Author: "Virginie Vignard" - Searchworks@Jio Institute Digital Library Search Results

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1. Understanding neurodevelopmental proteasomopathies as new rare disease entities: A review of current concepts, molecular biomarkers, and perspectives

Author: Silvestre Cuinat, Stéphane Bézieau, Wallid Deb, Sandra Mercier, Virginie Vignard, Bertrand Isidor, Sébastien Küry, and Frédéric Ebstein
Subjects: Biomarkers, Loss-of-function variants, Neurodevelopmental disorders, Proteasome, Rare diseases, Therapeutic targets, Medicine (General), R5-920, Genetics, QH426-470
Abstract: The recent advances in high throughput sequencing technology have drastically changed the practice of medical diagnosis, allowing for rapid identification of hundreds of genes causing human diseases. This unprecedented progress has made clear that most forms of intellectual disability that affect more than 3% of individuals worldwide are monogenic diseases. Strikingly, a substantial fraction of the mendelian forms of intellectual disability is associated with genes related to the ubiquitin-proteasome system, a highly conserved pathway made up of approximately 1200 genes involved in the regulation of protein homeostasis. Within this group is currently emerging a new class of neurodevelopmental disorders specifically caused by proteasome pathogenic variants which we propose to designate “neurodevelopmental proteasomopathies”. Besides cognitive impairment, these diseases are typically associated with a series of syndromic clinical manifestations, among which facial dysmorphism, motor delay, and failure to thrive are the most prominent ones. While recent efforts have been made to uncover the effects exerted by proteasome variants on cell and tissue landscapes, the molecular pathogenesis of neurodevelopmental proteasomopathies remains ill-defined. In this review, we discuss the cellular changes typically induced by genomic alterations in proteasome genes and explore their relevance as biomarkers for the diagnosis, management, and potential treatment of these new rare disease entities.
Published: 2024
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2. Exploring the origins of neurodevelopmental proteasomopathies associated with cardiac malformations: are neural crest cells central to certain pathological mechanisms?

Author: Virginie Vignard, Alban-Elouen Baruteau, Bérénice Toutain, Sandra Mercier, Bertrand Isidor, Richard Redon, Jean-Jacques Schott, Sébastien Küry, Stéphane Bézieau, Anne H. Monsoro-Burq, and Frédéric Ebstein
Subjects: neurodevelopmental proteasomopathies, cardiac malformations, craniofacial anomalies, neural crest cells, protein homeostasis, compensatory pathways, Biology (General), QH301-705.5
Abstract: Neurodevelopmental proteasomopathies constitute a recently defined class of rare Mendelian disorders, arising from genomic alterations in proteasome-related genes. These alterations result in the dysfunction of proteasomes, which are multi-subunit protein complexes essential for maintaining cellular protein homeostasis. The clinical phenotype of these diseases manifests as a syndromic association involving impaired neural development and multisystem abnormalities, notably craniofacial anomalies and malformations of the cardiac outflow tract (OFT). These observations suggest that proteasome loss-of-function variants primarily affect specific embryonic cell types which serve as origins for both craniofacial structures and the conotruncal portion of the heart. In this hypothesis article, we propose that neural crest cells (NCCs), a highly multipotent cell population, which generates craniofacial skeleton, mesenchyme as well as the OFT of the heart, in addition to many other derivatives, would exhibit a distinctive vulnerability to protein homeostasis perturbations. Herein, we introduce the diverse cellular compensatory pathways activated in response to protein homeostasis disruption and explore their potential implications for NCC physiology. Altogether, the paper advocates for investigating proteasome biology within NCCs and their early cranial and cardiac derivatives, offering a rationale for future exploration and laying the initial groundwork for therapeutic considerations.
Published: 2024
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3. 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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4. 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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5. TCR Analyses of Two Vast and Shared Melanoma Antigen-Specific T Cell Repertoires: Common and Specific Features

Author: Sylvain Simon, Zhong Wu, J. Cruard, Virginie Vignard, Agnes Fortun, Amir Khammari, Brigitte Dreno, Francois Lang, Samuel J. Rulli, and Nathalie Labarriere
Subjects: TCR sequencing, melanoma, Melan-A, MELOE-1, immunotherapy, Immunologic diseases. Allergy, RC581-607
Abstract: Among Immunotherapeutic approaches for cancer treatment, the adoptive transfer of antigen specific T cells is still a relevant approach, that could have higher efficacy when further combined with immune check-point blockade. A high number of adoptive transfer trials have been performed in metastatic melanoma, due to its high immunogenic potential, either with polyclonal TIL or antigen-specific polyclonal populations. In this setting, the extensive characterization of T cell functions and receptor diversity of infused polyclonal T cells is required, notably for monitoring purposes. We developed a clinical grade procedure for the selection and amplification of polyclonal CD8 T cells, specific for two shared and widely expressed melanoma antigens: Melan-A and MELOE-1. This procedure is currently used in a clinical trial for HLA-A2 metastatic melanoma patients. In this study, we characterized the T-cell diversity (T-cell repertoire) of such T cell populations using a new RNAseq strategy. We first assessed the added-value of TCR receptor sequencing, in terms of sensitivity and specificity, by direct comparison with cytometry analysis of the T cell populations labeled with anti-Vß-specific antibodies. Results from these analyzes also confirmed specific features already reported for Melan-A and MELOE-1 specific T cell repertoires in terms of V-alpha recurrence usage, on a very high number of T cell clonotypes. Furthermore, these analyses also revealed undescribed features, such as the recurrence of a specific motif in the CDR3α region for MELOE-1 specific T cell repertoire. Finally, the analysis of a large number of T cell clonotypes originating from various patients revealed the existence of public CDR3α and ß clonotypes for Melan-A and MELOE-1 specific T cells. In conclusion, this method of high throughput TCR sequencing is a reliable and powerful approach to deeply characterize polyclonal T cell repertoires, and to reveal specific features of a given TCR repertoire, that would be useful for immune follow-up of cancer patients treated by immunotherapeutic approaches.
Published: 2018
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6. 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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7. Overexpression of meloe gene in melanomas is controlled both by specific transcription factors and hypomethylation.

