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1. Oncolytic viruses alter the biogenesis of tumor extracellular vesicles and influence their immunogenicity

Author: Ugo Hirigoyen, Coraly Guilbaud, Morgane Krejbich, Morgane Fouet, Judith Fresquet, Bastien Arnaud, Emmanuelle Com, Charles Pineau, Gwenann Cadiou, Julien Burlaud-Gaillard, Philippe Erbs, Delphine Fradin, Nathalie Labarrière, Jean-François Fonteneau, Tacien Petithomme, and Nicolas Boisgerault
Subjects: MT: Regular Issue, oncolytic viruses, extracellular vesicles, vesicular stomatitis virus, vaccinia virus, t cell, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Extracellular vesicles (EVs) are mediators of intercellular communication in the tumor microenvironment. Tumor EVs are commonly associated with metastasis, immunosuppression or drug resistance. Viral infections usually increase EV secretion, but little is known about the effect of oncolytic viruses (OVs) on tumor EVs. Here, we investigated the impact of oncolytic vesicular stomatitis virus (VSV) and vaccinia virus on EVs secreted by human melanoma and thoracic cancer cells. We found that OV infection increases the production of EVs by tumor cells. These EVs contain proteins of viral origin, such as VSV-G, thus creating a continuum of particles sharing markers of both canonical EVs and viruses. As such, the presence of VSV-G on EVs improves the transfer of their protein content to cell types commonly found in the tumor microenvironment. A proteomic analysis also revealed that EVs-OV secreted during VSV infection are enriched in immunity-related proteins. Finally, CD8+ T cells incubated with EVs-OV from infected cells display slightly enhanced cytotoxic functions. Taken together, these data suggest that OVs enhance the communication mediated by tumor EVs, which could participate in the therapeutic efficacy of OVs. These results also provide rationale for engineering OVs to exploit EVs and disseminate therapeutic proteins within the tumor microenvironment.
Published: 2024
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2. hnRNP‐A1 binds to the IRES of MELOE‐1 antigen to promote MELOE‐1 translation in stressed melanoma cells

Author: Maud Charpentier, Emilie Dupré, Agnès Fortun, Floriane Briand, Mike Maillasson, Emmanuelle Com, Charles Pineau, Nathalie Labarrière, Catherine Rabu, and François Lang
Subjects: ER stress, IRES, ITAF, long noncoding RNA, melanoma, tumor antigens, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: The major challenge in antigen‐specific immunotherapy of cancer is to select the most relevant tumor antigens to target. To this aim, understanding their mode of expression by tumor cells is critical. We previously identified a melanoma‐specific antigen, melanoma‐overexpressed antigen 1 (MELOE‐1)—coded for by a long noncoding RNA—whose internal ribosomal entry sequence (IRES)‐dependent translation is restricted to tumor cells. This restricted expression is associated with the presence of a broad‐specific T‐cell repertoire that is involved in tumor immunosurveillance in melanoma patients. In the present work, we explored the translation control of MELOE‐1 and provide evidence that heterogeneous nuclear ribonucleoprotein A1 (hnRNP‐A1) binds to the MELOE‐1 IRES and acts as an IRES trans‐activating factor (ITAF) to promote the translation of MELOE‐1 in melanoma cells. In addition, we showed that endoplasmic reticulum (ER) stress induced by thapsigargin, which promotes hnRNP‐A1 cytoplasmic translocation, enhances MELOE‐1 translation and recognition of melanoma cells by a MELOE‐1‐specific T‐cell clone. These findings suggest that pharmacological stimulation of stress pathways may enhance the efficacy of immunotherapies targeting stress‐induced tumor antigens such as MELOE‐1.
Published: 2022
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3. Targeting NKG2A to boost anti-tumor CD8 T-cell responses in human colorectal cancer

Author: Kathleen Ducoin, Romain Oger, Linda Bilonda Mutala, Cécile Deleine, Nicolas Jouand, Juliette Desfrançois, Juliette Podevin, Emilie Duchalais, Jonathan Cruard, Houssem Benlalam, Nathalie Labarrière, Céline Bossard, Anne Jarry, and Nadine Gervois-Segain
Subjects: NKG2A, CD8+ TILs, colorectal cancer, immune checkpoint inhibitor, Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Recently, the inhibitory CD94/NKG2A receptor has joined the group of immune checkpoints (ICs) and its expression has been documented in NK cells and CD8+ T lymphocytes in several cancers and some infectious diseases. In colorectal cancer (CRC), we previously reported that NKG2A+ tumor-infiltrating lymphocytes (TILs) are predominantly CD8+ αβ T cells and that CD94 overexpression and/or its ligand HLA-E were associated with a poor prognosis. This study aimed to thoroughly characterize the NKG2A+ CD8+ TIL subpopulation and document the impact of NKG2A on anti-tumor responses in CRC. Our findings highlight new features of this subpopulation: (i) enrichment in colorectal tumors compared to paired normal colonic mucosa, (ii) their character as tissue-resident T cells and their majority terminal exhaustion status, (iii) co-expression of other ICs delineating two subgroups differing mainly in the level of NKG2A expression and the presence of PD-1, (iv) high functional avidity despite reduced proliferative capacity and finally (v) inhibition of anti-tumor reactivity that is overcome by blocking NKG2A. From a clinical point of view, these results open a promising alternative for immunotherapies based on NKG2A blockade in CRC, which could be performed alone or in combination with other IC inhibitors, adoptive cell transfer or therapeutic vaccination.
Published: 2022
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4. The DCMU Herbicide Shapes T-cell Functions By Modulating Micro-RNA Expression Profiles

Author: Pierre Autin, Sophie Deshayes, Juliette Lea, Nicolas Boisgerault, Emilie Dupré, Nathalie Labarrière, Rémy Leguevel, Jean-François Fonteneau, Christophe Blanquart, and Delphine Fradin
Subjects: diuron, herbicide, CD8+ T cells, micro-RNA, cancer, Immunologic diseases. Allergy, RC581-607
Abstract: DCMU [N-(3,4-dichlorophenyl)-N-dimethylurea] or diuron is a widely used herbicide, which can cause adverse effects on human, especially on immune cells, due to their intrinsic properties and wide distribution. These cells are important for fighting not only against virus or bacteria but also against neoplastic cell development. We developed an approach that combines functional studies and miRNA and RNA sequencing data to evaluate the effects of DCMU on the human immune response against cancer, particularly the one carried out by CD8+ T cells. We found that DCMU modulates the expression of miRNA in a dose-dependent manner, leading to a specific pattern of gene expression and consequently to a diminished cytokine and granzyme B secretions. Using mimics or anti-miRs, we identified several miRNA, such as hsa-miR-3135b and hsa-miR-21-5p, that regulate these secretions. All these changes reduce the CD8+ T cells’ cytotoxic activity directed against cancer cells, in vitro and in vivo in a zebrafish model. To conclude, our study suggests that DCMU reduces T-cell abilities, participating thus to the establishment of an environment conducive to cancer development.
Published: 2022
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5. 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, and Jacques Le Pendu
Subjects: COVID-19, O-glycans, natural antibodies, Tn antigen, histo-blood group antigens, Microbiology, QR1-502
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.
Published: 2021
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6. PD-1 and TIGIT coexpression identifies a circulating CD8 T cell subset predictive of response to anti-PD-1 therapy

Author: Nathalie Labarrière, Sylvain Simon, Virginie Vignard, Tiffany Beauvais, Valentin Voillet, Camille Dabrowski, Nicolas Jouand, Amir Khammari, Cécile Braudeau, Régis Josien, Caroline Laheurte, François Aubin, Charles Nardin, Samuel Rulli, Raphael Gottardo, and Candice D Church
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Background Clinical 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.Methods We 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.Results We 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.Conclusions Our 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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7. Increased antitumor efficacy of PD-1-deficient melanoma-specific human lymphocytes

Author: Nathalie Labarrière, Lucine Marotte, Sylvain Simon, Virginie Vignard, Emilie Dupre, Malika Gantier, Jonathan Cruard, Jean-Baptiste Alberge, Melanie Hussong, Cecile Deleine, Jean-Marie Heslan, Jonathan Shaffer, Tiffany Beauvais, Joelle Gaschet, Emmanuel Scotet, Delphine Fradin, and Anne Jarry
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: BackgroundGenome editing offers unique perspectives for optimizing the functional properties of T cells for adoptive cell transfer purposes. So far, PDCD1 editing has been successfully tested mainly in chimeric antigen receptor T (CAR-T) cells and human primary T cells. Nonetheless, for patients with solid tumors, the adoptive transfer of effector memory T cells specific for tumor antigens remains a relevant option, and the use of high avidity T cells deficient for programmed cell death-1 (PD-1) expression is susceptible to improve the therapeutic benefit of these treatments.MethodsHere we used the transfection of CAS9/sgRNA ribonucleoproteic complexes to edit PDCD1 gene in human effector memory CD8+ T cells specific for the melanoma antigen Melan-A. We cloned edited T cell populations and validated PDCD1 editing through sequencing and cytometry in each T cell clone, together with T-cell receptor (TCR) chain’s sequencing. We also performed whole transcriptomic analyses on wild-type (WT) and edited T cell clones. Finally, we documented in vitro and in vivo through adoptive transfer in NOD scid gamma (NSG) mice, the antitumor properties of WT and PD-1KO T cell clones, expressing the same TCR.ResultsHere we demonstrated the feasibility to edit PDCD1 gene in human effector memory melanoma-specific T lymphocytes. We showed that PD-1 expression was dramatically reduced or totally absent on PDCD1-edited T cell clones. Extensive characterization of a panel of T cell clones expressing the same TCR and exhibiting similar functional avidity demonstrated superior antitumor reactivity against a PD-L1 expressing melanoma cell line. Transcriptomic analysis revealed a downregulation of genes involved in proliferation and DNA replication in PD-1-deficient T cell clones, whereas genes involved in metabolism and cell signaling were upregulated. Finally, we documented the superior ability of PD-1-deficient T cells to significantly delay the growth of a PD-L1 expressing human melanoma tumor in an NSG mouse model.ConclusionThe use of such lymphocytes for adoptive cell transfer purposes, associated with other approaches modulating the tumor microenvironment, would be a promising alternative to improve immunotherapy efficacy in solid tumors.
Published: 2020
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8. Thoracic and cutaneous sarcoid-like reaction associated with anti-PD-1 therapy: longitudinal monitoring of PD-1 and PD-L1 expression after stopping treatment

Author: Léa Paolini, Caroline Poli, Simon Blanchard, Thierry Urban, Anne Croué, Marie-Christine Rousselet, Sarah Le Roux, Nathalie Labarrière, Pascale Jeannin, and José Hureaux
Subjects: Lung cancer, Sarcoid-like reaction, Nivolumab, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Immune checkpoint inhibitors (ICI) target T cell inhibitory pathways that are responsible for cancer tolerance by down-modulating immune functions. ICI have revolutionized patients care with lung cancer. Nevertheless, restoring endogenous antitumor T-cell responses can induce immune related adverse events, such as sarcoidosis. Case presentation We report here the first case of a thoracic and cutaneous sarcoid-like reaction in a patient with a relapsing unresectable non-small cell lung cancer (NSCLC) treated with nivolumab, an anti-PD-1 mAb. The expression of PD-1 and its ligands, PD-L1 and PD-L2, was assessed by flow cytometry on peripheral blood mononuclear cells (PBMC) and compared to patients who had discontinued nivolumab therapy without having developed any immune related adverse events. PD-L1 expression was transiently increased on B cells, T cells and monocytes, whereas PD-L2 expression was not modulated. PD-1 was transiently undetectable when PD-L1 was maximal, before returning to basal level. Sarcoidosis spontaneously resolved, without corticotherapy. Conclusion This case sheds the light on a complex regulation of PD-L1 expression in vivo on PBMC after nivolumab arrest and triggers the question of monitoring the expression of immune checkpoint on immune cells during and after treatment with ICI.
Published: 2018
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9. Cancer vaccines: designing artificial synthetic long peptides to improve presentation of class I and class II T cell epitopes by dendritic cells

Author: Catherine Rabu, Laurie Rangan, Laetitia Florenceau, Agnès Fortun, Maud Charpentier, Emilie Dupré, Léa Paolini, Céline Beauvillain, Estelle Dupel, Jean-Baptiste Latouche, Olivier Adotevi, Nathalie Labarrière, and François Lang
Subjects: cancer vaccines, melanoma, synthetic long peptides, Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: There is now a consensus that efficient peptide vaccination against cancer requires that peptides should (i) be exclusively presented by professional APC and (ii) stimulate both CD4 and CD8-specific T cell responses. To this aim, in recent trials, patients were vaccinated with pools of synthetic long peptides (SLP) (15–30 aa long) composed of a potential class I epitope(s) elongated at both ends with native antigen sequences to also provide a potential class II epitope(s). Using MELOE-1 as a model antigen, we present an alternative strategy consisting in linking selected class I and class II epitopes with an artificial cathepsin-sensitive linker to improve epitope processing and presentation by DC. We provide evidence that some linker sequences used in our artificial SLPs (aSLPs) could increase up to 100-fold the cross-presentation of class I epitopes to CD8-specific T cell clones when compared to cross-presentation of the corresponding native long peptide. Presentation of class II epitopes were only slightly increased. We confirmed this increased cross-presentation after in vitro stimulation of PBMC from healthy donors with aSLP and assessment of CD8-specific responses and also in vivo following aSLP vaccination of HLA*A0201/HLA-DRB0101 transgenic mice. Finally, we provide some evidence that vaccination with aSLP could inhibit the growth of transplanted tumors in mice. Our data thus support the use of such aSLPs in future cancer vaccination trials to improve anti-tumor CD8 T cell responses and therapeutic efficacy.
Published: 2019
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10. Oncolytic viruses sensitize human tumor cells for NY-ESO-1 tumor antigen recognition by CD4+ effector T cells.

