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7 results on '"Plateforme CYTOCELL Nantes (CRCINA-CYTOCELL)"'

1. Low Levels of Natural Anti-α-N-Acetylgalactosamine (Tn) Antibodies Are Associated With COVID-19

Author

Adrien Breiman, Nathalie Ruvoën-Clouet, Marie Deleers, Tiffany Beauvais, Nicolas Jouand, Jézabel Rocher, Nicolai Bovin, Nathalie Labarrière, Hanane El Kenz, Jacques Le Pendu, Host-Pathogen Interactions in the Regulation of Immune Responses (CRCINA-ÉQUIPE 5), 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), Centre Hospitalier Universitaire Brugmann [Bruxelles] (CHU), Université libre de Bruxelles (ULB), Anti-Tumor Immunosurveillance and Immunotherapy (CRCINA-ÉQUIPE 3), Structure fédérative de recherche François Bonamy (SFR François Bonamy), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN), the Russian Academy of Sciences [Moscow, Russia] (RAS), 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), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Plateforme CYTOCELL Nantes (CRCINA-CYTOCELL), 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), Russian Academy of Sciences [Moscow] (RAS), Dupuis, Christine, and Bernardo, Elizabeth

Subjects
Microbiology (medical), Microbiologie et protistologie [parasitologie hum. et anim.], Glycan, [SDV]Life Sciences [q-bio], Tn antigen, lcsh:QR1-502, [SDV.CAN]Life Sciences [q-bio]/Cancer, 030204 cardiovascular system & hematology, Microbiology, Asymptomatic, Epitope, lcsh:Microbiology, N-Acetylgalactosamine, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, natural antibodies, Antibody Repertoire, Antigen, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, O-glycans, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, biology, COVID-19, [SDV] Life Sciences [q-bio], Microbiologie et protistologie [entomologie,phytoparasitolog.], chemistry, Immunology, biology.protein, Antibody, medicine.symptom, Microbiologie et protistologie [bacteriol.virolog.mycolog.], histo-blood group antigens
Abstract

Human serum contains large amounts of anti-carbohydrate antibodies, some of which may recognize epitopes on viral glycans. Here, we tested the hypothesis that such antibodies may confer protection against COVID-19 so that patients would be preferentially found among people with low amounts of specific anti-carbohydrate antibodies since individual repertoires vary considerably. After selecting glycan epitopes commonly represented in the human anti-carbohydrate antibody repertoire that may also be expressed on viral glycans, plasma levels of the corresponding antibodies were determined by ELISA in 88 SARS-CoV-2 infected individuals, including 13 asymptomatic, and in 82 non-infected controls. We observed that anti-Tn antibodies levels were significantly lower in patients as compared to non-infected individuals. This was not observed for any of the other tested carbohydrate epitopes, including anti-αGal antibodies used as a negative control since the epitope cannot be synthesized by humans. Owing to structural homologies with blood groups A and B antigens, we also observed that anti-Tn and anti-αGal antibodies levels were lower in blood group A and B, respectively. Analyses of correlations between anti-Tn and the other anti-carbohydrates tested revealed divergent patterns of correlations between patients and controls, suggesting qualitative differences in addition to the quantitative difference. Furthermore, anti-Tn levels correlated with anti-S protein levels in the patients’ group, suggesting that anti-Tn might contribute to the development of the specific antiviral response. Overall, this first analysis allows to hypothesize that natural anti-Tn antibodies might be protective against COVID-19., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2021
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2. PD-1 and TIGIT coexpression identifies a circulating CD8 T cell subset predictive of response to anti-PD-1 therapy