Author: Mathilde Bobinet, Virginie Vignard, Laetitia Florenceau, Francois Lang, Nathalie Labarriere, and Agnès Moreau-Aubry
Subjects: Medicine, Science
Abstract: The melanoma antigens MELOE-1 and MELOE-2 are encoded by a messenger, called meloe, overexpressed in melanomas compared with other tumour cell types and healthy tissues. They are both able to elicit melanoma-specific T cell responses in melanoma patients, and MELOE-1-specific CD8 T cells have been involved in melanoma immunosurveillance. With the aim to develop immunotherapies targeting this antigen, we investigated the transcriptional mechanisms leading to the preferential expression of meloe messenger in the melanocytic lineage. We defined the minimal promoter region of meloe gene and identified binding motifs for a set of transcription factors. Using mutagenesis, co-transfection experiments and chromatin immunoprecipitation, we showed that transcription factors involved in meloe promoter activity in melanomas were the melanocytic specific SOX9 and SOX10 proteins together with the activated P-CREB protein. Furthermore, we showed that meloe promoter was hypomethylated in melanomas and melanocytes, and hypermethylated in colon cancer cell lines and mesotheliomas, thus explaining the absence of P-CREB binding in these cell lines. This was a second key to explain the overerexpression of meloe messenger in the melanocytic lineage. To our knowledge, such a dual transcriptional control conferring tissue-specificity has never been described for the expression of tumour antigens.
Published: 2013
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8. The melanoma antigens MELOE-1 and MELOE-2 are translated from a bona fide polycistronic mRNA containing functional IRES sequences.

Author: Delphine Carbonnelle, Virginie Vignard, Delphine Sehedic, Agnes Moreau-Aubry, Laetitia Florenceau, Maud Charpentier, Wolfgang Mikulits, Nathalie Labarriere, and François Lang
Subjects: Medicine, Science
Abstract: 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
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9. MELOE-1 antigen contains multiple HLA class II T cell epitopes recognized by Th1 CD4+ T cells from melanoma patients.

Author: Mathilde Bobinet, Virginie Vignard, Anne Rogel, Amir Khammari, Brigitte Dreno, Francois Lang, and Nathalie Labarriere
Subjects: Medicine, Science
Abstract: MELOE-1 is an overexpressed melanoma antigen containing a HLA-A2 restricted epitope, involved in melanoma immunosurveillance of patients adoptively transferred with tumour infiltrating lymphocytes (TIL). The use of the full-length antigen (46 aa) for anti-melanoma vaccination could be considered, subject to the presence of Th epitopes all along MELOE-1 sequence. Thus, in this study we evaluated in vitro the immunoprevalence of the different regions of MELOE-1 (i.e. their ability to induce CD4 T cell responses in vitro from PBMC). Stimulation of PBMC from healthy subjects with MELOE-1 induced the amplification of CD4 T cells specific for various regions of the protein in multiple HLA contexts, for each tested donor. We confirmed these results in a panel of melanoma patients, and documented that MELOE-1 specific CD4 T cells, were mainly Th1 cells, presumably favourable to the amplification of CD8 specific T cells. Using autologous DC, we further showed that these class II epitopes could be naturally processed from MELOE-1 whole protein and identified minimal epitopes derived from each region of MELOE-1, and presented in four distinct HLA contexts. In conclusion, vaccination with MELOE-1 whole polypeptide should induce specific Th1 CD4 responses in a majority of melanoma patients, stimulating the amplification of CD8 effector cells, reactive against melanoma cells.
Published: 2012
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10. Serum soluble HLA-E in melanoma: a new potential immune-related marker in cancer.

Author: Mathilde Allard, Romain Oger, Virginie Vignard, Jean-Michel Percier, Giulia Fregni, Aurélie Périer, Anne Caignard, Béatrice Charreau, Karine Bernardeau, Amir Khammari, Brigitte Dréno, and Nadine Gervois
Subjects: Medicine, Science
Abstract: BackgroundTumor-derived soluble factors, including soluble HLA molecules, can contribute to cancer immune escape and therefore impact on clinical course of malignant diseases. We previously reported that melanoma cells produce, in vitro, soluble forms of the non-classical MHC class I molecule HLA-E (sHLA-E). In order to investigate sHLA-E production by various tumors and to address its potential value as a tumor-associated marker, we developed a specific ELISA for the quantification of sHLA-E in biological fluids.Methodology/principal findingsWe developed a sHLA-E specific and sensitive ELISA and we showed that serum sHLA-E levels were significantly elevated (PConclusions/significanceIn view of the broad tumor tissue release of HLA-E and its up-regulation by inflammatory cytokines, sHLA-E should be studied for its involvement in immune responses against tumors. Interestingly, our results demonstrated a positive association between the presence of serum sHLA-E and melanoma. Therefore, the determination of sHLA-E levels, using ELISA approach, may be investigated as a clinical marker in cancer patients.
Published: 2011
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11. Double positive CD4CD8 alphabeta T cells: a new tumor-reactive population in human melanomas.

Author: Juliette Desfrançois, Agnès Moreau-Aubry, Virginie Vignard, Yann Godet, Amir Khammari, Brigitte Dréno, Francine Jotereau, and Nadine Gervois
Subjects: Medicine, Science
Abstract: BACKGROUND: Double positive (DP) CD4CD8 Talphabeta cells have been reported in normal individuals as well as in different pathological conditions including inflammatory diseases, viral infections and cancer, but their function remains to be elucidated. We recently reported the increased frequency of DP Talphabeta cells in human breast pleural effusions. This manuscript addresses the question of the existence and above all the role of this non-conventional DP sub-population among tumor associated lymphocytes in melanomas. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed the intratumoral cell infiltrate in solid metastasis (n = 6) and tumor invaded lymph nodes (n = 26) samples from melanomas patients by multiparametric cytometry. Here we documented for the first time significant increased frequency of DP T cells in about 60% of melanoma tumors compared to blood samples. Interestingly, a high proportion of these cells produced TNF-alpha in response to autologous melanoma cell lines. Besides, they are characterized by a unique cytokine profile corresponding to higher secretion of IL-13, IL-4 and IL-5 than simple positive T cells. In deep analysis, we derived a representative tumor-reactive DP T cell clone from a melanoma patient's invaded lymph node. This clone was restricted by HLA-A*2402 and recognized both autologous and allogeneic tumor cells of various origins as well as normal cells, suggesting that the target antigen was a ubiquitous self antigen. However, this DP T cell clone failed to kill HLA-A*2402 EBV-transformed B cells, probably due to the constitutive expression of immunoproteasome by these cells. CONCLUSIONS/SIGNIFICANCE: In conclusion, we can postulate that, according to their broad tumor reactivity and to their original cytokine profile, the tumor associated DP T cells could participate in immune responses to tumors in vivo. Therefore, the presence of these cells and their role will be crucial to address in cancer patients, especially in the context of immunotherapies.
Published: 2010
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12. Rare pathogenic variants in WNK3 cause X-linked intellectual disability