Author: Tiphaine Delaunay, Mathilde Violland, Nicolas Boisgerault, Soizic Dutoit, Virginie Vignard, Christian Münz, Monique Gannage, Brigitte Dréno, Kristine Vaivode, Dace Pjanova, Nathalie Labarrière, Yaohe Wang, E. Antonio Chiocca, Fabrice Le Boeuf, John C. Bell, Philippe Erbs, Frédéric Tangy, Marc Grégoire, and Jean-François Fonteneau
Subjects: oncolytic immunotherapy, oncolytic viruses, melanoma, cd4+ t lymphocytes, tumor-associated antigens, Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Oncolytic immunotherapy using oncolytic viruses (OV) has been shown to stimulate the antitumor immune response by inducing the release of tumor-associated antigens (TAA) and danger signals from the dying infected tumor cells. In this study, we sought to determine if the lysis of tumor cells induced by different OV: measles virus, vaccinia virus, vesicular stomatitis virus, herpes simplex type I virus, adenovirus or enterovirus, has consequences on the capacity of tumor cells to present TAA, such as NY-ESO-1. We show that the co-culture of NY-ESO-1neg/HLA-DP4pos melanoma cells with NY-ESO-1pos/HLA-DP4neg melanoma cells infected and killed by different OV induces an intercellular transfer of NY-ESO-1 that allows the recognition of NY-ESO-1neg/HLA-DP4pos tumor cells by an HLA-DP4/NY-ESO-1(157–170)-specific CD4+ cytotoxic T cell clone, NY67. We then confirmed this result in a second model with an HLA-DP4+ melanoma cell line that expresses a low amount of NY-ESO-1. Recognition of this cell line by the NY67 clone is largely increased in the presence of OV productive infection. Altogether, our results show for the first time another mechanism of stimulation of the anti-tumor immune response by OV, via the loading of tumor cells with TAA that sensitizes them for direct recognition by specific effector CD4+ T cells, supporting the use of OV for cancer immunotherapy.
Published: 2018
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11. CD4CD8αα lymphocytes, a novel human regulatory T cell subset induced by colonic bacteria and deficient in patients with inflammatory bowel disease.

Author: Guillaume Sarrabayrouse, Céline Bossard, Joe-Marc Chauvin, Anne Jarry, Guillaume Meurette, Elodie Quévrain, Chantal Bridonneau, Laurence Preisser, Karim Asehnoune, Nathalie Labarrière, Frédéric Altare, Harry Sokol, and Francine Jotereau
Subjects: Biology (General), QH301-705.5
Abstract: How the microbiota affects health and disease is a crucial question. In mice, gut Clostridium bacteria are potent inducers of colonic interleukin (IL)-10-producing Foxp3 regulatory T cells (Treg), which play key roles in the prevention of colitis and in systemic immunity. In humans, although gut microbiota dysbiosis is associated with immune disorders, the underlying mechanism remains unknown. In contrast with mice, the contribution of Foxp3 Treg in colitis prevention has been questioned, suggesting that other compensatory regulatory cells or mechanisms may exist. Here we addressed the regulatory role of the CD4CD8 T cells whose presence had been reported in the intestinal mucosa and blood. Using colonic lamina propria lymphocytes (LPL) and peripheral blood lymphocytes (PBL) from healthy individuals, and those with colon cancer and irritable bowel disease (IBD), we demonstrated that CD4CD8αα (DP8α) T lymphocytes expressed most of the regulatory markers and functions of Foxp3 Treg and secreted IL-10. Strikingly, DP8α LPL and PBL exhibited a highly skewed repertoire toward the recognition of Faecalibacterium prausnitzii, a major Clostridium species of the human gut microbiota, which is decreased in patients with IBD. Furthermore, the frequencies of DP8α PBL and colonic LPL were lower in patients with IBD than in healthy donors and in the healthy mucosa of patients with colon cancer, respectively. Moreover, PBL and LPL from most patients with active IBD failed to respond to F. prausnitzii in contrast to PBL and LPL from patients in remission and/or healthy donors. These data (i) uncover a Clostridium-specific IL-10-secreting Treg subset present in the human colonic LP and blood, (ii) identify F. prausnitzii as a major inducer of these Treg, (iii) argue that these cells contribute to the control or prevention of colitis, opening new diagnostic and therapeutic strategies for IBD, and (iv) provide new tools to address the systemic impact of both these Treg and the intestinal microbiota on the human immune homeostasis.
Published: 2014
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12. Supplementary Table 2 from MicroRNAs in Tumor Exosomes Drive Immune Escape in Melanoma

Author: Delphine Fradin, Nathalie Labarrière, Jean-François Fonteneau, Nicolas Jouand, Gwennan André-Grégoire, Nadège Marec, Maureen Labbé, and Virginie Vignard
Abstract: Supplementary Table 2
Published: 2023

13. Supplementary Figures 1-7 and Supplementary Tables 1 and 3 from MicroRNAs in Tumor Exosomes Drive Immune Escape in Melanoma

Author: Delphine Fradin, Nathalie Labarrière, Jean-François Fonteneau, Nicolas Jouand, Gwennan André-Grégoire, Nadège Marec, Maureen Labbé, and Virginie Vignard
Abstract: Supplementary Figures 1-7 and Supplementary Tables 1 and 3
Published: 2023

14. hnRNP‐A1 binds to the IRES of MELOE‐1 antigen to promote MELOE‐1 translation in stressed melanoma cells

Author: Emmanuelle Com, François Lang, Charles Pineau, Catherine Rabu, Nathalie Labarrière, Agnès Fortun, Emilie Dupré, Floriane Briand, Maud Charpentier, and Mike Maillasson
Subjects: Cancer Research, Heterogeneous Nuclear Ribonucleoprotein A1, medicine.medical_treatment, Internal Ribosome Entry Sites, Biology, 03 medical and health sciences, 0302 clinical medicine, Antigen, IRES, Antigens, Neoplasm, melanoma, Genetics, medicine, Humans, long noncoding RNA, RC254-282, Research Articles, 030304 developmental biology, 0303 health sciences, Melanoma, Endoplasmic reticulum, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Translation (biology), General Medicine, Immunotherapy, medicine.disease, ITAF, Neoplasm Proteins, 3. Good health, Cell biology, Internal ribosome entry site, tumor antigens, Oncology, Protein Biosynthesis, 030220 oncology & carcinogenesis, Unfolded protein response, Molecular Medicine, ER stress, Ribosomes, Research Article
Abstract: The major challenge in antigen‐specific immunotherapy of cancer is to select the most relevant tumor antigens to target. To this aim, understanding their mode of expression by tumor cells is critical. We previously identified a melanoma‐specific antigen, melanoma‐overexpressed antigen 1 (MELOE‐1)—coded for by a long noncoding RNA—whose internal ribosomal entry sequence (IRES)‐dependent translation is restricted to tumor cells. This restricted expression is associated with the presence of a broad‐specific T‐cell repertoire that is involved in tumor immunosurveillance in melanoma patients. In the present work, we explored the translation control of MELOE‐1 and provide evidence that heterogeneous nuclear ribonucleoprotein A1 (hnRNP‐A1) binds to the MELOE‐1 IRES and acts as an IRES trans‐activating factor (ITAF) to promote the translation of MELOE‐1 in melanoma cells. In addition, we showed that endoplasmic reticulum (ER) stress induced by thapsigargin, which promotes hnRNP‐A1 cytoplasmic translocation, enhances MELOE‐1 translation and recognition of melanoma cells by a MELOE‐1‐specific T‐cell clone. These findings suggest that pharmacological stimulation of stress pathways may enhance the efficacy of immunotherapies targeting stress‐induced tumor antigens such as MELOE‐1., Our study demonstrates that reticular stress in melanoma cells promoted the translocation of the IRES transacting factor hnRPN‐A1 to the cytoplasm. By binding to the IRES site of meloe mRNA, hnRPN‐A1 promoted the translation of the melanoma‐specific antigen MELOE‐1 and led to the expression of a new immunogenic HLA/peptide complex at the cell surface. Altogether, our data suggest that pharmacological stimulation of stress pathways may enhance the efficacy of T‐cell based immunotherapies in targeting stress‐induced tumor antigens, such as MELOE‐1 in patients with melanoma.
Published: 2021

15. STING‐ATF3/type I interferon crosstalk: A potential target to improve anti‐tumour immunity in chemotherapy‐treated urothelial carcinoma

Author: Alexandra Fauvre, Margot Machu, Audrey Merienne, Nadia Vie, Thomas Bessede, Mathilde Robin, Veronique Garambois, Clara Taffoni, Nadine Laguette, Nadine Gervois‐Segain, Anne Jarry, Nathalie Labarriere, Yves Allory, Christel Larbouret, Laurent Gros, Diego Tosi, David B. Solit, Philippe Pourquier, Nadine Houédé, and Celine Gongora
Subjects: Medicine (General), R5-920
Published: 2024
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16. Selective SIRPα blockade reverses tumor T cell exclusion and overcomes cancer immunotherapy resistance

Author: Riad Abes, Kevin Biteau, Alexandre Glémain, Christophe Blanquart, Dominique Costantini, Catherine Ruiz, David Laplaud, Hélène Aublé, Stéphanie Le Bas-Bernardet, E. Sergio Trombetta, Véronique Catros, Gilles Blancho, Isabelle Archambeaud, Sylvie Métairie, Isabelle Girault, Emmanuelle Wilhelm, Masayuki Miyasaka, Jean-François Mosnier, Vanessa Gauttier, Sabrina Pengam, Charlène Trilleaud, Alexandra Garcia, Pierre-Antoine Gouraud, Pierre Duplouye, Bernard Martinet, Géraldine Teppaz, Georgia Porto, Fabienne Haspot, Sarah Bruneau, Aurore Morello, Justine Durand, Caroline Mary, Richard Danger, Sophie Conchon, Nathalie Labarrière, Kerry L. M. Ralph, Virginie Thepenier, Nicolas Vince, Nicolas Poirier, Bernard Vanhove, Virginie Vignard, Mélanie Néel, Safa Dehmani, OSE Immunotherapeutics [Nantes, France], Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), 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), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Boehringer Ingelheim Pharma GmbH & Co. KG, Osaka University, Anti-Tumor Immunosurveillance and Immunotherapy (CRCINA-ÉQUIPE 3), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), 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 Nantes (UN), Immunogenic Cell Death and Mesothelioma Therapy (CRCINA-ÉQUIPE 4), Nutrition, Métabolismes et Cancer (NuMeCan), 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)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CHU Pontchaillou [Rennes], Centre de Ressources Biologiques Santé (CRB Santé), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-CRLCC Eugène Marquis (CRLCC), Institut des maladies de l'appareil digestif [Nantes] (IMAD), BPI EFFI-CLIN PSPC grant,INCA MDSCAN PRT-K15-136, the French Public Bank of Investment and French Institut National du Cancer, 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 de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Rennes (UR)-CHU Pontchaillou [Rennes]-CRLCC Eugène Marquis (CRLCC), and Jonchère, Laurent
Subjects: 0301 basic medicine, T-Lymphocytes, [SDV]Life Sciences [q-bio], T cell, medicine.medical_treatment, Immunology, T cells, Cancer immunotherapy, Therapeutics, Mice, 03 medical and health sciences, 0302 clinical medicine, medicine, Animals, Receptors, Immunologic, Mice, Inbred BALB C, Tumor microenvironment, Chemistry, Macrophages, CD47, Mammary Neoplasms, Experimental, General Medicine, Immune checkpoint, Neoplasm Proteins, 3. Good health, Blockade, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Chemokine secretion, Cancer research, Female, Immunotherapy, Immunologic Memory, Memory T cell, Research Article
Abstract: International audience; T cell exclusion causes resistance to cancer immunotherapies via immune checkpoint blockade (ICB). Myeloid cells contribute to resistance by expressing signal regulatory protein-α (SIRPα), an inhibitory membrane receptor that interacts with ubiquitous receptor CD47 to control macrophage phagocytosis in the tumor microenvironment. Although CD47/SIRPα-targeting drugs have been assessed in preclinical models, the therapeutic benefit of selectively blocking SIRPα, and not SIRPγ/CD47, in humans remains unknown. We report a potent synergy between selective SIRPα blockade and ICB in increasing memory T cell responses and reverting exclusion in syngeneic and orthotopic tumor models. Selective SIRPα blockade stimulated tumor nest T cell recruitment by restoring murine and human macrophage chemokine secretion and increased anti-tumor T cell responses by promoting tumor-antigen crosspresentation by dendritic cells. However, nonselective SIRPα/SIRPγ blockade targeting CD47 impaired human T cell activation, proliferation, and endothelial transmigration. Selective SIRPα inhibition opens an attractive avenue to overcoming ICB resistance in patients with elevated myeloid cell infiltration in solid tumors.
Published: 2020

17. Author response for 'hnRNP‐A1 binds to the IRES of MELOE‐1 antigen to promote its translation in stressed melanoma cells'

Author: Agnès Fortun, Emilie Dupré, Nathalie Labarrière, Emmanuelle Com, François Lang, Charles Pineau, Floriane Briand, Catherine Rabu, Mike Maillasson, and Maud Charpentier
Subjects: Internal ribosome entry site, Antigen, Meloe, Melanoma, medicine, Translation (biology), Biology, medicine.disease, biology.organism_classification, Cell biology
Published: 2021