Author

Valentin Voillet, Tiffany Beauvais, Brigitte Dréno, Charles Nardin, Régis Josien, Camille Dabrowski, Nathalie Labarrière, Stanley R. Riddell, Sylvain Simon, Candice D. Church, Nicolas Jouand, Raphael Gottardo, Olivier Adotevi, Amir Khammari, François Aubin, Steven P. Fling, Cécile Braudeau, Martin A. Cheever, Virginie Vignard, Paul Nghiem, Samuel Rulli, Nirasha Ramchurren, Caroline Laheurte, Zhong Wu, Anti-Tumor Immunosurveillance and Immunotherapy (CRCINA-ÉQUIPE 3), 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), LabEX IGO Immunothérapie Grand Ouest, Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Centre hospitalier universitaire de Nantes (CHU Nantes), Qiagen Sciences [Frederick, MD, USA], Plateforme CYTOCELL Nantes (CRCINA-CYTOCELL), Clinical and Translational Research in Skin Cancer (CRCINA-ÉQUIPE 2), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Université de Nantes (UN)-Université de Nantes (UN), 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), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service de dermatologie (CHRU Besançon), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), SIRIC ILIAD (INCA-DGOS-Inserm_12558)BMS FoundationLigue contre le CancerRégion Pays de la Loire, ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), 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), Nantes Université (Nantes Univ), Département de dermatologie, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Hôpital Saint-Jacques-Université de Franche-Comté (UFC), LABARRIERE, Nathalie, and Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID

Subjects
0301 basic medicine, Cancer Research, medicine.medical_treatment, Programmed Cell Death 1 Receptor, CD8-Positive T-Lymphocytes, 0302 clinical medicine, T-Lymphocyte Subsets, Immunotherapy Biomarkers, Immunology and Allergy, Cytotoxic T cell, Receptors, Immunologic, Immune Checkpoint Inhibitors, RC254-282, education.field_of_study, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, medicine.anatomical_structure, Oncology, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, 030220 oncology & carcinogenesis, Molecular Medicine, immunotherapy, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, Receptors, CXCR5, costimulatory and inhibitory T-Cell receptors, T cell, Immunology, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, TIGIT, Predictive Value of Tests, medicine, melanoma, Humans, education, Pharmacology, Immunotherapy, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Gene signature, Carcinoma, Merkel Cell, 030104 developmental biology, Cancer research, CD8
Abstract

BackgroundClinical benefit from programmed cell death 1 receptor (PD-1) inhibitors relies on reinvigoration of endogenous antitumor immunity. Nonetheless, robust immunological markers, based on circulating immune cell subsets associated with therapeutic efficacy are yet to be validated.MethodsWe isolated peripheral blood mononuclear cell from three independent cohorts of melanoma and Merkel cell carcinoma patients treated with PD-1 inhibitor, at baseline and longitudinally after therapy. Using multiparameter flow cytometry and cell sorting, we isolated four subsets of CD8+ T cells, based on PD-1 and TIGIT expression profiles. We performed phenotypic characterization, T cell receptor sequencing, targeted transcriptomic analysis and antitumor reactivity assays to thoroughly characterize each of these subsets.ResultsWe documented that the frequency of circulating PD-1+TIGIT+ (DPOS) CD8+ T-cells after 1 month of anti-PD-1 therapy was associated with clinical response and overall survival. This DPOS T-cell population was enriched in highly activated T-cells, tumor-specific and emerging T-cell clonotypes and T lymphocytes overexpressing CXCR5, a key marker of the CD8 cytotoxic follicular T cell population. Additionally, transcriptomic profiling defined a specific gene signature for this population as well as the overexpression of specific pathways associated with the therapeutic response.ConclusionsOur results provide a convincing rationale for monitoring this PD-1+TIGIT+ circulating population as an early cellular-based marker of therapeutic response to anti-PD-1 therapy.