Author: Sébastien Küry, Jinwei Zhang, Thomas Besnard, Alfonso Caro-Llopis, Xue Zeng, Stephanie M. Robert, Sunday S. Josiah, Emre Kiziltug, Anne-Sophie Denommé-Pichon, Benjamin Cogné, Adam J. Kundishora, Le T. Hao, Hong Li, Roger E. Stevenson, Raymond J. Louie, Wallid Deb, Erin Torti, Virginie Vignard, Kirsty McWalter, F. Lucy Raymond, Farrah Rajabi, Emmanuelle Ranza, Detelina Grozeva, Stephanie A. Coury, Xavier Blanc, Elise Brischoux-Boucher, Boris Keren, Katrin Õunap, Karit Reinson, Pilvi Ilves, Ingrid M. Wentzensen, Eileen E. Barr, Solveig Heide Guihard, Perrine Charles, Eleanor G. Seaby, Kristin G. Monaghan, Marlène Rio, Yolande van Bever, Marjon van Slegtenhorst, Wendy K. Chung, Ashley Wilson, Delphine Quinquis, Flora Bréhéret, Kyle Retterer, Pierre Lindenbaum, Emmanuel Scalais, Lindsay Rhodes, Katrien Stouffs, Elaine M. Pereira, Sara M. Berger, Sarah S. Milla, Ankita B. Jaykumar, Melanie H. Cobb, Shreyas Panchagnula, Phan Q. Duy, Marie Vincent, Sandra Mercier, Brigitte Gilbert-Dussardier, Xavier Le Guillou, Séverine Audebert-Bellanger, Sylvie Odent, Sébastien Schmitt, Pierre Boisseau, Dominique Bonneau, Annick Toutain, Estelle Colin, Laurent Pasquier, Richard Redon, Arjan Bouman, Jill. A. Rosenfeld, Michael J. Friez, Helena Pérez-Peña, Syed Raza Akhtar Rizvi, Shozeb Haider, Stylianos E. Antonarakis, Charles E. Schwartz, Francisco Martínez, Stéphane Bézieau, Kristopher T. Kahle, Bertrand Isidor, Clinical Genetics, Clinical sciences, Medical Genetics, Reproduction and Genetics, Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-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), University of Exeter, MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), The Greenwood Genetic Center, GeneDx [Gaithersburg, MD, USA], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Genève = University of Geneva (UNIGE), Yale School of Medicine [New Haven, Connecticut] (YSM), This work was granted by the French network of University Hospitals HUGO ('Hôpitaux Universitaires du Grand Ouest'), the French Ministry of Health, and and the Health Regional Agencies from Poitou-Charentes (represented by Frédérique Allaire), Bretagne, Pays de la Loire, and Centre-Val de Loire (HUGODIMS, 2013, RC14_0107). W.K.C. was supported by grants from Simons Foundation Autism Research Initiative, United
Subjects: MESH: Symporters, Exome sequencing, Male, KCC2, Mutation, Missense, MESH: Catalytic Domain, Neurodevelopmental disease, Protein Serine-Threonine Kinases, X-linked intellectual disability, MESH: Brain, WNK3, SDG 3 - Good Health and Well-being, Loss of Function Mutation, Catalytic Domain, MESH: Mental Retardation, X-Linked, Humans, Phosphorylation, MESH: Hemizygote, Genetics (clinical), Hemizygote, MESH: Mutation, Missense, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Phosphorylation, Symporters, Brain, MESH: Loss of Function Mutation, MESH: Protein Serine-Threonine Kinases, MESH: Male, Mental Retardation, X-Linked, Maternal Inheritance, MESH: Maternal Inheritance
Abstract: PURPOSE: WNK3 kinase (PRKWNK3) has been implicated in the development and function of the brain via its regulation of the cation-chloride cotransporters, but the role of WNK3 in human development is unknown. METHOD: We ascertained exome or genome sequences of individuals with rare familial or sporadic forms of intellectual disability (ID). RESULTS: We identified a total of 6 different maternally-inherited, hemizygous, 3 loss-of-function or 3 pathogenic missense variants (p.Pro204Arg, p.Leu300Ser, p.Glu607Val) in WNK3 in 14 male individuals from 6 unrelated families. Affected individuals had identifier with variable presence of epilepsy and structural brain defects. WNK3 variants cosegregated with the disease in 3 different families with multiple affected individuals. This included 1 large family previously diagnosed with X-linked Prieto syndrome. WNK3 pathogenic missense variants localize to the catalytic domain and impede the inhibitory phosphorylation of the neuronal-specific chloride cotransporter KCC2 at threonine 1007, a site critically regulated during the development of synaptic inhibition. CONCLUSION: Pathogenic WNK3 variants cause a rare form of human X-linked identifier with variable epilepsy and structural brain abnormalities and implicate impaired phospho-regulation of KCC2 as a pathogenic mechanism.
Published: 2022

