lung Cancer: Time to Revisit Ancient Dogmas?

5. PD-1 blockade restores helper activity of tumor-infiltrating, exhausted PD-1hiCD39+ CD4 T cells

6. Phased differentiation of γδ T and T CD8 tumor-infiltrating lymphocytes revealed by single-cell transcriptomics of human cancers

7. Circulating CD14high CD16low intermediate blood monocytes as a biomarker of ascites immune status and ovarian cancer progression

8. Colon-specific immune microenvironment regulates cancer progression versus rejection

9. Modulation of Cytokine Secretion Allows CD4 T Cells Secreting IL-10 and IL-17 to Simultaneously Participate in Maintaining Tolerance and Immunity.

10. MHC class II/ESO tetramer-based generation of in vitro primed anti-tumor T-helper lines for adoptive cell therapy of cancer

11. NY-ESO-1-specific circulating CD4+ T cells in ovarian cancer patients are prevalently T(H)1 type cells undetectable in the CD25+ FOXP3+ Treg compartment.

12. Antibody responses to NY-ESO-1 in primary breast cancer identify a subtype target for immunotherapy.

13. Using modified antigenic sequences to develop cancer vaccines: are we losing the focus?

14. PD-1 blockade restores helper activity of tumor-infiltrating, exhausted PD-1hiCD39+ CD4 T cells

15. Phased differentiation of γδ T and T CD8 tumorinfiltrating lymphocytes revealed by single-cell transcriptomics of human cancers

16. Eomes-Dependent Loss of the Co-activating Receptor CD226 Restrains CD8+ T Cell Anti-tumor Functions and Limits the Efficacy of Cancer Immunotherapy

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

18. Dual Relief of T-lymphocyte Proliferation and Effector Function Underlies Response to PD-1 Blockade in Epithelial Malignancies

19. Circulating CD14high CD16low intermediate blood monocytes as a biomarker of ascites immune status and ovarian cancer progression

20. Colon-specific immune microenvironment regulates cancer progression versus rejection

21. Molecular and immunological evaluation of the expression of cancer/testis gene products in human colorectal cancer

22. Predictors of responses to immune checkpoint blockade in advanced melanoma

23. Immunophenotyping of Stage III Melanoma Reveals Parameters Associated with Patient Prognosis

24. Melanoma and immunotherapy bridge 2015 : Naples, Italy. 1-5 December 2015

25. Modulation of Cytokine Secretion Allows CD4 T Cells Secreting IL-10 and IL-17 to Simultaneously Participate in Maintaining Tolerance and Immunity

26. Classification of current anticancer immunotherapies

27. Regulation of CD4+NKG2D+ Th1 Cells in Patients with Metastatic Melanoma Treated with Sorafenib: Role of IL-15Rα and NKG2D Triggering

28. Antibody responses to NY-ESO-1 in primary breast cancer identify a subtype target for immunotherapy

29. Vaccination with NY-ESO-1 protein and CpG in Montanide induces integrated antibody/Th1 responses and CD8 T cells through cross-priming

30. A peripheral circulating compartment of natural naive CD4+ Tregs

31. Using Modified Antigenic Sequences to Develop Cancer Vaccines: Are We Losing the Focus?

32. Ex-Vivo Analysis of CD8+ T Cells Infiltrating Colorectal Tumors Identifies a Major Effector-Memory Subset with Low Perforin Content.

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