18. Phase I/II clinical trial of adoptive cell transfer of sorted specific T cells for metastatic melanoma patients

Author: François Lang, Sylvain Simon, Agnès Fortun, Amir Khammari, Virginie Vignard, Brigitte Dréno, Nicolas Jouand, Soraya Saiagh, Nathalie Labarrière, Tiffany Beauvais, Sylvain Bercegay, CIC - Nantes, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Centre hospitalier universitaire de Nantes (CHU Nantes), LabEX IGO Immunothérapie Grand Ouest, Unité de Thérapie Cellulaire et Génique [CHU Nantes] (UTCG), Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), CIC biothérapies CBT 0503 [Nantes], Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), 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), LABARRIERE, Nathalie, 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 Nantes Université (Nantes Univ)
Subjects: Oncology, Adult, Cancer Research, medicine.medical_specialty, Adoptive cell transfer, T-Lymphocytes, Immunology, Peripheral blood mononuclear cell, Immunotherapy, Adoptive, 03 medical and health sciences, 0302 clinical medicine, TIGIT, In vivo, Internal medicine, Cell Line, Tumor, Immunology and Allergy, Medicine, Humans, Avidity, Melanoma, 030304 developmental biology, Aged, 0303 health sciences, MELOE-1, business.industry, T-cell receptor, Melan-A, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Middle Aged, medicine.disease, 3. Good health, Clinical trial, Clinical Trial Report, 030220 oncology & carcinogenesis, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, business, TCR
Abstract: Adoptive cell transfer (ACT) of tumor-specific T lymphocytes represents a relevant therapeutic strategy to treat metastatic melanoma patients. Ideal T-cells should combine tumor specificity and reactivity with survival in vivo, while avoiding autoimmune side effects. Here we report results from a Phase I/II clinical trial (NCT02424916, performed between 2015 and 2018) in which 6 metastatic HLA-A2 melanoma patients received autologous antigen-specific T-cells produced from PBMC, after peptide stimulation in vitro, followed by sorting with HLA-peptide multimers and amplification. Each patient received a combination of Melan-A and MELOE-1 polyclonal specific T-cells, whose specificity and anti-tumor reactivity were checked prior to injection, with subcutaneous IL-2. Transferred T-cells were also characterized in terms of functional avidity, diversity and phenotype and their blood persistence was evaluated. An increase in specific T-cells was detected in the blood of all patients at day 1 and progressively disappeared from day 7 onwards. No serious adverse events occurred after this ACT. Clinically, five patients progressed and one patient experienced a partial response following therapy. Melan-A and MELOE-1 specific T-cells infused to this patient were diverse, of high avidity, with a high proportion of T lymphocytes co-expressing PD-1 and TIGIT but few other exhaustion markers. In conclusion, we demonstrated the feasibility and safety of ACT with multimer-sorted Melan-A and MELOE-1 specific T cells to metastatic melanoma patients. The clinical efficacy of such therapeutic strategy could be further enhanced by the selection of highly reactive T-cells, based on PD-1 and TIGIT co-expression, and a combination with ICI, such as anti-PD-1. Supplementary Information The online version contains supplementary material available at 10.1007/s00262-021-02961-0.
Published: 2021

19. Differential impact of genetic deletion of TIGIT or PD-1 on melanoma-specific T-lymphocytes

Author: Gwenann Cadiou, Tiffany Beauvais, Lucine Marotte, Sylvia Lambot, Cécile Deleine, Caroline Vignes, Malika Gantier, Melanie Hussong, Samuel Rulli, Anne Jarry, Sylvain Simon, Bernard Malissen, and Nathalie Labarriere
Subjects: Adoptive cell transfer, CD8+ T cell clones, gene editing, immunotherapy, melanoma, PD-1, Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Immune checkpoint (IC) blockade and adoptive transfer of tumor-specific T-cells (ACT) are two major strategies to treat metastatic melanoma. Their combination can potentiate T-cell activation in the suppressive tumor microenvironment, but the autoimmune adverse effects associated with systemic injection of IC blockers persist with this strategy. ACT of tumor-reactive T-cells defective for IC expression would overcome this issue. For this purpose, PD-1 and TIGIT appear to be relevant candidates, because their co-expression on highly tumor-reactive lymphocytes limits their therapeutic efficacy within the tumor microenvironme,nt. Our study compares the consequences of PDCD1 or TIGIT genetic deletion on anti-tumor properties and T-cell fitness of melanoma-specific T lymphocytes. Transcriptomic analyses revealed down-regulation of cell cycle-related genes in PD-1KO T-cells, consistent with biological observations, whereas proliferative pathways were preserved in TIGITKO T-cells. Functional analyses showed that PD-1KO and TIGITKO T-cells displayed superior antitumor reactivity than their wild-type counterpart in vitro and in a preclinical melanoma model using immunodeficient mice. Interestingly, it appears that TIGITKO T-cells were more effective at inhibiting tumor cell proliferation in vivo, and persist longer within tumors than PD-1KO T-cells, consistent with the absence of impact of TIGIT deletion on T-cell fitness. Taken together, these results suggest that TIGIT deletion, over PD-1 deletion, in melanoma-specific T-cells is a compelling option for future immunotherapeutic strategies.
Published: 2024
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20. Low Levels of Natural Anti-α

Author: Adrien, Breiman, Nathalie, Ruvoën-Clouet, Marie, Deleers, Tiffany, Beauvais, Nicolas, Jouand, Jézabel, Rocher, Nicolai, Bovin, Nathalie, Labarrière, Hanane, El Kenz, and Jacques, Le Pendu
Subjects: natural antibodies, Tn antigen, COVID-19, O-glycans, Microbiology, histo-blood group antigens, Original Research
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.
Published: 2020

21. 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

22. 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

23. Tumor infiltrating lymphocytes as adjuvant treatment in stage III melanoma patients with only one invaded lymph node after complete resection: results from a multicentre, randomized clinical phase III trial

Author: Soraya Saiagh, Brigitte Dréno, Bernard Guillot, Marie-Christine Pandolfino, Gaëlle Quéreux, Jean-Michel Nguyen, Nathalie Labarrière, Amir Khammari, Anne Chiffolettau, Anne-Chantal Knol, Marie-Thérèse Leccia, 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), Hôpital Michallon, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Unité de Thérapie Cellulaire et Génique [CHU Nantes] (UTCG), Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Régional de Pharmacovigilance [Nantes] (CRP), Anti-Tumor Immunosurveillance and Immunotherapy (CRCINA-ÉQUIPE 3), LabEX IGO Immunothérapie Grand Ouest, Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Bernardo, Elizabeth, 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 Nantes Université (Nantes Univ)
Subjects: Male, Cancer Research, medicine.medical_treatment, Immunotherapy, Adoptive, Gastroenterology, Complete resection, 0302 clinical medicine, Immunology and Allergy, Melanoma, Lymph node, 0303 health sciences, hemic and immune systems, Middle Aged, Prognosis, 3. Good health, Survival Rate, medicine.anatomical_structure, Oncology, Lymphatic Metastasis, 030220 oncology & carcinogenesis, Female, Adjuvant, Adult, medicine.medical_specialty, Adolescent, Immunology, chemical and pharmacologic phenomena, [SDV.CAN]Life Sciences [q-bio]/Cancer, Young Adult, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, Adjuvants, Immunologic, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Adjuvant therapy, Humans, Stage III melanoma, Adult stage, Aged, 030304 developmental biology, Tumor-infiltrating lymphocytes, business.industry, medicine.disease, Interleukin-2, Lymph Nodes, Neoplasm Recurrence, Local, business, Follow-Up Studies
Abstract: International audience; Background: Adoptive tumor-infiltrating lymphocytes (TIL) therapy and interleukin-2 (IL-2) have been investigated in melanoma.Aim: To confirm previously observed preventive effects of TIL + IL2 in a subgroup of patients with relapsing metastatic stage III melanoma.Methodology: Open-label, randomized two-group, multicenter five-year trial in adult stage III melanoma patients with only one invaded lymph node after complete resection. Patients received TIL + IL2 or abstention. TIL + IL2 was administered within 8 weeks after lymph node resection and 4 weeks after. Disease-free survival was assessed every 2 months up to month 18, every 3 months up to month 36 and every 4 months up to 5 years. A once-a-year follow-up was scheduled beyond the five-year follow-up. Safety was assessed throughout the trial.Results: Overall, 49 patients accounted for the modified intent-to-treat and 47 for the PP. Slightly more male than female patients participated; mean age was 57.7 ± 11.4 years in the TIL + IL2 group and 53.5 ± 13.0 years in the abstention group. After 5 years of follow-up, 11/26 patients in the TIL + IL2 group and 13/23 in the abstention group had relapsed. There was no statistical difference between the groups (HR: 0.63 CI 95% [0.28-1.41], p = 0.258), nine patients in the TIL + IL2 and 11 in the abstention group died with no significant difference between the two groups (HR: 0.65 CI95% [0.27 - 1.59], p = 0.34). Safety was good.Conclusion: We did not confirm results of a previous trial. However, ulceration of the primary melanoma may be considered predictive of the efficacy of TIL in melanoma in adjuvant setting, in a manner similar to interferon α.
Published: 2020

24. Viral and tumor antigen-specific CD8 T-cell responses in Merkel cell carcinoma

Author: Nathalie Labarrière, Pauline Gaboriaud, Laetitia Florenceau, Virginie Vignard, Delphine Fradin, Astrid Blom, Mahtab Samimi, Thibault Kervarrec, Houssem Benlalam, Pascal Aumond, Nadine Gervois, Antoine Touzé, Département de Dermathologie [CHRU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Laboratoire 'Biologie des infections à polyomavirus' [UNIV TOURS] (ISP-1282 INRA), Institut National de la Recherche Agronomique (INRA)-Université de Tours, Anti-tumor immunosurveillances and immunotherapy (CRCINA - Département INCIT - Equipe 3), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers (CRCINA), Université d'Angers (UA)-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 de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Université d'Angers (UA)-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 de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), LabEX IGO Immunothérapie Grand Ouest, Département de Pathologie [CHRU Tours], Université Francois Rabelais [Tours]-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Service de Dermatologie Générale et Oncologique [AP-HP Hôpital Ambroise-Paré, Paris], AP-HP Hôpital Ambroise Paré (Boulogne-Billancourt), This work was supported by the Canceropole Grand Ouest [POCAME] and was realized in the context of the LabEX IGO program supported by the National Research Agency via the investment of the future program ANR-11-LABX-0016-01'., ANR-11-LABX-0016/11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), 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), Infectiologie et Santé Publique (UMR ISP), Institut National de la Recherche Agronomique (INRA)-Université de Tours (UT), Nantes Université (Nantes Univ), Université Francois Rabelais [Tours], Hôpital Ambroise Paré [AP-HP], ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), LABARRIERE, Nathalie, Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID, 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 Régional Universitaire de Tours (CHRU Tours), and Université Francois Rabelais [Tours]-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)
Subjects: 0301 basic medicine, Male, Skin Neoplasms, [SDV.IMM] Life Sciences [q-bio]/Immunology, medicine.medical_treatment, Immunology, Merkel cell polyomavirus, Epitopes, T-Lymphocyte, [SDV.CAN]Life Sciences [q-bio]/Cancer, CD8-Positive T-Lymphocytes, Epitope, 03 medical and health sciences, 0302 clinical medicine, Immune system, Merkel cell carcinoma, Antigen, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigens, Neoplasm, HLA Antigens, Cell Line, Tumor, Chlorocebus aethiops, medicine, Cytotoxic T cell, Animals, Humans, Antigens, Viral, MAGE-A3, biology, food and beverages, Immunotherapy, TIL, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, biology.organism_classification, medicine.disease, Tumor antigen, 3. Good health, Neoplasm Proteins, Carcinoma, Merkel Cell, 030104 developmental biology, CD8 T lymphocytes, COS Cells, Cancer research, LT antigen, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, 030215 immunology
Abstract: International audience; Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous cancer, which is immunogenic, regardless of the presence of MCPyV (80% of cases). The identification of MCC-specific epitopes recognized by CD8 T cells is crucial to expand the arsenal of immunotherapeutic treatments. Until now, most efforts focused on the identification of virus-specific epitopes, whereas immune responses directed against shared cellular tumor-specific antigens have not been evidenced. In this study, we measured T-cell responses against viral (n = 3) and tumor antigens (n = 47) from TILs derived from 21 MCC tumors. Virus-specific CD8 T-cell responses dominated MCC-specific immune responses, and we identified two new HLA-peptide complexes derived from the LT antigen, located in a region encompassing 3 previously identified epitopes. Finally, we show that MAGE-A3 antigen, frequently expressed by MCC tumors, was recognized by CD8 TILs from a virus-negative MCC tumor and thus could be a target for immunotherapy in this setting.
Published: 2019

25. Cancer vaccines: designing artificial synthetic long peptides to improve presentation of class I and class II T cell epitopes by dendritic cells