Published
2020
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3. Transcriptomic features of tumour- infiltrating CD4 low CD8 high double positive αβ T cells in melanoma

Author

Parrot, Tiphaine, Oger, Romain, Allard, Mathilde, Desfrançois, Juliette, Raingeard de la Blétìère, Diane, Coutolleau, Anne, Preisser, Laurence, Khammari, Amir, Dréno, Brigitte, Delneste, Yves, Guardiola, Philippe, Fradin, Delphine, Gervois, Nadine, Anti-Tumor Immunosurveillance and Immunotherapy (CRCINA-ÉQUIPE 3), 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), LabEX IGO Immunothérapie Grand Ouest, Nuclear Oncology (CRCINA-ÉQUIPE 13), Plateforme CYTOCELL Nantes (CRCINA-CYTOCELL), Service de Génomique Onco-Hématologique [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Clinical and Translational Research in Skin Cancer (CRCINA-ÉQUIPE 2), Immunogenic Cell Death and Mesothelioma Therapy (CRCINA-ÉQUIPE 4), Cancéropôle Grand OuestRégion Pays de la LoireLigue Nationale contre le Cancer, ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), 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), Nantes Université (Nantes Univ), Bernardo, Elizabeth, and Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID

Subjects
[SDV.CAN] Life Sciences [q-bio]/Cancer, lcsh:R, lcsh:Medicine, lcsh:Q, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:Science
Abstract

International audience; Peripheral CD4 + CD8 + double positive (DP) T cells are a phenotypically and functionally heterogeneous population depending on their origin and pathologic context. We previously identified among tumour infiltrating lymphocytes in melanoma, a tumour-reactive MHC class-I restricted CD4 low CD8 high DP αβ T-cell subpopulation with CD4-like function. In this study, we used an in-depth comparative transriptomic analysis of intra-melanoma DP T cells and CD4 and CD8 single positive (SP) T cells, to better comprehend the origin of this DP phenotype, and define the transcriptomic signature of activated DP T cells. We observed that intra-melanoma DP T cells were transcriptome-wise closer to their CD8 SP T-cell counterparts in terms of number of genes differentially expressed (97 in common with CD8 SP T cells and 15 with CD4 SP T cells) but presented hallmarks of a transition to a CD4-like functional profile (CD40LG) with a decreased cytotoxic signature (KLRC1) in favour of an increased cytokine-receptor interaction signature (IL4, IL24, IL17A…). This unleashed CD4-like program could be the results of the observed unbalanced expression of the THPOK/Runx3 transcription factors in DP T cells. Overall, this study allow us to speculate that intra-melanoma DP T cells arise from CD8 SP T cells being reprogrammed to a helper function. Contrary to the CD4 + CD8 + double positive (DP) thymocytes, well described as a T cell development stage, peripheral DP αβ T cells had attracted less attention mostly because of their weak frequency in the peripheral blood of healthy human donors (1 to 3%) 1,2. Nonetheless, following diverse inflammatory processes from viral or parasitic infections 3-5 , to autoimmune diseases 6,7 or cancer 8-14 , this subpopulation can become quite predominant in the blood or in the inflamed tissue/organ. This suggests a causal relationship between DP T cell emergence and disease. From these studies, DP T cells appeared as a more heterogeneous population than initially thought. Based on the co-expression level of the CD8 and CD4 co-receptors, peripheral DP T cells can be subdivided into three major subtypes: (i) the CD4 high CD8 low phenotype expressing the CD8αα homodimer, (ii) the CD4 high CD8 high phenotype and (iii) the CD4 low CD8 high phenotype both expressing the CD8αβ heterodimer 15,16. Although not always clearly demonstrated, these diverse phenotypes are presumably resulting from diverse origins. Thus, it has been proposed that CD4 high CD8 low DP T cells derive from peripheral CD4 T cells that following activation with the appropriate co-stimuli such as IL-4, TGF-β or retinoic acid can induce the CD8αα co-receptor expression at a low level 17. On the other hand, the CD4 low CD8 high phenotype is considered to be emerging from peripheral CD8 T cells that after activation with strong stimuli can reexpress the CD4 co-receptor at a low level 18,19. Regarding the CD4 high CD8 high phenotype, less is known and either a thymus or a peripheral origin can be considered. In our previous work, we have described the enrichment in the tumour infiltrate of several solid cancers including melanoma, of a class-I-restricted DP T-cell population presenting the CD4 low CD8 high phenotype 9,10. This population was not increased in the peripheral blood suggesting the influence of the tumour microenviron-ment upon the development of DP T cells. Because of their class-I restriction and their CD4 low CD8 high phenotype