13. PSMC3 proteasome subunit variants are associated with neurodevelopmental delay and type I interferon production

Author: Frédéric Ebstein, Sébastien Küry, Victoria Most, Cory Rosenfelt, Marie-Pier Scott-Boyer, Geeske M. van Woerden, Thomas Besnard, Jonas Johannes Papendorf, Maja Studencka-Turski, Tianyun Wang, Tzung-Chien Hsieh, Richard Golnik, Dustin Baldridge, Cara Forster, Charlotte de Konink, Selina M.W. Teurlings, Virginie Vignard, Richard H. van Jaarsveld, Lesley Ades, Benjamin Cogné, Cyril Mignot, Wallid Deb, Marjolijn C.J. Jongmans, F. Sessions Cole, Marie-José H. van den Boogaard, Jennifer A. Wambach, Daniel J. Wegner, Sandra Yang, Vickie Hannig, Jennifer Ann Brault, Neda Zadeh, Bruce Bennetts, Boris Keren, Anne-Claire Gélineau, Zöe Powis, Meghan Towne, Kristine Bachman, Andrea Seeley, Anita E. Beck, Jennifer Morrison, Rachel Westman, Kelly Averill, Theresa Brunet, Judith Haasters, Melissa T. Carter, Matthew Osmond, Patricia G. Wheeler, Francesca Forzano, Shehla Mohammed, Yannis Trakadis, Andrea Accogli, Rachel Harrison, Yiran Guo, Hakon Hakonarson, Sophie Rondeau, Geneviève Baujat, Giulia Barcia, René Günther Feichtinger, Johannes Adalbert Mayr, Martin Preisel, Frédéric Laumonnier, Tilmann Kallinich, Alexej Knaus, Bertrand Isidor, Peter Krawitz, Uwe Völker, Elke Hammer, Arnaud Droit, Evan E. Eichler, Ype Elgersma, Peter W. Hildebrand, François Bolduc, Elke Krüger, Stéphane Bézieau, Clinical Genetics, and Neurosciences
Subjects: General Medicine
Abstract: A critical step in preserving protein homeostasis is the recognition, binding, unfolding, and translocation of protein substrates by six AAA-ATPase proteasome subunits (ATPase-associated with various cellular activities) termed PSMC1-6, which are required for degradation of proteins by 26 S proteasomes. Here, we identified 15 de novo missense variants in the PSMC3 gene encoding the AAA-ATPase proteasome subunit PSMC3/Rpt5 in 23 unrelated heterozygous patients with an autosomal dominant form of neurodevelopmental delay and intellectual disability. Expression of PSMC3 variants in mouse neuronal cultures led to altered dendrite development, and deletion of the PSMC3 fly ortholog Rpt5 impaired reversal learning capabilities in fruit flies. Structural modeling as well as proteomic and transcriptomic analyses of T cells derived from patients with PSMC3 variants implicated the PSMC3 variants in proteasome dysfunction through disruption of substrate translocation, induction of proteotoxic stress, and alterations in proteins controlling developmental and innate immune programs. The proteostatic perturbations in T cells from patients with PSMC3 variants correlated with a dysregulation in type I interferon (IFN) signaling in these T cells, which could be blocked by inhibition of the intracellular stress sensor protein kinase R (PKR). These results suggest that proteotoxic stress activated PKR in patient-derived T cells, resulting in a type I IFN response. The potential relationship among proteosome dysfunction, type I IFN production, and neurodevelopment suggests new directions in our understanding of pathogenesis in some neurodevelopmental disorders.
Published: 2023

14. 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

15. 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

16. Figure S1 from Emergence of High-Avidity Melan-A–Specific Clonotypes as a Reflection of Anti–PD-1 Clinical Efficacy

Author: Nathalie Labarriere, Brigitte Dreno, Francois Lang, Nadine Gervois, Amir Khammari, Anne-Chantal Knol, Tiphaine Parrot, Emilie Varey, Virginie Vignard, and Sylvain Simon
Abstract: Figure S1 illustrates the robustness and reproducibility of the methodolgy used to sort and amplify Melan-A specific T cells from HLA-A2 PBMC.
Published: 2023

17. Supplemental figure legends from Emergence of High-Avidity Melan-A–Specific Clonotypes as a Reflection of Anti–PD-1 Clinical Efficacy

Author: Nathalie Labarriere, Brigitte Dreno, Francois Lang, Nadine Gervois, Amir Khammari, Anne-Chantal Knol, Tiphaine Parrot, Emilie Varey, Virginie Vignard, and Sylvain Simon
Abstract: Legends of supplemental figures S1, S2, S3 and S4
Published: 2023

18. Data from Emergence of High-Avidity Melan-A–Specific Clonotypes as a Reflection of Anti–PD-1 Clinical Efficacy

Author: Nathalie Labarriere, Brigitte Dreno, Francois Lang, Nadine Gervois, Amir Khammari, Anne-Chantal Knol, Tiphaine Parrot, Emilie Varey, Virginie Vignard, and Sylvain Simon
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: 2023

19. Rare germline heterozygous missense variants in BRCA1-associated protein 1, BAP1, cause a syndromic neurodevelopmental disorder