Author: Léa Paolini, Olivier Adotevi, Maud Charpentier, E Dupel, Agnès Fortun, Emilie Dupré, Catherine Rabu, Nathalie Labarrière, Céline Beauvillain, L. Rangan, Jean-Baptiste Latouche, François Lang, Laetitia Florenceau, 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), LabEX IGO Immunothérapie Grand Ouest, 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), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Nantes (CHU Nantes)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes (UN)-Université d'Angers (UA), 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]), Anti-Tumor Immunosurveillance and Immunotherapy (CRCINA-ÉQUIPE 3), 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), LabEx IGO 'Immunotherapy, Graft, Oncology' [Nantes], Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Département de génétique [CHU Rouen] (Centre Normandie de Génomique et de Médecine Personnalisée), CHU Rouen, Normandie Université (NU)-Normandie Université (NU), This work was carried out with the support of the LabEx IGO project (n° ANR-11-LABX-0016–01) funded by the «Investissements d’Avenir» French Government program, managed by the French National Research Agency (ANR)., ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), Bernardo, Elizabeth, Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID, 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 Nantes Université (Nantes Univ)
Subjects: 0301 basic medicine, lcsh:Immunologic diseases. Allergy, [SDV.IMM] Life Sciences [q-bio]/Immunology, T cell, Immunology, Peptide, [SDV.CAN]Life Sciences [q-bio]/Cancer, Human leukocyte antigen, Biology, Cancer vaccines, lcsh:RC254-282, Epitope, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigen, medicine, melanoma, Immunology and Allergy, Cytotoxic T cell, ComputingMilieux_MISCELLANEOUS, Original Research, chemistry.chemical_classification, Cancer, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, synthetic long peptides, 3. Good health, Vaccination, 030104 developmental biology, medicine.anatomical_structure, Oncology, chemistry, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, lcsh:RC581-607
Abstract: International audience; There is now a consensus that efficient peptide vaccination against cancer requires that peptides should (i) be exclusively presented by professional APC and (ii) stimulate both CD4 and CD8-specific T cell responses. To this aim, in recent trials, patients were vaccinated with pools of synthetic long peptides (SLP) (15-30 aa long) composed of a potential class I epitope(s) elongated at both ends with native antigen sequences to also provide a potential class II epitope(s). Using MELOE-1 as a model antigen, we present an alternative strategy consisting in linking selected class I and class II epitopes with an artificial cathepsin-sensitive linker to improve epitope processing and presentation by DC. We provide evidence that some linker sequences used in our artificial SLPs (aSLPs) could increase up to 100-fold the cross-presentation of class I epitopes to CD8-specific T cell clones when compared to cross-presentation of the corresponding native long peptide. Presentation of class II epitopes were only slightly increased. We confirmed this increased cross-presentation after in vitro stimulation of PBMC from healthy donors with aSLP and assessment of CD8-specific responses and also in vivo following aSLP vaccination of HLA*A0201/HLA-DRB0101 transgenic mice. Finally, we provide some evidence that vaccination with aSLP could inhibit the growth of transplanted tumors in mice. Our data thus support the use of such aSLPs in future cancer vaccination trials to improve anti-tumor CD8 T cell responses and therapeutic efficacy. ARTICLE HISTORY
Published: 2019

26. TIL en adjuvant chez des patients au stade III du mélanome avec un seul ganglion envahi. Étude multicentrique de phase III

Author: Amir Khammari, M.-T. Leccia, A. Chiffoleau, S. Saiagh, Jean-Michel Nguyen, G. Quereux-Baumgartner, C. Frenard, Brigitte Dréno, Marie-Christine Pandolfino, Bernard Guillot, and Nathalie Labarrière
Subjects: Dermatology
Abstract: Introduction Le transfert adoptif par les lymphocytes infiltrant la tumeur (TIL) constitue l’approche cellulaire d’immunotherapie. Notre equipe a publie en 2002 l’etude phase I/II demontrant un effet benefique des TIL sur la survie sans recidive (SSR) et la survie globale (SG) dans un sous-groupe de patients avec un seul ganglion envahi lors du curage. L’objectif de cette etude de phase III etait de confirmer les resultats de la phase I/II. Materiel et methodes Etude prospective, randomisee, ouverte, multicentrique ( NCT00200577 ). L’objectif principal etait la SSR. Les objectifs secondaires etaient la SG, la tolerance et la reponse immune. Les principaux criteres d’inclusion : âge ≤ 75 ans, stade III avec un seul ganglion locoregional envahi et ECOG 0-2. Les patients etaient randomises dans un bras traite par TIL + IL2 et un bras controle-abstention ne recevant aucun traitement. Le bras TIL a recu deux injections TIL espacees de 4 semaines associees a 10 injections d’IL2 a 6 M UI en sc (J1-J5 et J8-J12). La SSR a ete evaluee tous les 2, 3 et 4 mois respectivement jusqu’a M18, M36 et 5 ans. La securite du traitement a ete evaluee selon les criteres CTCAE. Pour la taille de l’echantillon, 70 patients etaient attendus pour une difference de 35 % entre les deux bras dans une situation bilaterale avec un risque alpha de 5 % et un risque beta de 20 %. Resultats L’etude a porte sur 70 patients d’un âge moyen de 57,7 ± 11,4 ans dans le bras TIL et de 53,5 ± 13,0 ans dans le bras abstention et un sexe-ratio = 1,23. La quantite moyenne de TIL injectee etait de 8 × 109 ± 3,9 (3,5–19,6 × 109) contenant entre 0,005 et 2,5 × 109 (moyenne de 0,08 109) lymphocytes specifiques. L’analyse en intention de traiter modifiee et en per protocole ont porte respectivement sur 49 et 47 patients. Pour la SSR, 11/26 patients du bras TIL et 13/23 du bras abstention ont recidives sans difference statistique significative (HR : 0,63 CI 95 % [0,28–1,41], p = 0,26). Pour la SG, 9 patients du bras TIL et 11 du bras abstention sont decedes sans difference significative (HR : 0,65 CI 95 % [0,27–1,59], p = 0,35). La tolerance au traitement de l’etude a ete tres bonne sans evenement grave lie au transfert adoptif. Discussion Cette etude montre un benefice des patients traites par TIL aussi bien sur la survie sans recidive que la survie globale, mais sans que la survie soit statistiquement significative. Deux raisons principales pourraient expliquer ces resultats : un nombre de patients insuffisant et un changement de milieu de production des TIL, impose par l’ANSM, ayant conduit a une quantite moins importante de TIL contenant moins de T specifiques. En conclusion, la therapie adoptive par TIL reste une alternative dans la prise en charge du melanome et pourrait representer au stade metastatique une approche combinee avec les inhibiteurs de points de controle notamment les anti-PD-1.
Published: 2020

27. 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

28. Abstract 4476: PD-1 and TIGIT co-expression identifies a circulating CD8 T cell population predictive of response to anti-PD-1 therapy in melanoma and Merkel-cell carcinoma patients

Author: Stanley R. Riddell, Régis Josien, Camille Dabrowski, Olivier Adotevi, Virginie Vignard, Nathalie Labarrière, Raphael Gottardo, Amir Khammari, Tiffany Beauvais, Valentin Voillet, Cécile Braudeau, Steven P. Fling, Nirasha Ramchurren, Charles Nardin, Cheever Martin, Samuel Rulli, Brigitte Dréno, Paul Nghiem, Zhong Wu, Caroline Laheurte, Francçois Aubin, Nicolas Jouand, Sylvain Simon, and Candice D. Church
Subjects: Cancer Research, education.field_of_study, Tumor microenvironment, business.industry, T cell, Melanoma, Population, Cancer, medicine.disease, medicine.anatomical_structure, Oncology, TIGIT, Cancer research, Medicine, Cytotoxic T cell, business, education, CD8
Abstract: Immunotherapies targeting the PD-1 pathway have profoundly transformed the clinical care of cancer patients for a growing variety of cancer types. However, most patients do not experience durable clinical benefit. The definition of robust and convenient biomarkers of PD-1 therapy efficacy to stratify patients beforehand or early after initiation of the therapy that could guide therapeutic management is still lacking while being a very active research field. Biomarkers described to date include tumor burden, neoantigen load, presence and number of PD-1+ CD8+ at the tumor margin, T-cell inflamed tumor microenvironment and PD-L1 expression by the tumor cells or other immune cells and composition of the gut microbiota. Most of these parameters are closely related/influenced by the presence, activation status and functional capacities of CD8+ T cells infiltrating the tumor site demonstrating their pivotal role for anti-PD-1 mediated anti-tumor efficacy. A population of PD-1high CD8 TILs was consequently described as predictive of PD-1 blockade in NSCLC. The exact contribution for clinical efficacy of TILs versus distinct CD8+ T cells from peripheral origins recirculating to the tumor site remains to be elucidated. Notably, immunological responses to PD-1 blockade at the periphery were described within the very first days following the first therapy dose. Therefore, describing circulating cellular population predictive of PD-1 inhibitor efficacy could represent a convenient, non-invasive and rapid method to assess anti-tumor benefits. Original findings reported in this study identified a circulating CD8 T cell population delineated by the co-expression of TIGIT and PD-1 inhibitory receptors as an early immune marker of anti-PD-1 efficacy in three independent cohorts of cancer patients (two melanoma patient's cohorts and one Merkel-cell carcinoma patient's cohort). The frequency of this double positive (DPOS) population even appeared predictive of PD-1 inhibitor therapy efficacy at baseline in the MCC cohort. Furthermore, to understand the mechanistical relevance of this subset for PD-1 blockade efficacy, we thoroughly described this DPOS T cell subset by flow cytometry, gene expression analysis, anti-tumor reactivity assay and TCR repertoire analysis, and compared it to its double negative (DNEG), PD-1 and TIGIT single positive counterparts. This DPOS subset was enriched in activated and proliferative T cells, retained expression of co-stimulatory molecules and was enriched for common features with Tfc. Moreover, this subpopulation exhibited a specific gene signature, strongly predictive of long-term survival in melanoma patients (TCGA analyses). We demonstrated that this subpopulation was enriched in tumor-specific T-cells (ELISPOT analysis against 11 antigen-derived peptides). Finally, clustering of TCR clonotypes revealed that the DPOS T cell population was significantly enriched in emerging clonotypes in responding patients, after 1 month of anti-PD-1 therapy echoing recent work from others. Our findings provide a compelling rationale to measure PD-1+TIGIT+ CD8 T-cell subset in the blood of cancer patients to monitor early anti-PD1 mediated clinical efficacy, and to use DPOS T cells as a window to study the dynamic changes that underly successful antitumor immunity. Citation Format: Sylvain Simon, Valentin Voillet, Virginie Vignard, Zhong Wu, Camille Dabrowski, Nicolas Jouand, Tiffany Beauvais, Amir Khammari, Cecile Braudeau, Regis Josien, Olivier Adotevi, Caroline Laheurte, Francçois Aubin, Charles Nardin, Samuel Rulli, Raphaël Gottardo, Nirasha Ramchurren, Cheever Martin, Steven P. Fling, Candice D. Church, Paul Nghiem, Brigitte Dreno, Stanley R. Riddell, Nathalie Labarriere. PD-1 and TIGIT co-expression identifies a circulating CD8 T cell population predictive of response to anti-PD-1 therapy in melanoma and Merkel-cell carcinoma patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4476.
Published: 2020

29. Thoracic and cutaneous sarcoid-like reaction associated with anti-PD-1 therapy: longitudinal monitoring of PD-1 and PD-L1 expression after stopping treatment

Author: Sarah Le Roux, Anne Croue, Caroline Poli, José Hureaux, Thierry Urban, Simon Blanchard, Marie-Christine Rousselet, Léa Paolini, Nathalie Labarrière, Pascale Jeannin, Bernardo, Elizabeth, Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), 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), LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ), Laboratoire d'Immunologie et d'Allergologie, CHU d'Angers, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Service de Pneumologie [CHU Angers] (Pôle Hippocrate), Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Département de Pathologie Cellulaire et Tissulaire [Angers] (Laboratoire d’Histopathologie-Cytopathologie), LabEx ImmunoGraftOnco [Angers-Nantes], Anti-Tumor Immunosurveillance and Immunotherapy (CRCINA-ÉQUIPE 3), Laboratoire d'Immunologie et d'Allergologie [CHU Angers], This work was supported by institutional grants from INSERM and University of Angers., 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), and 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)
Subjects: Cancer Research, Lung Neoplasms, Programmed Cell Death 1 Receptor, Case Report, B7-H1 Antigen, 030207 dermatology & venereal diseases, Antineoplastic Agents, Immunological, 0302 clinical medicine, Carcinoma, Non-Small-Cell Lung, Immunology and Allergy, Skin, Middle Aged, Thorax, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, medicine.anatomical_structure, Nivolumab, Oncology, Sarcoid-like reaction, 030220 oncology & carcinogenesis, Molecular Medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Lung cancer, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, Sarcoidosis, [SDV.IMM] Life Sciences [q-bio]/Immunology, medicine.drug_class, T cell, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Monoclonal antibody, Skin Diseases, Peripheral blood mononuclear cell, lcsh:RC254-282, 03 medical and health sciences, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Humans, Pharmacology, business.industry, Cancer, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, Immune checkpoint, Leukocytes, Mononuclear, Cancer research, Lymph Nodes, business
Abstract: International audience; Background: Immune checkpoint inhibitors (ICI) target T cell inhibitory pathways that are responsible for cancer tolerance by down-modulating immune functions. ICI have revolutionized patients care with lung cancer. Nevertheless, restoring endogenous antitumor T-cell responses can induce immune related adverse events, such as sarcoidosis.Case presentation: We report here the first case of a thoracic and cutaneous sarcoid-like reaction in a patient with arelapsing unresectable non-small cell lung cancer (NSCLC) treated with nivolumab, an anti-PD-1 mAb. The expressionof PD-1 and its ligands, PD-L1 and PD-L2, was assessed by flow cytometry on peripheral blood mononuclear cells(PBMC) and compared to patients who had discontinued nivolumab therapy without having developed any immunerelated adverse events. PD-L1 expression was transiently increased on B cells, T cells and monocytes, whereas PD-L2expression was not modulated. PD-1 was transiently undetectable when PD-L1 was maximal, before returning to basallevel. Sarcoidosis spontaneously resolved, without corticotherapy.Conclusion: This case sheds the light on a complex regulation of PD-L1 expression in vivo on PBMC after nivolumabarrest and triggers the question of monitoring the expression of immune checkpoint on immune cells during and aftertreatment with ICI.
Published: 2018