Published
2020
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4. IL-9 promotes the survival and function of human melanoma-infiltrating CD4+CD8+double-positive T cells

Author

Nathalie Labarrière, Yves Delneste, Nadine Gervois, Romain Oger, Houssem Benlalam, Diane Raingeard de la Blétière, Tiphaine Parrot, Amir Khammari, Laurence Preisser, Mathilde Allard, Anne Coutolleau, Juliette Desfrançois, Philippe Guardiola, Brigitte Dréno, 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), Plateforme SNP, Transcriptome & Epigénomique, PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Plateforme CYTOCELL Nantes (CRCINA-CYTOCELL), 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), GMP Unit of Cellular Therapy, Centre hospitalier universitaire de Nantes (CHU Nantes), Unit of Skin Cancer, Canceropole Grand Ouest, Région Pays de la Loire, ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), 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), Bernardo, Elizabeth, and Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID

Subjects
CD4-Positive T-Lymphocytes, Cytotoxicity, Immunologic, 0301 basic medicine, [SDV.IMM] Life Sciences [q-bio]/Immunology, Cell Survival, Immunology, Gene Expression, [SDV.CAN]Life Sciences [q-bio]/Cancer, Apoptosis, CD8-Positive T-Lymphocytes, Biology, Lymphocyte Activation, 03 medical and health sciences, Interleukin 21, Lymphocytes, Tumor-Infiltrating, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, T-Lymphocyte Subsets, Humans, Immunology and Allergy, Cytotoxic T cell, Interleukin 9, Melanoma, Cells, Cultured, Receptors, Interleukin-9, Interleukin-9, Degranulation, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, T lymphocyte, 3. Good health, Granzyme B, 030104 developmental biology, Cancer research, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cytokines, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, CD8
Abstract

International audience; We previously demonstrated an accumulation of tumor-reactive CD4 + CD8 + double positive (DP) T cells within melanoma-infiltrating lymphocytes, supporting their role in the regulation of anti-tumor immune responses. Similarly to their CD8 + counterparts, intra-tumor DP T cells are MHC class-I restricted but differed by a limited lytic activity against autologous melanoma cells. Based on these observations and to further characterize DP T cells, both populations were compared at the transcriptional level. Our results revealed the overexpression of the IL-9 receptor (IL-9R) by DP T cells and prompted us to investigate the impact of IL-9 on their biology. We show that IL-9 favors DP T-cell survival by protecting them from apoptosis and by promoting their proliferation. In addition, IL-9 enhances their ability to produce cytokines and increased their levels of granzyme B/perforin as well as degranulation capacity, leading to a strengthened cytotoxic activity against melanoma cells. Taken together, the IL-9R high DP T-cell population could be a new preferential target for IL-9, which could take part in their retention within the melanoma infiltrate while also favoring their anti-tumor activity. More generally, our results extend the pleiotropic effects of IL-9 to IL-9R-expressing intra-tumor T cells, which could further potentiate anti-tumor immune responses. Keywords: CD4 + CD8 + double-positive T lymphocyte r IL-9R r IL-9 r Melanoma r TIL Additional supporting information may be found in the online version of this article at the publisher's web-site

Published
2016
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5. The inflammasome of tumor cells modulates the biology of tumor-infiltrating T lymphocytes in colorectal cancer