Author: Sébastien Küry, Frédéric Ebstein, Alice Mollé, Thomas Besnard, Ming-Kang Lee, Virginie Vignard, Tiphaine Hery, Mathilde Nizon, Grazia M.S. Mancini, Jacques C. Giltay, Benjamin Cogné, Kirsty McWalter, Wallid Deb, Hagar Mor-Shaked, Hong Li, Rhonda E. Schnur, Ingrid M. Wentzensen, Anne-Sophie Denommé-Pichon, Cynthia Fourgeux, Frans W. Verheijen, Eva Faurie, Rachel Schot, Cathy A. Stevens, Daphne J. Smits, Eileen Barr, Ruth Sheffer, Jonathan A. Bernstein, Chandler L. Stimach, Eliana Kovitch, Vandana Shashi, Kelly Schoch, Whitney Smith, Richard H. van Jaarsveld, Anna C.E. Hurst, Kirstin Smith, Evan H. Baugh, Suzanne G. Bohm, Emílie Vyhnálková, Lukáš Ryba, Capucine Delnatte, Juanita Neira, Dominique Bonneau, Annick Toutain, Jill A. Rosenfeld, Séverine Audebert-Bellanger, Brigitte Gilbert-Dussardier, Sylvie Odent, Frédéric Laumonnier, Seth I. Berger, Ann C.M. Smith, Franck Bourdeaut, Marc-Henri Stern, Richard Redon, Elke Krüger, Raphaël Margueron, Stéphane Bézieau, Jeremie Poschmann, Bertrand Isidor, Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-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), Universität Greifswald - University of Greifswald, 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), Génétique et Biologie du Développement, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Erasmus University Medical Center [Rotterdam] (Erasmus MC), University Medical Center [Utrecht], GeneDx [Gaithersburg, MD, USA], Hadassah Hebrew University Medical Center [Jerusalem], Emory University School of Medicine, Emory University [Atlanta, GA], Laboratoire de Biologie Neurovasculaire Intégrée [Angers] (CNRS UMR6214 - INSERM U771), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers, MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Tennessee System, Stanford University, Duke University Medical Center, University of Alabama at Birmingham [ Birmingham] (UAB), Columbia University [New York], Charles University [Prague] (CU), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Baylor College of Medicine (BCM), Baylor University, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Unité neurovasculaire et troubles cognitifs (Neuvacod), Université de Poitiers, CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de référence Maladies Rares CLAD-Ouest [Rennes], Children's National Medical Center, National Human Genome Research Institute (NHGRI), Institut Curie [Paris], Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Greifswald University Hospital, Research reported in this manuscript was supported by the NIH Common Fund through the Office of Strategic Coordination/Office of the NIH Director under award number U01HG007672 to V.S. Further support was obtained by funding from the German Research Foundation (SFBTR 167 A4, GRK2719 B4) to E.K, and Clinical Genetics
Subjects: Male, Heterozygote, Proteasome Endopeptidase Complex, tumor, Adolescent, T-Lymphocytes, Ubiquitin-Protein Ligases, [SDV]Life Sciences [q-bio], Mutation, Missense, UPS, ubiquitin-proteasome system, chromatin remodeling, Histones, SDG 3 - Good Health and Well-being, Loss of Function Mutation, Report, ubiquitin, Genetics, Humans, cancer, Family, BAP1, Child, deubiquitination, Germ-Line Mutation, Genetics (clinical), [SDV.GEN]Life Sciences [q-bio]/Genetics, neurodevelopment, BRCA1 Protein, Tumor Suppressor Proteins, Ubiquitination, Infant, Chromatin Assembly and Disassembly, BRCA1, Chromatin, Gene Expression Regulation, Neurodevelopmental Disorders, intellectual disability, Child, Preschool, histone 2A, Female, Host Cell Factor C1, Ubiquitin Thiolesterase
Abstract: International audience; Nuclear deubiquitinase BAP1 (BRCA1-associated protein 1) is a core component of multiprotein complexes that promote transcription by reversing the ubiquitination of histone 2A (H2A). BAP1 is a tumor suppressor whose germline loss-of-function variants predispose to cancer. To our knowledge, there are very rare examples of different germline variants in the same gene causing either a neurodevelopmental disorder (NDD) or a tumor predisposition syndrome. Here, we report a series of 11 de novo germline heterozygous missense BAP1 variants associated with a rare syndromic NDD. Functional analysis showed that most of the variants cannot rescue the consequences of BAP1 inactivation, suggesting a loss-of-function mechanism. In T cells isolated from two affected children, H2A deubiquitination was impaired. In matching peripheral blood mononuclear cells, histone H3 K27 acetylation ChIP-seq indicated that these BAP1 variants induced genome-wide chromatin state alterations, with enrichment for regulatory regions surrounding genes of the ubiquitin-proteasome system (UPS). Altogether, these results define a clinical syndrome caused by rare germline missense BAP1 variants that alter chromatin remodeling through abnormal histone ubiquitination and lead to transcriptional dysregulation of developmental genes.
Published: 2022

20. Stankiewicz-Isidor syndrome

Author: Ignacio Briceño, Frédéric Ebstein, Alberto Gómez, Heidi Cope, Wallid Deb, Krzysztof Szczaluba, Hutton M. Kearney, Dominique Bonneau, Elke Krüger, Marie Vincent, Jill A. Rosenfeld, Karin E. M. Diderich, Dominique Bourgeois, Kay Metcalfe, Bryce A. Mendelssohn, Magalie Barth, Solène Conrad, Alanna Strong, Patrick R. Blackburn, Amanda Gerard, McKinsey L. Goodenberger, Benjamin Cogné, Geneviève Baujat, Caroline Camby, Thomas Besnard, Natasha L. Rudy, Karin Dahan, Estelle Colin, Carlos A. Bacino, Caleb Bupp, Christel Thauvin-Robinet, Yolande van Bever, Rafał Płoski, Anne de Saint Martin, Johannes A. Mayr, Ingrid Bader, Yong-Hui Jiang, Virginie Vignard, Kathryn Warren, Judith D. Ranells, Yves Alembik, Joanna Kennedy, Stéphane Bézieau, Bertrand Isidor, Anna C.E. Hurst, Amélie Piton, Sébastien Küry, Ange-Line Bruel, PaweƗ Stankiewicz, Ingrid Scurr, Anja Brehm, and Clinical Genetics
Subjects: Genetics, Phenotype, Intellectual Disability, Molecular phenotype, Humans, Language Development Disorders, Haploinsufficiency, Biology, Genetics (clinical), Musculoskeletal Abnormalities
Abstract: Purpose: Haploinsufficiency of PSMD12 has been reported in individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), facial dysmorphism, and congenital malformations, defined as Stankiewicz-Isidor syndrome (STISS). Investigations showed that pathogenic variants in PSMD12 perturb intracellular protein homeostasis. Our objective was to further explore the clinical and molecular phenotypic spectrum of STISS. Methods: We report 24 additional unrelated patients with STISS with various truncating single nucleotide variants or copy-number variant deletions involving PSMD12. We explore disease etiology by assessing patient cells and CRISPR/Cas9-engineered cell clones for various cellular pathways and inflammatory status. Results: The expressivity of most clinical features in STISS is highly variable. In addition to previously reported DD/ID, speech delay, cardiac and renal anomalies, we also confirmed preaxial hand abnormalities as a feature of this syndrome. Of note, 2 patients also showed chilblains resembling signs observed in interferonopathy. Remarkably, our data show that STISS patient cells exhibit a profound remodeling of the mTORC1 and mitophagy pathways with an induction of type I interferon-stimulated genes. Conclusion: We refine the phenotype of STISS and show that it can be clinically recognizable and biochemically diagnosed by a type I interferon gene signature.
Published: 2022

21. 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

22. 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

23. 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

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. 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