30. Oncolytic viruses sensitize human tumor cells for NY-ESO-1 tumor antigen recognition by CD4+ effector T cells

Author: Frédéric Tangy, E. Antonio Chiocca, Monique Gannagé, Yaohe Wang, Mathilde Violland, Jean-François Fonteneau, Fabrice Le Boeuf, John C. Bell, Nathalie Labarrière, Soizic Dutoit, Dace Pjanova, Brigitte Dréno, Marc Grégoire, Tiphaine Delaunay, Philippe Erbs, Virginie Vignard, Kristine Vaivode, Nicolas Boisgerault, Christian Münz, University of Zurich, Fonteneau, Jean-François, 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), LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ), Anti-Tumor Immunosurveillance and Immunotherapy (CRCINA-ÉQUIPE 3), Institute of Experimental Immunology - IEI [Zürich, Switzerland], Université de Zurich [Switzerland], School of Medicine [Geneva, Switzerland], Université de Genève = University of Geneva (UNIGE), Service de dermatologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Clinical and Translational Research in Skin Cancer (CRCINA-ÉQUIPE 2), Latvian Biomedical Research and Study Centre [Rīga], Centre for Molecular Oncology [London, UK], Queen Mary University of London (QMUL)-Barts Cancer Institute [London, UK], National Centre for International Research in Cell and Gene Therapy [Henan Sheng, Chine], Sino-British Research Centre for Molecular Oncology [Henan Sheng, Chine]-Zhengzhou University [Chine], Harvey Cushing Neuro-Oncology Laboratories [Boston, USA] (Department of Neurosurgery), Harvard Medical School [Boston] (HMS)-Brigham and Women's Hospital [Boston], Center for Innovative Cancer Therapeutics [Ottawa, Canada], Ottawa Hospital Research Institute [Ottawa] (OHRI), University of Ottawa [Ottawa], Transgene SA [Illkirch], Génomique virale et vaccination, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), ANR-16-CE18-0016,OncoMeVax,Un virus de la rougeole modifié pour traiter le cancer(2016), 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 Genève (UNIGE), Zhengzhou University [Chine]-Sino-British Research Centre for Molecular Oncology [Henan Sheng, Chine], Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), and Bernardo, Elizabeth
Subjects: 0301 basic medicine, lcsh:Immunologic diseases. Allergy, [SDV.IMM] Life Sciences [q-bio]/Immunology, medicine.medical_treatment, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, 610 Medicine & health, 10263 Institute of Experimental Immunology, lcsh:RC254-282, 03 medical and health sciences, 0302 clinical medicine, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cancer immunotherapy, Antigen, cd4+ t lymphocytes, medicine, melanoma, Immunology and Allergy, Cytotoxic T cell, tumor-associated antigens, Original Research, 2403 Immunology, biology, Immunotherapy, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, biology.organism_classification, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Tumor antigen, 3. Good health, Oncolytic virus, 030104 developmental biology, Oncology, Vesicular stomatitis virus, oncolytic viruses, 030220 oncology & carcinogenesis, Cancer research, 2723 Immunology and Allergy, [SDV.IMM]Life Sciences [q-bio]/Immunology, 570 Life sciences, oncolytic immunotherapy, 2730 Oncology, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, lcsh:RC581-607
Abstract: International audience; Oncolytic immunotherapy using oncolytic viruses (OV) has been shown to stimulate the antitumor immune response by inducing the release of tumorassociated antigens (TAA) and danger signals from the dying infected tumor cells. In this study, we sought to determine if the lysis of tumor cells induced by different OV: measles virus, vaccinia virus, vesicular stomatitis virus, herpes simplex type I virus, adenovirus or enterovirus, has consequences on the capacity of tumor cells to present TAA, such as NY-ESO-1. We show that the co-culture of NY-ESO-1neg/HLADP4pos melanoma cells with NY-ESO-1pos/HLA-DP4neg melanoma cells infected and killed by different OV induces an intercellular transfer of NY-ESO-1 that allows the recognition of NY-ESO-1neg/HLA-DP4pos tumor cells by an HLA-DP4/NY-ESO-1(157- 170)-specific CD4+ cytotoxic T cell clone, NY67. We then confirmed this result in a second model with an HLA-DP4+ melanoma cell line that expresses a low amount of NY-ESO-1. Recognition of this cell line by the NY67 clone is largely increased in the presence of OV productive infection. Altogether, our results show for the first time another mechanism of stimulation of the anti-tumor immune response by OV, via the loading of tumor cells with TAA that sensitizes them for direct recognition by specific effector CD4+ T cells, supporting the use of OV for cancer immunotherapy.
Published: 2018

31. Merkel cell carcinoma and cellular cytotoxicity: sensitivity to cellular lysis and screening for potential target antigens suitable for antibodydependent cellular cytotoxicity

Author: Henri Vié, Béatrice Clémenceau, Antoine Touzé, Houssem Benlalam, Jocelyn Ollier, Pascal Aumont, Nathalie Labarrière, Thibault Kervarrec, Mahtab Samimi, Régine Vivien, Immunobiology of Human αβ and γδ T cells and Immunotherapeutic Applications (CRCINA - Département INCIT - Equipe 1), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers (CRCINA), Université d'Angers (UA)-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 de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Université d'Angers (UA)-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 de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), LabEX IGO Immunothérapie Grand Ouest, Département de Pathologie [CHRU Tours], Université Francois Rabelais [Tours]-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Infectiologie Santé Publique (ISP-311), Université de Tours-Institut National de la Recherche Agronomique (INRA), Département de Dermathologie [CHRU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Anti-tumor immunosurveillances and immunotherapy (CRCINA - Département INCIT - Equipe 3), Etablissement Français du Sang [Pays de la Loire] (EFS Pays de la Loire), EFS, Unité de Thérapie Cellulaire et Génique [CHU Nantes] (UTCG), Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Canceropole Grand Ouest, INSERM, Immunobiology of Human αβ and γδ T cells and Immunotherapeutic Applications ( CRCINA - Département INCIT - Equipe 1 ), Centre de recherche de Cancérologie et d'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 ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -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 ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), LabEx IGO 'Immunotherapy, Graft, Oncology' [Nantes], Université Francois Rabelais [Tours]-Centre Hospitalier Régional Universitaire de Tours ( CHRU TOURS ), Infectiologie Santé Publique ( ISP-311 ), Institut National de la Recherche Agronomique ( INRA ) -Université de Tours, Centre Hospitalier Régional Universitaire de Tours ( CHRU TOURS ), Anti-tumor immunosurveillances and immunotherapy ( CRCINA - Département INCIT - Equipe 3 ), Unité de Thérapie Cellulaire et Génique [CHU Nantes] ( UTCG ), Hôtel-Dieu-Centre hospitalier universitaire de Nantes ( CHU Nantes ), Etablissement Français du Sang [Pays de la Loire] ( EFS Pays de la Loire ), This work was supported by Cancéropole Grand Ouest (Project POCAME), and institutional Grant from Inserm., Bernardo, Elizabeth, Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), 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), Nantes Université (Nantes Univ), Université Francois Rabelais [Tours], Infectiologie et Santé Publique (UMR ISP), Institut National de la Recherche Agronomique (INRA)-Université de Tours (UT), Anti-Tumor Immunosurveillance and Immunotherapy (CRCINA-ÉQUIPE 3), 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 Francois Rabelais [Tours]-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), and Institut National de la Recherche Agronomique (INRA)-Université de Tours
Subjects: 0301 basic medicine, Cancer Research, Skin Neoplasms, Cytotoxicity, Cell, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Targeted therapy, 0302 clinical medicine, Merkel cell carcinoma, Tumor Cells, Cultured, Immunology and Allergy, Cells, Cultured, Antibody-dependent cell-mediated cytotoxicity, biology, Chemistry, Antibodies, Monoclonal, food and beverages, 3. Good health, Killer Cells, Natural, medicine.anatomical_structure, Phenotype, Oncology, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Antibody, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, ADCC, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Human leukocyte antigen, 03 medical and health sciences, Interferon-gamma, Immune system, Antigen, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigens, Neoplasm, medicine, Humans, Histocompatibility Antigens Class I, Antibody-Dependent Cell Cytotoxicity, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, Carcinoma, Merkel Cell, 030104 developmental biology, CTL, biology.protein, Cancer research, T-Lymphocytes, Cytotoxic
Abstract: The online version of this article ( https://doi.org/10.1007/s00262-018-2176-2) contains supplementary material, which is available to authorized users.; International audience; The recent success of checkpoint inhibitors in the treatment of Merkel cell carcinoma (MCC) confirms that MCC tumors can be immunogenic. However, no treatment directly targeting the tumor is available for use in combination with these checkpointinhibitors to enhance their efficacity. This study was carried out to characterize MCC line sensitivity to cellular lysis and to identify cell surface antigens that could be used for direct targeting of this tumor. For five representative MCC lines, the absence or low expression of MICA, MICB, HLA-I, and ICAM-1 was associated with low level of recognition by NK cells and T lymphocytes. However, expression of HLA-I and ICAM-1 and sensitivity to cellular lysis could be restored or increased after exposure to INFγ. We tested 41 antibodies specific for 41 different antigens using a novel antibody-dependent cellular cytotoxicity (ADCC) screening system for target antigens. Anti-CD326 (EpCAM) was the only antibody capable of inducing ADCC on the five MCC lines tested. Because MCC tumors are often directly accessible, local pharmacologic manipulation to restore HLA class-I and ICAM-1 cell surface expression (and thus sensitivity to cell lysis) can potentially benefit immune therapeutic intervention. In line with this, our observation that ADCC against EpCAM can induce lysis of MCC lines and suggests that therapeutic targeting of this antigen deserves to be explored further.
Published: 2018

32. Immunotherapies in transplantation and cancer: 22nd NAT meeting/2nd NAT LabEx IGO joint meeting; 1–2 June 2017, Nantes, France

Author: Sylvain Simon, Ignacio Anegon, Maud Charpentier, Nathalie Labarrière, 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), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Université de Nantes (UN)-Université de Nantes (UN), 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), LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ), Centre de Recherche en Transplantation et Immunologie - Center for Research in Transplantation and Translational Immunology (U1064 Inserm - CR2TI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Le Bihan, Sylvie
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Bone marrow transplantation, medicine.medical_treatment, Immunology, education, LabEx IGO, costimulation blockade, T-cell therapy, 03 medical and health sciences, Internal medicine, medicine, Immunology and Allergy, cancer, dendritic cells, Costimulation blockade, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, tolerance, business.industry, Cancer, Immunotherapy, medicine.disease, 3. Good health, Transplantation, 030104 developmental biology, France, immunotherapy, business, NAT, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, transplantation
Abstract: This 22nd edition of the Nantes Actualités Transplantation annual meeting was co-organized for the second time with the LabEx Immuno-Graft Oncology network. This international meeting was held on 1 and 2 June 2017 in Nantes (western France). The topic of this 2-day meeting was ‘Immunotherapies in transplantation and cancer’. This meeting brought together 17 international invited speakers, young researchers and 220 attendees mainly from Europe and North America. It was a unique opportunity to bring together the pioneers and leading immunologists in the fields of transplantation and cancer, focusing on shared mechanisms that control immune responses in organ or bone marrow transplantation and in cancer.
Published: 2017

33. Emergence of High-Avidity Melan-A-Specific Clonotypes as a Reflection of Anti-PD-1 Clinical Efficacy

Author: Brigitte Dréno, Anne-Chantal Knol, François Lang, Emilie Varey, Tiphaine Parrot, Amir Khammari, Sylvain Simon, Nadine Gervois, Nathalie Labarrière, Virginie Vignard, Bernardo, Elizabeth, Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID, 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), LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ), Centre hospitalier universitaire de Nantes (CHU Nantes), Département de Dermato-Cancerologie [CHU Nantes], Clinical and Translational Research in Skin Cancer (CRCINA-ÉQUIPE 2), 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), DHU Oncogreffe RC15_380_1., ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), 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), and 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)
Subjects: 0301 basic medicine, Cancer Research, [SDV.IMM] Life Sciences [q-bio]/Immunology, medicine.medical_treatment, Programmed Cell Death 1 Receptor, Antibody Affinity, [SDV.CAN]Life Sciences [q-bio]/Cancer, Substrate Specificity, 03 medical and health sciences, Immune system, MART-1 Antigen, TIGIT, Antigen, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigens, Neoplasm, medicine, Humans, Avidity, Melanoma, Cells, Cultured, biology, business.industry, Cancer, Antibodies, Monoclonal, Immunotherapy, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, 3. Good health, Clone Cells, 030104 developmental biology, Treatment Outcome, Oncology, Immunology, Antibody Formation, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Antibody, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, business
Abstract: Therapeutic strategies using anti–PD-1–blocking antibodies reported unparalleled effectiveness for melanoma immunotherapy, but deciphering immune responses modulated by anti–PD-1 treatment remains a crucial issue. Here, we analyzed the composition and functions of the large Melan-A–specific T-cell repertoire in the peripheral blood of 9 melanoma patients before and after 2 months of treatment with anti–PD-1. We observed amplification of Melan-A–specific Vß subfamilies undetectable before therapy (thereafter called emerging Vß subfamilies) in responding patients, with a predominant expansion in patients with a complete response. These emerging Vß subfamilies displayed a higher functional avidity for their cognate antigen than Vß subfamilies not amplified upon anti–PD-1 therapy and could be identified by a sustained coexpression of PD-1 and TIGIT receptors. Thus, in addition to the emergence of neoantigen-specific T cells previously documented upon anti–PD-1 therapy, our work describes the emergence of high-avidity Melan-A–specific clonotypes as a surrogate marker of treatment efficacy. Cancer Res; 77(24); 7083–93. ©2017 AACR.
Published: 2017