Author

Bilonda, Linda, Dansette, Delphine, Deleine, Cécile, Oger, Romain, Jouand, Nicolas, Podevin, Juliette, Fourquier, Pierre, Thibaudeau, Emilie, Chetritt, Jérôme, Mosnier, Jean-François, Bossard, Céline, Gervois, Nadine, Jarry, Anne, Anti-Tumor Immunosurveillance and Immunotherapy (CRCINA-ÉQUIPE 3), 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), Département de Pathologie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Plateforme CYTOCELL Nantes (CRCINA-CYTOCELL), Nouvelles Cliniques Nantaises - NCN [Nantes], Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Institut d'Histopathologie [Nantes], Bernardo, Elizabeth, and 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)

Subjects
[SDV.CAN] Life Sciences [q-bio]/Cancer, chemical and pharmacologic phenomena, [SDV.CAN]Life Sciences [q-bio]/Cancer
Abstract

International audience; In colorectal cancer (CRC), little is known about mechanisms by which tumor cells can influence the biology of Tumor Infiltrating T lymphocytes (TILs) present in the tumor microenvironment. One of these mechanisms could be modulation of the inflammasome of tumor cells. The inflammasome is a molecular platform present in normal intestinal epithelial cells, whose effector protein, caspase-1, can rapidly mature IL-18 and generate a mucosal Th1 (IFNγ) response. However, the inflammasome status of tumor cells in CRC and its potential role in the biology of TILs are unknown yet. This prospective study aimed to determine in CRC patients (n = 50) : i) the status of the inflammasome (caspase-1 / IL-18 axis) in tumor cells according to their microsatellite status [unstable (MSI) or stable (MSS)], in relation with the density of Th1/Tc1 TILs (T-bet+) and with the levels of the prototype Th1 cytokine IFNγ, secreted in an ex vivo explant culture model of CRC we developed and ii) the impact of the inflammasome-dependent cytokines potentially secreted by tumor cells on the biology of isolated TILs. Our study delineates two major groups of patients. The first group (33% of cases, mostly MSS with a low immunoscore) featured no active caspase-1 in tumor cells, no or low levels of mature IL-18 and IFNγ and only few T-bet+ TILs in the tumor microenvironment. This profile could correspond to an immune escape mechanism facilitating tumor progression. The second group (66% of cases, both MSI and MSS with high immunoscore) featured active caspase-1 in tumor cells associated with mature IL-18 secretion, high density of T-bet+ TILs expressing IL-18Rα and IFNγ release in most cases. In addition, isolated IL-18Rα+ TILs cultured with recombinant IL-18 were able to secrete IFNγ, either left unstimulated or stimulated with anti-CD3. In these CRC, the inflammasome of tumor cells, maintained and active, can contribute to a Th1/Tc1 antitumor response elicited by TILs present in the microenvironment that can modulate tumor growth. Interestingly, in a few cases of this second group (MSI CRC), the numerous T-bet+ TILs were unable to generate a Th1 response. Noticeably, these TILs express numerous immune checkpoints including PD1 and TIGIT, potentially responsible for their exhaustion. This study is the first to delineate functional interactions between tumor cells and TILs in CRC, using ex vivo explant cultures. Altogether, our findings support the inflammasome of tumor cells as a potential new therapeutic target to strengthen the Th1/Tc1 immune response in CRC, in association with immune checkpoint blockers. This work is supported by the “Ligue contre le Cancer Grand Ouest”Citation Format: Linda Bilonda, Delphine Dansette, Cecile Deleine, Romain Oger, Nicolas Jouand, Juliette Podevin, Pierre Fourquier, Emilie Thibaudeau, Jerome Chetritt, Jean-François Mosnier, Celine Bossard, Nadine Gervois, Anne Jarry. The inflammasome of tumor cells modulates the biology of tumor-infiltrating T lymphocytes in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4061.