26. Non-Coding RNAs in Cutaneous Melanoma Development, Progression and Dissemination

Author: Delphine Fradin, Virginie Vignard, 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), Bernardo, Elizabeth, and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)
Subjects: business.industry, Melanoma, Cancer, Tumor cells, [SDV.CAN]Life Sciences [q-bio]/Cancer, medicine.disease, Non-coding RNA, 3. Good health, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cutaneous melanoma, Cancer research, medicine, melanoma, cancer hallmarks, Epigenetics, High incidence, Skin cancer, business, ComputingMilieux_MISCELLANEOUS
Abstract: Melanoma is a highly aggressive skin cancer with high incidence worldwide. There are growing evidences that aberrantly expressed non-coding RNAs (ncRNAs) play a role in the development, progression and dissemination of melanoma tumor cells. Among the many types of ncRNAs, we will describe in this review, the function of micro- and long non-coding RNAs in the six hallmarks of cancer. Recently, ncRNAs were discovered in body fluids becoming one of the most promising biomarkers in oncology for non-invasive diagnosis, prognosis or therapeutic response prediction.
Published: 2018

27. 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

28. 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

29. 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

30. 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

31. Immunoregulatory function of IL-27 and TGF-β1 in cardiac allograft transplantation

Author: Elise Chiffoleau, Virginie Vignard, Emmanuel Merieau, Manuela Carvalho-Gaspar, Maria-Cristina Cuturi, Kathryn J. Wood, Claire Usal, Laetitia Le Texier, and Pamela Thebault
Subjects: CD4-Positive T-Lymphocytes, medicine.medical_treatment, Cellular differentiation, Inflammation, Biology, CD8-Positive T-Lymphocytes, Article, Transforming Growth Factor beta1, Mice, medicine, Animals, Transplantation, Homologous, Oligonucleotide Array Sequence Analysis, Regulation of gene expression, Mice, Knockout, Transplantation, Interleukin-17, Interleukin-2 Receptor alpha Subunit, Interleukin, Immunosuppression, Cell Differentiation, Dependovirus, Rats, Mice, Inbred C57BL, Disease Models, Animal, Gene Expression Regulation, Immunology, Mice, Inbred CBA, Heart Transplantation, Th17 Cells, Interleukin 17, medicine.symptom, Transforming growth factor
Abstract: Background: Deciphering the mechanisms of tolerance represents a crucial aim of research in transplantation. We previously identified by DNA chip interleukin (IL)-27 p28 and transforming growth factor (TGF)-β1 as overexpressed in a model of rat cardiac allograft tolerance mediated by regulatory CD4 +CD25 + T cells. The role of these two molecules on the control of the inflammatory response remains controversial. However, both are involved in the regulation of the T helper 17/Treg axis, suggesting their involvement in tolerance. Methods: We analyzed regulation of IL-27 and TGF-β1 expression in allograft response and their role in tolerance by using blocking anti-TGF-β antibody and by generating an adeno-associated virus encoding IL-27. Results: Here, we confirmed the overexpression of IL-27 and TGF-β1 in tolerated cardiac allografts in two different rodent models. We observed that their expression correlates with inhibition of T helper 17 differentiation and with expansion of regulatory CD4 +CD25 + T cells. We showed in a rat model that anti-TGF-β treatment abrogates infectious tolerance mediated by the transfer of regulatory CD4 +CD25 + T cells. Moreover, overexpression of IL-27 by adeno-associated virus administration in combination with a short-term immunosuppression allows prolongation of cardiac allograft survival and one tolerant recipient. We found that IL-27 overexpression did not induce Foxp3CD4 +CD25 + T-cell expansion but rather IL-10-expressing CD4 + T cells in the tolerant recipient. Conclusions: Taken together, these data suggest that both TGF-β1 and IL-27 play a role in the mechanisms of tolerance. However, in contrast to TGF-β1, IL-27 seems not to be involved in regulatory CD4CD25 T-cell expansion but rather in their mode of action. © 2012 Lippincott Williams and Wilkins.
Published: 2012

32. MELOE-1 Antigen Contains Multiple HLA Class II T Cell Epitopes Recognized by Th1 CD4+ T Cells from Melanoma Patients

Author: Brigitte Dréno, Mathilde Bobinet, Anne Rogel, Amir Khammari, Virginie Vignard, François Lang, Nathalie Labarrière, 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: CD4-Positive T-Lymphocytes, Melanomas, Skin Neoplasms, lcsh:Medicine, Epitopes, T-Lymphocyte, Adaptive Immunity, Epitope, Major Histocompatibility Complex, Interleukin 21, 0302 clinical medicine, Cytotoxic T cell, lcsh:Science, Melanoma, Immune Response, 0303 health sciences, Multidisciplinary, T Cells, T-Lymphocytes, Helper-Inducer, Flow Cytometry, Neoplasm Proteins, 3. Good health, Cytokines, Medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Immunotherapy, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, Research Article, Tumor Immunology, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immune Cells, Molecular Sequence Data, Immunology, Malignant Skin Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Dermatology, Human leukocyte antigen, Biology, Immune Activation, 03 medical and health sciences, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigen, Antigens, Neoplasm, Humans, Amino Acid Sequence, Antigen-presenting cell, 030304 developmental biology, lcsh:R, Histocompatibility Antigens Class II, Immunity, Dendritic Cells, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Immunologic Subspecialties, Peptide Fragments, Case-Control Studies, lcsh:Q, CD8, 030215 immunology
Abstract: International audience; MELOE-1 is an overexpressed melanoma antigen containing a HLA-A2 restricted epitope, involved in melanoma immunosurveillance of patients adoptively transferred with tumour infiltrating lymphocytes (TIL). The use of the full-length antigen (46 aa) for anti-melanoma vaccination could be considered, subject to the presence of Th epitopes all along MELOE-1 sequence. Thus, in this study we evaluated in vitro the immunoprevalence of the different regions of MELOE-1 (i.e. their ability to induce CD4 T cell responses in vitro from PBMC). Stimulation of PBMC from healthy subjects with MELOE-1 induced the amplification of CD4 T cells specific for various regions of the protein in multiple HLA contexts, for each tested donor. We confirmed these results in a panel of melanoma patients, and documented that MELOE-1 specific CD4 T cells, were mainly Th1 cells, presumably favourable to the amplification of CD8 specific T cells. Using autologous DC, we further showed that these class II epitopes could be naturally processed from MELOE-1 whole protein and identified minimal epitopes derived from each region of MELOE-1, and presented in four distinct HLA contexts. In conclusion, vaccination with MELOE-1 whole polypeptide should induce specific Th1 CD4 responses in a majority of melanoma patients, stimulating the amplification of CD8 effector cells, reactive against melanoma cells.
Published: 2012