34. Mélanome — Thérapeutique immunitaire : l’immunothérapie cellulaire et vaccinale

Author: Brigitte Dréno, Amir Khammari, Anne Chantal Knol, and Nathalie Labarrière
Subjects: Adoptive cell transfer, Tumor microenvironment, business.industry, Melanoma, medicine.medical_treatment, General Medicine, Immunotherapy, medicine.disease, Immune tolerance, Cell therapy, Immune system, Immunology, medicine, Cytotoxic T cell, business
Abstract: Melanoma is a malignancy in which the immune system plays a central role, thus explaining the effectiveness of therapeutic vaccination and cellular immunotherapy with tumor-infiltrating lymphocytes. The identification of specific melanoma antigens was an important step in the development of these new approaches. These treatments are capable of yielding tumor responses that last several years, but the response rate is currently inadequate. The crucial role of the tumor microenvironment has recently been shown: melanoma cells render their immediate environment immunotolerant, undermining the effectiveness of stimulated cytotoxic T lymphocytes. The mechanisms responsible for this state of immune tolerance are a major focus of research. Current therapeutic strategies are based on early adjuvant approaches, destruction of regulatory T cells by lymphodepletion prior to immunotherapy, selection of the melanoma antigens inducing the best cytotoxic T cell responses, and combining cellular therapy with monoclonal antibodies that block molecules inhibiting T lymphocyte activation. Immune therapy for melanoma is thus moving towards adjuvant strategies for early-stage disease and combined treatments for metastatic melanoma. It is also important to identify markers that can be used to predict which patients will respond to a given treatment.
Published: 2014

35. CD40L confers helper functions to human intra-melanoma class-I-restricted CD4 + CD8 + double positive T cells

Author: Yves Delneste, Nathalie Labarrière, Amir Khammari, Anne Coutolleau, Houssem Benlalam, Romain Oger, Tiphaine Parrot, Philippe Guardiola, Diane Raingeard de la Blétière, Nicolas Jouand, Brigitte Dréno, Laurence Preisser, Nadine Gervois, Bernardo, Elizabeth, Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID, 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), LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ), SNP, Transcriptome & Epigénomique [CHU Angers] (Plateforme STE), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service de Dermatologie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Unité GMP de thérapie cellulaire [CHU Nantes], This work was supported by grants awarded by the 'Cancéropôle Grand Ouest' and the 'Région Pays de la Loire.' This work was realized in the context of the LabEX IGO program supported by the National Research Agency via the investment of the future program ANR-11-LABX-0016-01. Tiphaine Parrot was supported by an allocation from the «Ligue Nationale contre le Cancer»., and ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011)
Subjects: 0301 basic medicine, Immunology, Context (language use), [SDV.CAN]Life Sciences [q-bio]/Cancer, Transcriptome, 03 medical and health sciences, Interleukin 21, 0302 clinical medicine, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, melanoma, Immunology and Allergy, Cytotoxic T cell, CD40L, Original Research, CD40, biology, Melanoma, TIL, medicine.disease, Molecular biology, 3. Good health, 030104 developmental biology, Oncology, CD4+CD8+ double positive T cells, biology.protein, CD8, helper function, 030215 immunology
Abstract: International audience; Although CD4 C CD8 C double positive (DP) T cells represent a small fraction of peripheral T lymphocytes in healthy human donors, their frequency is often increased under pathological conditions (in blood and targeted tissues). In solid cancers such as melanoma, we previously demonstrated an enrichment of tumor reactive CD4 low CD8 high ab DP T cells among tumor-infiltrating lymphocytes of unknown function. Similarly to their single positive (SP) CD8 C counterparts, intra-melanoma DP T cells recognized melanoma cell lines in an HLA-class-I restricted context. However, they presented a poor cytotoxic activity but a strong production of diverse Th1 and Th2 cytokines. The aim of this study was to clearly define the role of intra-melanoma CD4 low CD8 high ab DP T cells in the antitumor immune response. Based on a comparative transcriptome analysis between intra-melanoma SP CD4 C , SP CD8 C and DP autologous melanoma-infiltrating T-cell compartments, we evidenced an overexpression of the CD40L co-stimulatory molecule on activated DP T cells. We showed that, like SP CD4 C T cells, and through CD40L involvement, DP T cells are able to induce both proliferation and differentiation of B lymphocytes and maturation of functional DCs able to efficiently prime cytotoxic melanoma-specific CD8 T-cell responses. Taken together, these results highlight the helper potential of atypical DP T cells and their role in potentiating antitumor response.
Published: 2016

36. Modulation of the Type I Interferon Response Defines the Sensitivity of Human Melanoma Cells to Oncolytic Measles Virus

Author: Brigitte Dréno, Amel Benammar Elgaaied, Jean-François Fonteneau, Marc Grégoire, Clarisse Panterne, Carole Achard, Daniel Pouliquen, Nicolas Boisgerault, Frédéric Tangy, Ferdaous Allagui, Chantal Combredet, Nathalie Labarrière, Bernardo, Elizabeth, Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID, 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), Génomique virale et vaccination, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Service de dermatologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratory of Genetics, Immunology and Human Pathology [Tunis,Tunisie], Université de Tunis El Manar (UTM)-Faculty of Sciences of Tunis, ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Ruxolitinib, Cell, [SDV.CAN]Life Sciences [q-bio]/Cancer, Membrane Cofactor Protein, Measles virus, Mice, 03 medical and health sciences, Immune system, Cancer virotherapy, [SDV.CAN] Life Sciences [q-bio]/Cancer, In vivo, Interferon, Cell Line, Tumor, Drug Discovery, Genetics, medicine, Animals, Humans, Molecular Biology, Melanoma, Oncolytic, Genetics (clinical), Oncolytic Virotherapy, biology, medicine.disease, biology.organism_classification, Xenograft Model Antitumor Assays, Virology, 3. Good health, Oncolytic virus, Gene Expression Regulation, Neoplastic, Oncolytic Viruses, 030104 developmental biology, medicine.anatomical_structure, Interferon Type I, Molecular Medicine, medicine.drug
Abstract: International audience; Background: Oncolytic viruses such as live-attenuated, vaccine strains of measles virus (MV) have recently emerged as promising cancer treatments, having shown significant antitumor activity against a large variety of human tumors. Objective: Our study aims at determining which parameters define the sensitivity of human melanoma cells to oncolytic MV infection. Method: We analyzed both in vitro and in vivo the oncolytic activity of MV against a panel of human melanoma cell established in our laboratory. We tested whether either type I interferons or the inter-feron pathway inhibitor Ruxolitinib could modulate the sensitivity of these cells to oncolytic MV infection. Results: Human melanoma cells exhibit varying levels of sensitivity to MV infection in culture and as tumor xenografts. As these differences are not explained by their expression level of the CD46 receptor, we hypothesized that antiviral immune responses may be suppressed in certain cell resulting in their inability to control infection efficiently. By analyzing the type I IFN response, we found that resistant cells had a fully functional pathway that was activated upon MV infection. On the contrary, sensitive cell showed defects in this pathway. When pre-treated with IFN-α and IFN-β, all but one of the sensitive cell became resistant to MV. Cells resistant to MV were rendered sensitive to MV with Ruxolitinib. Conclusion: Type I interferon response is the main determinant for the sensitivity or resistance of melanoma to oncolytic MV infection. This will have to be taken into account for future clinical trials on oncolytic MV.
Published: 2016

37. IRES-dependent translation of the long non coding RNA meloe in melanoma cells produces the most immunogenic MELOE antigens

Author: Delphine Carbonnelle, Michel Krempf, Nathalie Labarrière, François Lang, Maud Charpentier, Laetitia Florenceau, Agnès Fortun, Mikaël Croyal, Catherine Rabu, 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), Nutrition périnatale [Nantes] (Centres de Recherche en Nutrition Humaine - CRNH), Centre de Recherche en Nutrition Humaine - Ouest, INRA: UMR1280 Physiologie des adaptations (UMR1280), Institut National de la Recherche Agronomique (INRA), Centre hospitalier universitaire de Nantes (CHU Nantes), ANR-11-LABX-0016/11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), Bernardo, Elizabeth, Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID, Physiopathologie des Adaptations Nutritionnelles (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), and Lang, François
Subjects: mélanome, 0301 basic medicine, 0302 clinical medicine, spectrométrie de masse, IRES, Cells, Cultured, 2. Zero hunger, acide ribonucléique, Melanoma, Immunogenicity, Neoplasm Proteins, 3. Good health, medicine.anatomical_structure, Oncology, tumor antigens, 030220 oncology & carcinogenesis, long non coding RNA, Melanocytes, [SDV.IMM]Life Sciences [q-bio]/Immunology, RNA, Long Noncoding, immunotherapy, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, Research Paper, [SDV.IMM] Life Sciences [q-bio]/Immunology, T cell, mélanocyte, [SDV.CAN]Life Sciences [q-bio]/Cancer, Internal Ribosome Entry Sites, Biology, Open Reading Frames, 03 medical and health sciences, immunogénétique, Antigen, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigens, Neoplasm, Cell Line, Tumor, medicine, melanoma, Humans, Amino Acid Sequence, antigène, Melanoma-associated antigen, Base Sequence, RNA, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, biology.organism_classification, Virology, Internal ribosome entry site, 030104 developmental biology, Meloe, Protein Biosynthesis, Leukocytes, Mononuclear
Abstract: // Maud Charpentier 1 , Mikael Croyal 2, 3 , Delphine Carbonnelle 1 , Agnes Fortun 1 , Laetitia Florenceau 1, 4 , Catherine Rabu 1 , Michel Krempf 2, 3, 4 , Nathalie Labarriere 1, 4 , Francois Lang 1 1 CRCNA, INSERM, CNRS, Universite d’Angers, Universite de Nantes, Nantes, France 2 UMR INRA 1280, CHU, Nantes, France 3 West Human Nutrition Research Center, CHU, Nantes, France 4 CHU, Nantes, France Correspondence to: Francois Lang, email: francois.lang@univ-nantes.fr Keywords: melanoma, IRES, long non coding RNA, tumor antigens, immunotherapy Received: June 07, 2016 Accepted: July 20, 2016 Published: July 29, 2016 ABSTRACT MELOE-1 and MELOE-2, two highly specific melanoma antigens involved in T cell immunosurveillance are produced by IRES-dependent translation of the long « non coding » and polycistronic RNA, meloe . In the present study, we document the expression of an additional ORF, MELOE-3, located in the 5′ region of meloe . Data from in vitro translation experiments and transfection of melanoma cells with bicistronic vectors documented that MELOE-3 is exclusively translated by the classical cap-dependent pathway. Using a sensitive tandem mass spectrometry technique, we detected the presence of MELOE-3 in total lysates of both melanoma cells and normal melanocytes. This contrasts with our previous observation of the melanoma-restricted expression of MELOE-1 and MELOE-2. Furthermore, in vitro stimulation of PBMC from 6 healthy donors with overlapping peptides from MELOE-1 or MELOE-3 revealed a very scarce MELOE-3 specific T cell repertoire as compared to the abundant repertoire observed against MELOE-1. The poor immunogenicity of MELOE-3 and its expression in melanocytes is consistent with an immune tolerance towards a physiologically expressed protein. In contrast, melanoma-restricted expression of IRES-dependent MELOE-1 may explain its high immunogenicity. In conclusion, within the MELOE family, IRES-dependent antigens represent the best T cell targets for immunotherapy of melanoma.
Published: 2016

38. Recognition of pleural mesothelioma by mucin-1(950-958)/human leukocyte antigen A*0201-specific CD8+ T-cells

Author: Jean-François Fonteneau, Marc Grégoire, V. Vignard, Nathalie Labarrière, David Roulois, Fabien Gueugnon, 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), and LABARRIERE, Nathalie
Subjects: Mesothelioma, Pulmonary and Respiratory Medicine, Glycosylation, [SDV.IMM] Life Sciences [q-bio]/Immunology, medicine.drug_class, Pleural Neoplasms, medicine.medical_treatment, Antigen presentation, [SDV.CAN]Life Sciences [q-bio]/Cancer, Human leukocyte antigen, CD8-Positive T-Lymphocytes, Biology, Monoclonal antibody, immune response, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, glycobiology, Antigen, Cell Line, Tumor, HLA-A2 Antigen, medicine, Humans, Cytotoxic T cell, neoplasms, MUC1, 030304 developmental biology, Antigen Presentation, 0303 health sciences, Mucin-1, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Immunotherapy, mucin 1, Cytotoxic T-cells, Clone Cells, 3. Good health, 030220 oncology & carcinogenesis, Cancer research, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, Clone (B-cell biology), T-Lymphocytes, Cytotoxic
Abstract: International audience; Recent clinical investigations have demonstrated that T-cell-based immunotherapy of malignant pleural mesothelioma (MPM) could represent an alternative to the other therapeutic strategies. However, its development suffers from the lack of identified tumour antigenic targets. Mucin (MUC)1, which is expressed and recognised by cytotoxic T-cells in numerous cancer types, has not been investigated as a potential immune target in MPM. Thus, the objective of this study was to analyse MUC1 expression by MPM cells and to determine whether this antigen can be the target of cytotoxic CD8+ T-cells (cytotoxic T-lymphocytes (CTLs)). We first evaluated the expression and glycosylation of MUC1 by MPM cell lines using different MUC1-specific monoclonal antibodies. We then obtained a CTL clone specific for a MUC1 peptide (residues 950-958) presented by human leukocyte antigen (HLA)-A*0201 and studied its interferon-c and cytotoxic response to MPM cell lines. We found that all MPM cell lines expressed MUC1 protein at the cell surface with different glycosylation profiles. We also observed that HLA-A*0201+ MPM cell lines are recognised and lysed by a HLA-A*0201/MUC1(950-958)-specific CTL clone independently of the MUC1 glycosylation profile. Thus, MUC1 expression and antigen presentation by MPM cells may represent an attractive target for immunotherapeutic treatment of MPM despite its hyperglycosylated profile.
Published: 2011