Published
2018
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6. PEGylated Anionic Magneto-Fluorescent Nanoassemblies: Impact of their Interface Structure on MRI Contrast and Cellular Uptake

Author

Linot, Camille, Poly, Julien, Boucard, Joanna, Pouliquen, Daniel, Nedellec, Steven, Hulin, Philippe, Marec, Nadège, Arosio, Paolo, Lascialfari, Alessandro, Guerrini, Andrea, Sangregorio, Claudio, Lecouvey, Marc, Lartigue, Lenaic, Blanquart, Christophe, Ishow, Eléna, Bernardo, Elizabeth, Immunogenic Cell Death and Mesothelioma Therapy (CRCINA-ÉQUIPE 4), 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), Institut de Science des Matériaux de Mulhouse (IS2M), Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-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 de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Chimie Et Interdisciplinarité : Synthèse, Analyse, Modélisation (CEISAM), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Structure fédérative de recherche François Bonamy (SFR François Bonamy), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN), Plateforme CYTOCELL Nantes (CRCINA-CYTOCELL), Dipartimento di Fisica = Department of Physics [Univ Pavia] (UNIPV), Università degli Studi di Pavia = University of Pavia (UNIPV), Università degli Studi di Milano = University of Milan (UNIMI), Istituto di Chimica dei Composti Organometallici (ICCOM), Consiglio Nazionale delle Ricerche (CNR), Chimie, Structures et Propriétés de Biomatériaux et d'Agents Thérapeutiques (CSPBAT), Université Paris 13 (UP13)-Institut Galilée-Université Sorbonne Paris Cité (USPC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), The 'Ligue contre le cancer 44' is gratefully acknowledged for their strong support as well as CNRS through its 'Mission pour l’Interdisciplinarité' board (program 'Nano Challenge: Health and Welfare' / ETHICAM project) and its France-Italy partnership (program PICS / MOCACINO project), and Région des Pays de la Loire through the PhD program of LUMOMAT RFI (ONASSIS project)., 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), Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Department of Physics [Pavia], Università degli Studi di Pavia, Università degli Studi di Milano [Milano] (UNIMI), and Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 13 (UP13)-Institut Galilée-Université Sorbonne Paris Cité (USPC)

Subjects
live cells, [SDV.CAN] Life Sciences [q-bio]/Cancer, iron oxide nanoparticles water-soluble RAFT polymers, organic nanoparticles, spheroids, [SDV.CAN]Life Sciences [q-bio]/Cancer, fluorescence, Multimodal nanoassemblies, MRI
Abstract

International audience; Controlling the interactions of functional nanostructures with water and biological media represents high challenges in the field of bioimaging applications. Large contrast at low doses, high colloidal stability in physiological conditions, absence of cell cytotoxicity and efficient cell internalization represent strong additional needs. To achieve such requirements, we report on high payload magneto-fluorescent architectures, made of a shell of superparamagnetic iron oxide nanoparticles tightly anchored around fluorescent organic nanoparticles. Their external coating is simply modulated using anionic polyelectrolytes in a final step to provide efficient MRI and fluorescence imaging of live cells. Various structures of pegylated polyelectrolytes have been synthesized and investigated, differing from their iron oxide complexing units (carboxylic versus phosphonic acid), their structure (block or comb-like), their hydrophobicity and their fabrication process (conventional or RAFT-controlled radical polymerization) while keeping the central magneto-fluorescent platforms the same. Combined photophysical, magnetic, NMRD and structural investigations proved the superiority of RAFT polymer coatings containing carboxylate units and a hydrophobic tail to impart the magnetic nanoassemblies with enhanced-MRI negative contrast, characterized by a high r2/r1 ratio andtransverse relaxation r2 equal to 21 and 125 s-1mmol-1L respectively at 60 MHz clinical frequency (~1.5 T). Thanks to their dual modality, cell internalization of the nanoassemblies in mesothelioma cancer cells could be evidenced both by confocal fluorescence microscopy and magnetophoresis. A 72 h follow-up showed efficient uptake after 24 h with no notable cell mortality. These studies again pointed out the distinct behavior of RAFT polyelectrolyte-coated bimodal nanoassemblies that internalize at a slower rate with no adverse cytotoxicity. Extension to multicellular tumor cell spheroids that mimic solid tumors revealed successful internalization of the nanoassemblies in the periphery cells, which provides efficient deep-imaging labels thanks to their induced T2* contrast, large emission Stokes shift and bright dot-like signal, popping out of the strong spheroid autofluorescence.