33. Frequent occurrence of high affinity T cells against MELOE-1 makes this antigen an attractive target for melanoma immunotherapy

Author: Yann Godet, Juliette Desfrançois, Brigitte Dréno, Nathalie Labarrière, Francine Jotereau, Dirk Schadendorf, Amir Khammari, 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), Centre hospitalier universitaire de Nantes (CHU Nantes), University of Essen [Essen], and LABARRIERE, Nathalie
Subjects: [SDV.IMM] Life Sciences [q-bio]/Immunology, medicine.medical_treatment, T-Lymphocytes, Immunology, Medizin, Receptors, Antigen, T-Cell, Epitopes, T-Lymphocyte, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Separation, Biology, Epitope, 03 medical and health sciences, 0302 clinical medicine, Lymphocytes, Tumor-Infiltrating, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigen, Antigens, Neoplasm, T-Lymphocyte Subsets, medicine, Immunology and Allergy, Humans, Melanoma, 030304 developmental biology, 0303 health sciences, Tumor-infiltrating lymphocytes, T-cell receptor, Cell Differentiation, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Immunotherapy, medicine.disease, Flow Cytometry, 3. Good health, Neoplasm Proteins, CTL, Phenotype, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, CD8, 030215 immunology
Abstract: International audience; We recently showed that the infusion of tumor infiltrating lymphocytes specific for the MELOE-1 antigen was associated with a prolonged relapse-free survival for HLA-A2 1 melanoma patients who received tumor infiltrating lymphocytes therapy. Here, we characterized the MELOE-1/A2-specific T-cell repertoire in healthy donors and melanoma patients to further support an immunotherapy targeting this epitope. Using tetramer enrichment followed by multicolor staining, we found that MELOE-1-specific T cells were present in the blood of healthy donors and patients at similar frequencies (around 1 in 1 Â 10 5 CD8 1 cells). These cells mainly displayed a naïve phenotype in 4/6 healthy donors and 3/6 patients, whereas high proportions of memory cells were observed in the remaining individuals of both groups. There was a recurrent usage of the Va12.1 chain for 17/18 MELOE-1-specific T-cell clones derived from healthy donors or patients, associated with diverse Vb chains and V(D)J junctional sequences. All clones derived from melanoma patients (9/9) were reactive against the MELOE-1 36-44 peptide and against HLA-A2 1 melanoma cell lines. This study documents the existence of a large TCR repertoire specific for the MELOE-1/A2 epitope and its capacity to give rise to antitumor CTL that supports the development of immunotherapies targeting this epitope.
Published: 2010

34. Double Positive CD4CD8 αβ T Cells: A New Tumor-Reactive Population in Human Melanomas

Author: Yann Godet, Juliette Desfrançois, Amir Khammari, Francine Jotereau, Brigitte Dréno, Agnès Moreau-Aubry, Virginie Vignard, Nadine Gervois, 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), Université de Nantes (UN), Centre hospitalier universitaire de Nantes (CHU Nantes), and GERVOIS, Nadine
Subjects: CD4-Positive T-Lymphocytes, [SDV]Life Sciences [q-bio], Immunology, Immunology/Immunomodulation, Clone (cell biology), lcsh:Medicine, CD8-Positive T-Lymphocytes, Biology, Oncology/Skin Cancers, 03 medical and health sciences, Interleukin 21, 0302 clinical medicine, Immune system, Antigen, medicine, Humans, Cytotoxic T cell, Neoplasm Metastasis, Antigen-presenting cell, lcsh:Science, Melanoma, Lymph node, 030304 developmental biology, 0303 health sciences, Multidisciplinary, lcsh:R, Flow Cytometry, medicine.disease, Clone Cells, 3. Good health, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Immunology/Immune Response, lcsh:Q, Research Article, 030215 immunology
Abstract: International audience; Background: Double positive (DP) CD4CD8 Tab cells have been reported in normal individuals as well as in different pathological conditions including inflammatory diseases, viral infections and cancer, but their function remains to be elucidated. We recently reported the increased frequency of DP Tab cells in human breast pleural effusions. This manuscript addresses the question of the existence and above all the role of this non-conventional DP sub-population among tumor associated lymphocytes in melanomas. Methodology/Principal Findings: We analyzed the intratumoral cell infiltrate in solid metastasis (n = 6) and tumor invaded lymph nodes (n = 26) samples from melanomas patients by multiparametric cytometry. Here we documented for the first time significant increased frequency of DP T cells in about 60% of melanoma tumors compared to blood samples. Interestingly, a high proportion of these cells produced TNF-a in response to autologous melanoma cell lines. Besides, they are characterized by a unique cytokine profile corresponding to higher secretion of IL-13, IL-4 and IL-5 than simple positive T cells. In deep analysis, we derived a representative tumor-reactive DP T cell clone from a melanoma patient's invaded lymph node. This clone was restricted by HLA-A*2402 and recognized both autologous and allogeneic tumor cells of various origins as well as normal cells, suggesting that the target antigen was a ubiquitous self antigen. However, this DP T cell clone failed to kill HLA-A*2402 EBV-transformed B cells, probably due to the constitutive expression of immunoproteasome by these cells. Conclusions/Significance: In conclusion, we can postulate that, according to their broad tumor reactivity and to their original cytokine profile, the tumor associated DP T cells could participate in immune responses to tumors in vivo. Therefore, the presence of these cells and their role will be crucial to address in cancer patients, especially in the context of immunotherapies.
Published: 2010

35. An additional ORF on meloe cDNA encodes a new melanoma antigen, MELOE-2, recognized by melanoma-speciWc T cells in the HLA-A2 context