39. [Melanoma: Cellular and vaccinal immunotherapy]

Author: Brigitte, Dréno, Amir, Khammari, Anne Chantal, Knol, and Nathalie, Labarrière
Subjects: Lymphocytes, Tumor-Infiltrating, Skin Neoplasms, Immune Tolerance, Tumor Microenvironment, Humans, Neoplasm Metastasis, Adoptive Transfer, Cancer Vaccines, Melanoma
Abstract: Melanoma is a malignancy in which the immune system plays a central role, thus explaining the effectiveness of therapeutic vaccination and cellular immunotherapy with tumor-infiltrating lymphocytes. The identification of specific melanoma antigens was an important step in the development of these new approaches. These treatments are capable of yielding tumor responses that last several years, but the response rate is currently inadequate. The crucial role of the tumor microenvironment has recently been shown: melanoma cells render their immediate environment immunotolerant, undermining the effectiveness of stimulated cytotoxic T lymphocytes. The mechanisms responsible for this state of immune tolerance are a major focus of research. Current therapeutic strategies are based on early adjuvant approaches, destruction of regulatory T cells by lymphodepletion prior to immunotherapy, selection of the melanoma antigens inducing the best cytotoxic T cell responses, and combining cellular therapy with monoclonal antibodies that block molecules inhibiting T lymphocyte activation. Immune therapy for melanoma is thus moving towards adjuvant strategies for early-stage disease and combined treatments for metastatic melanoma. It is also important to identify markers that can be used to predict which patients will respond to a given treatment.
Published: 2015

40. A lineage-specific methylation pattern controls the transcription of the polycistronic mRNA coding MELOE melanoma antigens

Author: Laetitia Florenceau, Nathalie Labarrière, Benjamin Chalopin, Delphine Fradin, Agnès Moreau-Aubry, 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), Thérapie génique, Génomique et Epigénomique (U 1169), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Ligue contre le cancer, and Bernardo, Elizabeth
Subjects: Cancer Research, Transcription, Genetic, [SDV.IMM] Life Sciences [q-bio]/Immunology, Bisulfite sequencing, [SDV.CAN]Life Sciences [q-bio]/Cancer, Dermatology, Biology, 03 medical and health sciences, 0302 clinical medicine, antigen, [SDV.CAN] Life Sciences [q-bio]/Cancer, Transcription (biology), Antigens, Neoplasm, Cell Line, Tumor, melanoma, Humans, Epigenetics, RNA, Messenger, Promoter Regions, Genetic, 030304 developmental biology, 0303 health sciences, Base Sequence, Methylation, Sequence Analysis, DNA, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, DNA Methylation, biology.organism_classification, Molecular biology, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, Oncology, Meloe, CpG site, 030220 oncology & carcinogenesis, DNA methylation, Cancer research, Melanocytes, [SDV.IMM]Life Sciences [q-bio]/Immunology, immunotherapy, methylation, Melanoma-Specific Antigens, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, transcription
Abstract: International audience; We recently characterized two melanoma antigens MELOE-1 and MELOE-2 derived from a polycistronic RNA overexpressed in the melanocytic lineage. This transcription profile was because of hypomethylation of the meloe proximal promoter in melanomas and melanocytes. Here, we investigated whether this demethylation was restricted to the meloe promoter or was linked to a general lack of methylation at the meloe locus in the melanocytic lineage. We established the methylation pattern of the locus spanning more than 40 kbp, focusing on CpG islands, using DNA bisulfite conversion and pyrosequencing. The study was carried out on cultured cell lines (melanoma, melanocyte, colon cancer, and mesothelioma cell lines), healthy tissues (skin and colon), and melanoma tumors. Demethylation, specifically observed in the melanocytic lineage, involves a large promoter area and not the entire meloe locus. This enables updating a tight regulation of meloe transcription in this lineage, suggesting tissue-specific epigenetic mechanisms. Associated with the previously described translational mechanisms, leading to the specific expression of MELOE-1 and MELOE-2 in melanomas, this makes MELOE-derived antigens a relevant candidate for immunotherapy of melanoma. Melanoma Res 00:000–000
Published: 2015

41. PD-1 expression conditions T cell avidity within an antigen-specific repertoire

Author: Sylvain Simon, François Lang, Laetitia Florenceau, Brigitte Dréno, Nathalie Labarrière, Virginie Vignard, Amir Khammari, LabEX IGO Immunothérapie Grand Ouest, 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), Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Cancéro-Dermatologie, Ligue contre le cancer, Canceropole Grand Ouest, ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), Nantes Université (Nantes Univ), Bernardo, Elizabeth, and Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID
Subjects: T cell avidity, 0301 basic medicine, [SDV.IMM] Life Sciences [q-bio]/Immunology, T cell, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Streptamer, 03 medical and health sciences, Interleukin 21, [SDV.CAN] Life Sciences [q-bio]/Cancer, PD-1, melanoma, medicine, Immunology and Allergy, Cytotoxic T cell, IL-2 receptor, Antigen-presenting cell, Original Research, business.industry, ZAP70, Melan-A, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Natural killer T cell, Molecular biology, 3. Good health, Adoptive T cell transfer, 030104 developmental biology, medicine.anatomical_structure, Oncology, [SDV.IMM]Life Sciences [q-bio]/Immunology, immunotherapy, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, business
Abstract: Despite its negative regulatory role on tumor-specific T cells, Programmed cell death 1 (PD-1) is also a marker of activated tumor-infiltrating T cells. In cancer, PD-1 blockade partially reverses T cell dysfunction allowing the amplification of tumor reactive T cells. Here, we investigated the role of PD-1 signaling on effector/memory human T cells specific for shared melanoma antigens, derived from blood. We documented for the first time the existence of melanoma-specific T cell clones unable to express PD-1. This stable feature was due to the persistent methylation of the PDCD1 promoter. These PD-1neg clones were of lower avidity than their PD-1pos counterparts, suggesting that high-affinity-specific T cell clones unable to express PD-1 are not or rarely present in peripheral blood, as they are probably eliminated by negative selection, due to their high reactivity. We also documented the existence of such PD-1neg T cell clones in melanoma tumor-infiltrating lymphocytes (TIL), which also exhibited a lower functional avidity than PD-1pos TIL clones. This clearly shows that PD-1 expression identifies antigen-specific T cell clonotypes of high functional avidity. Finally, we demonstrated that PD-1 blockade during the in vitro selection process of Melan-A-specific T cells favored the amplification of higher avidity T cell clonotypes. This preferential amplification of high-avidity memory T cells upon PD-1 blockade resonates with the expansion of reactive T cells, including neo-antigen-specific T cells observed in anti-PD-1-treated patients. This feature should also be a useful biomarker of clinical efficiency, while providing new insights for adoptive transfer treatments.
Published: 2015

42. Randomized trial of adoptive transfer of melanoma tumor-infiltrating lymphocytes as adjuvant therapy for stage III melanoma

Author: Jean-Michel Nguyen, Marie Christine Pandolfino, Amir Khammari, Brigitte Dréno, Philippe Lemarre, Francine Jotereau, Marie Helene Tessier, Alain Cassidanius, Sylvain Bercegeay, Nathalie Labarrière, Sylviane Billaudel, LABARRIERE, Nathalie, Service de dermatologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Unité de Thérapie Cellulaire et Génique [CHU Nantes] (UTCG), Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), PIMESP [CHU Nantes, Hôpital Saint-Jacques], Service de virologie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Interactions récepteurs ligands en immunocancérologie et immunopathologie, and IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Adult, Male, Oncology, Cancer Research, medicine.medical_specialty, Adoptive cell transfer, Adolescent, [SDV.IMM] Life Sciences [q-bio]/Immunology, T-Lymphocytes, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Immunotherapy, Adoptive, Disease-Free Survival, Metastasis, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, 0302 clinical medicine, Adjuvants, Immunologic, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Adjuvant therapy, Humans, Immunology and Allergy, Melanoma, Survival rate, Lymph node, Aged, Tumor-infiltrating lymphocytes, business.industry, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Middle Aged, medicine.disease, Combined Modality Therapy, 3. Good health, Surgery, Survival Rate, medicine.anatomical_structure, Lymphatic Metastasis, 030220 oncology & carcinogenesis, Interleukin-2, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Lymph, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, business, 030215 immunology
Abstract: International audience; The aim of this study was to demonstrate the interest of using tumor-infiltrating lymphocytes (TIL) as adjuvant therapy for stage III (regional lymph nodes) melanoma. After lymph node excision, patients without any detectable metastases were randomly assigned to receive either TIL plus interleukin-2 (IL-2) for 2 months, or IL-2 only. The primary endpoint was determination of the duration of the relapse-free interval. Eighty-eight patients determined as eligible for treatment were enrolled in the study. After a median follow-up of 46.9 months, for the study population the analysis did not show a significant extension of the relapse-free interval or overall survival. However, a significant interaction (P
Published: 2002

43. Soluble HLA-I/Peptide Monomers Mediate Antigen-Specific CD8 T Cell Activation through Passive Peptide Exchange with Cell-Bound HLA-I Molecules

Author: Mathilde Allard, Laetitia Florenceau, Karine Bernardeau, Klara Echasserieau, Nadine Gervois, Romain Oger, François Lang, Nathalie Labarrière, Houssem Benlalam, 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), LabEx IGO, Ligue Régionale contre le Cancer, and GERVOIS, Nadine
Subjects: Male, [SDV.IMM] Life Sciences [q-bio]/Immunology, T cell, Immunology, Peptide, Human leukocyte antigen, CD8-Positive T-Lymphocytes, law.invention, 03 medical and health sciences, 0302 clinical medicine, Immune system, law, medicine, Immunology and Allergy, Cytotoxic T cell, Humans, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Effector, Histocompatibility Antigens Class I, In vitro, 3. Good health, Protein Transport, medicine.anatomical_structure, Biochemistry, chemistry, Solubility, Recombinant DNA, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Peptides, 030215 immunology, HeLa Cells
Abstract: Accumulating evidence that serum levels of soluble class I HLA molecules (sHLA-I) can, under various pathological conditions, correlate with disease stage and/or patient survival, has stimulated interest in defining whether sHLA-I can exert immunological functions. However, despite a mounting number of publications suggesting the ability of sHLA-I to affect immune effectors in vitro, the precise underlying mechanism still remains controversial. In this article, we address potential functions of both classical and nonclassical sHLA-I, using soluble recombinant HLA-I/peptide monomers, and clearly demonstrate their ability to trigger Ag-specific activation of CD8 T cells in vitro. Furthermore, we provide strong evidence that this behavior results from the passive transfer of peptides from monomers to T cell–bound HLA-I molecules, allowing for fratricide representation and activation. Hence, we proposed a unifying model of T cell activation by HLA-I/peptide monomers, reappraising the potential involvement of sHLA-I molecules in the immune response.
Published: 2014

44. Comprehensive analysis of the frequency of recognition of melanoma-associated antigen (MAA) by CD8 melanoma infiltrating lymphocytes (TIL): implications for immunotherapy

Author: Laurent Derré, Elisabeth Diez, Marc Bonneville, Francine Jotereau, Houssem Benlalam, Marie-Christine Pandolfino, Nathalie Labarrière, Boris Linard, LABARRIERE, Nathalie, Interactions récepteurs ligands en immunocancérologie et immunopathologie, IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Thérapie Cellulaire et Génique [CHU Nantes] (UTCG), Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), and Université de Nantes (UN)
Subjects: [SDV.IMM] Life Sciences [q-bio]/Immunology, medicine.medical_treatment, Lymphocyte, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, chemical and pharmacologic phenomena, Human leukocyte antigen, Biology, Transfection, Cancer Vaccines, Epitope, Epitopes, Mice, Lymphocytes, Tumor-Infiltrating, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigen, Antigens, Neoplasm, HLA Antigens, Tumor Cells, Cultured, medicine, Animals, Humans, Immunology and Allergy, Melanoma, Antigen Presentation, Melanoma-associated antigen, Tumor Necrosis Factor-alpha, Cell Differentiation, hemic and immune systems, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Immunotherapy, medicine.disease, Clone Cells, Neoplasm Proteins, 3. Good health, medicine.anatomical_structure, COS Cells, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, Melanoma-Specific Antigens, CD8, T-Lymphocytes, Cytotoxic
Abstract: International audience; Fifty-nine tumor-infiltrating lymphocyte (TIL) cultures established from melanoma-invaded lymph nodes were screened for recognition of 28 melanoma-associated antigens (MAA) in association with 31 HLA molecules. Twenty-three (39%) TIL lines reacted to at least one mel-anoma antigen. Melanosomal proteins were recognized by 19 TIL populations and the most prominent responses against these proteins were directed against Melan-A/MART-1 (mainly in association with HLA-A*0201) and gp100 (in association with diverse HLA contexts). Ten TIL populations reacted against 10 tumor-specific antigens, in association with 8 different HLA molecules. HLA-A*0201 and B*3501-restricted responses were the most frequent with, respectively, 17 and 7 responses directed against 5 distinct antigens. Unexpectedly, the recognition by TIL of different MAA was frequently restricted by a single HLA in individual tumors, and there was no evidence for the existence of dominant MAA epitopes between tumors, except for Melan-A/MART-1 antigen. This analysis also led to the detection of 21 new HLA-peptide complexes recognized by melanoma TIL. This study, which is to our knowledge the most comprehensive analysis of TIL specificity to tumor antigens, has several implications for the design of immunotherapeutic strategies based on immunization against selected tumor epitopes.
Published: 2001