Published
2017
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7. Intraepithelial CD94+ tumor-infiltrating lymphocytes in a context of HLA-E overexpression as a new immune checkpoint to predict prognosis in colorectal carcinomas

Author

Edouard Leveque, Anne Jarry, Delphine Dansette, Nicolas Jouand, Tamara Matysiak, Emilie Thibaudeau, Juliette Podevin, Olivier Kerdraon, Jerome Chetritt, Jean-François Mosnier, Pierre Fourquier, Stéphane Bézieau, Nadine Gervois, Juliette Eugene, Céline Bossard, Anti-Tumor Immunosurveillance and Immunotherapy (CRCINA-ÉQUIPE 3), 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), Département de Pathologie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Plateforme CYTOCELL Nantes (CRCINA-CYTOCELL), Service de Chirurgie Digestive et Endocrinienne [CHU Nantes] (Hôtel Dieu), 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), and Bernardo, Elizabeth

Subjects
Cancer Research, business.industry, Tumor-infiltrating lymphocytes, Immune resistance, hemic and immune systems, [SDV.CAN]Life Sciences [q-bio]/Cancer, chemical and pharmacologic phenomena, Context (language use), Tumor cells, Immune control, digestive system diseases, Immune checkpoint, 3. Good health, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, Oncology, HLA-E, Immunology, Medicine, business
Abstract

e14592 Background: A better understanding of the immune-modulating interactions between tumor cells and immune cells underlying the balance between immune control and immune resistance in colorectal cancer (CRC) is crucial for the design of immunotherapies. We have previously demonstrated that overexpression of the human MHC class Ib molecule - HLA-E/β2 microglobulin - by tumor cells in CRC was associated with an unfavorable prognosis, suggesting its involvement in immune escape. However, the specific receptor of HLA-E/β2m - CD94/NKG2A, inhibitory or CD94/NKG2C, activating - expressed by tumor-infiltrating lymphocytes (TIL), as well as the influence of the microsatellite status in HLA-E/β2m overexpression, remain unknown. Methods: We investigated in the primary tumor of 245 CRC patients 1) the association of HLA-E/β2m overexpression and the density of CD94+ intraepithelial TIL (IEL-TIL) with the microsatellite status, 2) the nature of CD94+ TIL and the receptor expressed - CD94/NKG2A or CD94/NKG2C - and 3) the prognostic influence of CD94+ IEL-TIL. Results: HLA-E/β2m was preferentially overexpressed in MSI compared with MSS CRC (44,6 % vs 18,4 % respectively, p = 0.0001), and significantly associated with a high density of CD94+ IEL-TIL in MSI (0,9% in HLA-E/β2m+ vs 0,2% in HLA-E/β2m– CRC, p = 0,001), and in MSS CRC (0,38% vs 0,15%, p < 0,0001). These CD94+ TIL mostly corresponded to CD8+ αβ T cells preferentially expressing the inhibitory NKG2A chain. Finally, a high density of CD94+ IEL-TIL was independently associated with a worse OS (p = 0.03). Conclusions: These results strongly suggest that HLA-E/β2m - CD94/NKG2A interactions, preferentially up-regulated in MSI CRC, represent a promising inhibitory immune checkpoint. From a clinical point of view, this inhibitory immune checkpoint could be blocked by the new anti-NKG2A monoclonal antibody.

Published
2017
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