45. A Processed Pseudogene Codes for a New Antigen Recognized by a Cd8+ T Cell Clone on Melanoma

Author: Soizic Le Guiner, Francine Jotereau, Richard Breathnach, Marie-Claude Gesnel, Agnès Moreau-Aubry, and Nathalie Labarrière
Subjects: Cytotoxicity, Immunologic, Untranslated region, Pseudogene, Molecular Sequence Data, Immunology, CD8-Positive T-Lymphocytes, Biology, Lymphocyte Activation, Antigens, Neoplasm, Sequence Homology, Nucleic Acid, Complementary DNA, Humans, Immunology and Allergy, Coding region, Amino Acid Sequence, Melanoma, Peptide sequence, Gene, Gene Library, Homeodomain Proteins, Genetics, Antigen Presentation, epitope, Base Sequence, Brief Definitive Report, Molecular biology, Peptide Fragments, peptide, Stop codon, Clone Cells, tumor immunity, Open reading frame, HLA-B Antigens, CTL, Codon, Terminator, processing, Pseudogenes
Abstract: The M88.7 T cell clone recognizes an antigen presented by HLA B*1302 on the melanoma cell line M88. A cDNA encoding this antigen (NA88-A) was isolated using a library transfection approach. Analysis of the genomic gene's sequence identified it is a processed pseudogene, derived from a retrotranscript of mRNA coding for homeoprotein HPX42B. The NA88-A gene exhibits several premature stop codons, deletions, and insertions relative to the HPX42B gene. In NA88-A RNA, a short open reading frame codes for the peptide MTQGQHFLQKV from which antigenic peptides are derived; a stop codon follows the peptide's COOH-terminal Val codon. Part of the HPX42B mRNA's 3′ untranslated region codes for a peptide of similar sequence (MTQGQHFSQKV). If produced, this peptide can be recognized by M88.7 T cells. However, in HPX42B mRNA, the peptide's COOH-terminal Val codon is followed by a Trp codon. As a result, expression of HPX42B mRNA does not lead to antigen production. A model is proposed for events that participated in creation of a gene coding for a melanoma antigen from a pseudogene.
Published: 2000

46. Frequency and relative fraction of tumor antigen-specific T cells among lymphocytes from melanoma-invaded lymph nodes

Author: Soizic Le Guiner, Marie-Christine Pandolfino, Diane Raingeard, Brigitte Dréno, Eric Le Dréan, Francine Jotereau, Nathalie Labarrière, and Elisabeth Diez
Subjects: Cancer Research, T-Lymphocytes, Biology, Sensitivity and Specificity, Epitopes, Interferon-gamma, MART-1 Antigen, Antigen, Antigens, Neoplasm, HLA-A2 Antigen, Lymph node stromal cell, medicine, Humans, Cytotoxic T cell, Neoplasm Invasiveness, Melanoma, Lymph node, Pan-T antigens, Monophenol Monooxygenase, Tumor Necrosis Factor-alpha, medicine.disease, Molecular biology, Tumor antigen, Neoplasm Proteins, medicine.anatomical_structure, Oncology, Immunology, Interleukin-2, Lymph Nodes, Lymph, T-Lymphocytes, Cytotoxic
Abstract: Several tumor antigens have been described as candidates for immunotherapy. Our study compared HLA-A2-restricted epitopes from 5 antigens commonly expressed by melanomas, i.e., Melan-A/MART-1 peptides (26–35 and 27–35), tyrosinase (368–376), gp-100 (280–288), MAGE-3 (271–279) and NA17-A (1–10), for their relative capacity to promote the development of cytotoxic and cytokine-producing specific CD8+ lymphocytes within melanoma-invaded lymph nodes. We used short-term cultured melanoma-invaded lymph node lymphocytes (MILLs) and tested responses developed by these cells to peptide-pulsed TAP-deficient T2 cells. We measured both the lytic response developed by MILLs and the fraction of these cells that secreted interferon-γ (IFN-γ), as deduced from intracellular cytokine labeling. Reverse transcription-polymerase chain reaction (RT-PCR) was used to analyze the expression of the 5 antigens within melanoma-invaded lymph nodes. Melan-A/MART-1, tyrosinase and gp-100 peptides were recognized by MILLs derived, respectively, from 8 of 20, 5 of 19 and 4 of 20 melanoma-invaded lymph nodes expressing these antigens. Most MILLs specific for Melan-A/MART-1 and tyrosinase exhibited both lysis and IFN-γ responses, whereas most of those specific for gp-100 developed only lysis. Weak lysis without IFN-γ secretion was developed against NA17-A and MAGE-3 peptides by MILLs from, respectively, 3 of 9 and 2 of 14 lymph nodes expressing these antigens. Our data show a prevalence of both cytotoxic and IFN-γ-secreting effector T cells specific for differentiation antigens within HLA-A2 melanoma-invaded lymph nodes, which makes these antigens attractive targets for specific immunotherapy. Int. J. Cancer 78:209–215, 1998.© 1998 Wiley-Liss, Inc.
Published: 1998

47. The Melanoma Antigens MELOE-1 and MELOE-2 Are Translated from a Bona Fide Polycistronic mRNA Containing Functional IRES Sequences

Author: Wolfgang Mikulits, Laetitia Florenceau, Agnès Moreau-Aubry, Nathalie Labarrière, Delphine Carbonnelle, Maud Charpentier, François Lang, Delphine Sehedic, Virginie Vignard, 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), Comprehensive Cancer Center [Vienna, Austria], Institute of Cancer Research [Vienna, Austria]-Medizinische Universität Wien = Medical University of Vienna, This work was supported by grant #SFI20111203534 from the Association pour la Recherche sur le Cancer., Dupuis, Christine, and Medizinische Universität Wien = Medical University of Vienna-Institute of Cancer Research [Vienna, Austria]
Subjects: [SDV.IMM] Life Sciences [q-bio]/Immunology, T cell, Green Fluorescent Proteins, lcsh:Medicine, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigens, Neoplasm, medicine, Protein biosynthesis, Humans, RNA, Messenger, RNA, Small Interfering, ORFS, lcsh:Science, Melanoma, 030304 developmental biology, 0303 health sciences, Multidisciplinary, lcsh:R, RNA, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, biology.organism_classification, Molecular biology, Neoplasm Proteins, 3. Good health, Internal ribosome entry site, Open reading frame, medicine.anatomical_structure, Meloe, Protein Biosynthesis, 030220 oncology & carcinogenesis, RNA splicing, [SDV.IMM]Life Sciences [q-bio]/Immunology, lcsh:Q, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, Research Article
Abstract: International audience; Our previous studies on melanoma antigens identified two new polypeptides, named MELOE-1 and MELOE-2, that are involved in immunosurveillance. Intriguingly, these antigens are coded by distinct open reading frames (ORF) of the meloe mRNA which is significantly expressed only in the melanocytic lineage. In addition, MELOE-1 and -2 specific T cell clones recognized melanoma cells but very poorly normal melanocytes suggesting differential translation of meloe in normal vs tumor cells. This prompted us to elucidate the mechanisms of translation of these antigens in melanoma cells. We first demonstrated that no splicing event or cryptic promoter could generate shorter meloe transcripts containing only one of the two ORFs. Triggering meloe RNA degradation with a siRNA close to the ORF coding for MELOE-2 abrogated expression of both MELOE-1 and MELOE-2, thus confirming that the two ORFs are always associated. Next we showed, in a bicistronic reporter system, that IRES activities could be detected upstream of MELOE-1 and MELOE-2 and finally confirmed their translation from full length meloe cDNA in melanoma cells with eGFP constructs. In conclusion, meloe is a polycistronic mRNA that generates both MELOE-1 and MELOE-2 antigens through IRES-dependent translation in melanoma cells and that may explain their tumor specificity.
Published: 2013

48. A Full GMP Process to Select and Amplify Epitope-Specific T Lymphocytes for Adoptive Immunotherapy of Metastatic Melanoma

Author: Amir Khammari, Soraya Saiagh, Agnès Fortun, Nathalie Labarrière, François Lang, A. Bellec, 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), Unité de Thérapie Cellulaire et Génétique [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Unité du cancer de la peau [CHU Nantes], This work was supported by a grant from the 'National Research Agency,' BiotecS program 2009., ANR-09-BIOT-0009,SASTIM,Développement de réactifs GMP pour la sélection de lymphocytes T spécifiques d'antigènes de mélanome de grade clinique(2009), Dupuis, Christine, and Biotech : Biotechnologies - Développement de réactifs GMP pour la sélection de lymphocytes T spécifiques d'antigènes de mélanome de grade clinique - - SASTIM2009 - ANR-09-BIOT-0009 - Biotech - VALID
Subjects: lcsh:Immunologic diseases. Allergy, Adoptive cell transfer, [SDV.IMM] Life Sciences [q-bio]/Immunology, Article Subject, T-Lymphocytes, medicine.medical_treatment, Immunology, Epitopes, T-Lymphocyte, [SDV.CAN]Life Sciences [q-bio]/Cancer, Human leukocyte antigen, Lymphocyte Activation, Immunotherapy, Adoptive, Epitope, 03 medical and health sciences, MART-1 Antigen, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, HLA-A2 Antigen, medicine, Humans, Immunology and Allergy, Neoplasm Metastasis, Melanoma, 030304 developmental biology, 0303 health sciences, Melanoma-associated antigen, business.industry, General Medicine, Immunotherapy, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, 3. Good health, Cell culture, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, lcsh:RC581-607, Peptides, business, Research Article, 030215 immunology
Abstract: A number of trials of adoptive transfer of tumor-specific T lymphocytes have been performed in the last 20 years in metastatic melanoma, with increasingly encouraging results as the relevant melanoma antigens were identified and the purity/specificity of injected T cells improved. We have previously described a sorting method of epitope-specific T lymphocytes that uses magnetic beads coated with HLA/peptide complexes and we suggested that this method could be applied to a clinical setting. In the present work, we provide a detailed description of the whole GMP process of sorting and amplification of clinical grade T cells specific for the melanoma antigens Melan-A and MELOE-1. All the reagents used in this process including the sorting reagent were produced in GMP conditions and we document the optimization of the different steps of the process such as peptide stimulation, sorting, and amplification. The optimized procedure, validated in 3 blank runs in a clinical setting, allowed the production of at least 108pure (>90%) Melan-A- and MELOE-1-specific T cells within 28 days starting with 100 mL of blood from metastatic melanoma patients. This GMP process is thus ready to be used in an upcoming phase I/II clinical trial on metastatic melanoma patients.
Published: 2013

49. A Novel Transcriptional Activator Originating from an Upstream Promoter in the Human Growth Hormone Gene

Author: Dominique Maiter, Frédéric P. Lemaigre, Philippe L. Selvais, Nathalie Labarrière, Alain Michel, and Guy G. Rousseau
Subjects: Messenger RNA, Reporter gene, DNA, Complementary, Base Sequence, Sequence Homology, Amino Acid, Base pair, C-terminus, Molecular Sequence Data, Cell Biology, Transfection, Biology, Biochemistry, Molecular biology, Open reading frame, Transcription (biology), Growth Hormone, Trans-Activators, Humans, Amino Acid Sequence, RNA, Messenger, Cloning, Molecular, Promoter Regions, Genetic, Molecular Biology, Transcription factor, Transcription Factors
Abstract: Transcription of the human growth hormone gene can start in vitro and in vivo 197 base pairs upstream from the cap site of growth hormone mRNA (Courtois, S. J., Lafontaine, D., and Rousseau, G. G. (1992) J. Biol. Chem. 267, 19736-19743). We have now characterized the mRNA that originates from this optional promoter and have found that it occurs in human hypophysis and placenta but not in 10 other tissues. This mRNA contains an open reading frame for a protein of 107 residues that shares sequence similarity with three domains of hepatic nuclear factor-1alpha. With antibodies directed against a peptide corresponding to the C terminus of this protein, immunoreactive material was detected in a subset of cells of the adenohypophysis. When fused to the DNA-binding domain of the yeast transcription factor GAL4, the protein stimulated transcription from a GAL4-sensitive reporter gene in transiently transfected pituitary and placental cells.
Published: 1995

50. The expression of carbohydrate blood group antigens correlates with heat resistance

Author: J. Le Pendu, Khaled Meflah, Antoine Ménoret, F. Piller, Nathalie Labarrière, M. E. Breimer, and C. Otry
Subjects: Hot Temperature, Glycosylation, Molecular Sequence Data, Gene Expression, Adenocarcinoma, H antigen, ABO Blood-Group System, chemistry.chemical_compound, Glycolipid, Antigen, Heat shock protein, Glycosyltransferase, Tumor Cells, Cultured, Animals, chemistry.chemical_classification, biology, Glycosyltransferases, Cell Biology, Transfection, Clone Cells, Rats, Kinetics, Carbohydrate Sequence, chemistry, Biochemistry, Colonic Neoplasms, biology.protein, Glycolipids, Glycoprotein
Abstract: Recent data indicate that cells may resist heat shock via more than one route: heat shock protein synthesis and other still ill-defined mechanisms. We investigated this phenomenon using four types of cells derived from a single rat colon carcinoma: clones REGb and PROb; PRO A+, a glycosylation variant of PROb selected for its high expression of blood group A antigen; and Ph8, a thermoresistant variant of PROb selected by repeated sublethal heat treatments. Basal heat resistance was clearly associated with the level of cell surface expression of blood group H and A antigens. Biosynthesis of these carbohydrate structures requires two glycosyltransferases, H and A enzymes, whose activities are also correlated with basal heat resistance. In addition, heat sensitive REGb cells were rendered more resistant by transfection with the gene encoding for H enzyme, allowing expression of H antigen. Thus, these terminal glycosylations could play a role as cellular protectors against heat treatment. Blood group carbohydrate antigens were mainly located on O-linked carbohydrate chains of a major glycoprotein of 200 kDa and to a lesser extent on N-linked chains. Only trace amounts were present as glycolipids.
Published: 1995

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