Author: Dimitri Mompelat, Brigitte Dréno, Yann Godet, Francine Jotereau, Amir Khammari, Nathalie Labarrière, François Lang, Agnès Moreau-Aubry, 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), Centre hospitalier universitaire de Nantes (CHU Nantes), and LABARRIERE, Nathalie
Subjects: Cancer Research, DNA, Complementary, Skin Neoplasms, [SDV.IMM] Life Sciences [q-bio]/Immunology, T-Lymphocytes, Immunology, Population, Molecular Sequence Data, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Epitope, 03 medical and health sciences, Open Reading Frames, 0302 clinical medicine, Lymphocytes, Tumor-Infiltrating, Antigen, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigens, Neoplasm, Complementary DNA, HLA-A2 Antigen, medicine, Immunology and Allergy, Humans, ORFS, education, Melanoma, Genetics, education.field_of_study, Clinical Trials as Topic, Base Sequence, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, biology.organism_classification, Molecular biology, 3. Good health, Neoplasm Proteins, Open reading frame, Oncology, Meloe, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, 030215 immunology
Abstract: International audience; We characterized a new melanoma antigen derived from one of the multiple open reading frames (ORFs) of the meloe transcript. The meloe gene is overex-pressed in melanomas as compared to other cancer cell lines and normal tissues. The corresponding transcript is rather unusual, in that it does not contain a long unique ORF but multiple short ORFs. We recently characterized a tumor epitope derived from a polypeptide (MELOE-1) encoded by the ORF 1230-1370 and involved in relapse prevention of melanoma patients treated with autologous tumor inWltrating lymphocytes (TIL). Here we show that the ORF 285-404 encodes a polypeptide called MELOE-2 that also generated a HLA-A2 epitope recognized by a mela-noma-speciWc T cell clone derived from the same TIL population from which we derived the MELOE-1-speciWc T cell clone. We also showed that HLA-A2 melanoma cells were spontaneously recognized by the MELOE-2-speciWc T cell clone, and we detected the presence of MELOE-2 reactive T cells in another TIL population infused to a patient who remained relapse-free after TIL treatment. These results demonstrate that translation of meloe transcript in melanoma cells can produce at least two immuno-genic polypeptides, MELOE-1 and MELOE-2, from two distinct ORFs that could be relevant target for melanoma immunotherapy.
Published: 2010

36. A new tyrosinase epitope recognized in the HLA-B*4002 context by CTL from melanoma patients

Author: Annabelle Bonnin, Dirk Schadendorf, Yann Godet, Nathalie Labarrière, Y Guilloux, Francine Jotereau, Brigitte Dréno, 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), German Cancer Research Center [Mannheim], University Hospital Mannheim, Service de dermatologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), and LABARRIERE, Nathalie
Subjects: Cancer Research, DNA, Complementary, [SDV.IMM] Life Sciences [q-bio]/Immunology, medicine.medical_treatment, Molecular Sequence Data, Immunology, Clone (cell biology), Galanin, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Epitope, Epitopes, Mice, 03 medical and health sciences, 0302 clinical medicine, Antigen, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, Chlorocebus aethiops, medicine, Animals, Humans, Immunology and Allergy, Neuropeptide Y, Amino Acid Sequence, Melanoma, 030304 developmental biology, 0303 health sciences, Monophenol Monooxygenase, Immunogenicity, Immunotherapy, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, Peptide Fragments, 3. Good health, CTL, Oncology, HLA-B Antigens, COS Cells, Leukocytes, Mononuclear, Peptide vaccine, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, Peptides, T-Lymphocytes, Cytotoxic, 030215 immunology
Abstract: International audience; Melanoma reactive CTL were obtained by stimulating PBL from a melanoma patient in remission since 1994 following adjuvant TIL immunotherapy, with the autologous melanoma cell line. They were cloned by limiting dilution. One CTL clone recognized melanoma cell lines expressing tyrosinase and the B*4002 molecule, either spontaneously or upon transfection. We demonstrated that this clone recognizes the tyrosinase-derived nonapeptide 316-324 (ADVEFCLSL) and the overlapping decapeptide 315-324 (SADVEFCLSL). We derived two distinct additional speciWc CTL clones from this same patient that were also reactive against B*4002 melanoma cell lines, suggesting a relative diversity of this speciWc repertoire in this patient. Stimulating PBMC derived from four additional B*4002 melanoma patients with the tyrosinase 316-324 nonapeptide induced the growth of speciWc cells for two of the patients, demonstrating the immunogenicity of this new epitope. Our data show that this nonapeptide is a new tool that could be used to generate melanoma-speciWc T cells for adoptive immunotherapy or serve as a peptide vaccine for HLA-B*4002 melanoma patients.
Published: 2009

37. Treatment of Metastatic Melanoma with Autologous Melan-A/Mart-1-Specific Cytotoxic T Lymphocyte Clones

Author: Jean-Michel Nguyen, Anabelle Brocard, Amir Khammari, Brigitte Dréno, Francine Jotereau, Anne Chantal Knol, Gaëlle Quéreux, Marie-Christine Pandolfino, Nathalie Labarrière, Virginie Vignard, Soraya Saiagh, LABARRIERE, Nathalie, 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), PIMESP [CHU Nantes, Hôpital Saint-Jacques], Unité de Thérapie Cellulaire et Génique [CHU Nantes] (UTCG), and Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes)
Subjects: Interleukin 2, Male, Adoptive cell transfer, Skin Neoplasms, [SDV.IMM] Life Sciences [q-bio]/Immunology, medicine.medical_treatment, Dacarbazine, Clone (cell biology), Alpha interferon, Skin Pigmentation, [SDV.CAN]Life Sciences [q-bio]/Cancer, Dermatology, CD8-Positive T-Lymphocytes, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, MART-1 Antigen, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigens, Neoplasm, medicine, Cytotoxic T cell, Humans, Molecular Biology, Melanoma, Aged, business.industry, Cell Biology, Immunotherapy, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Middle Aged, medicine.disease, Adoptive Transfer, 3. Good health, Clone Cells, Neoplasm Proteins, Treatment Outcome, 030220 oncology & carcinogenesis, Immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, business, 030215 immunology, medicine.drug, T-Lymphocytes, Cytotoxic
Abstract: International audience; Immunotherapy by adoptive T-cell transfer aims at maximizing tumor antigen-specific T-cell responses. We treated 14 patients at the metastatic stage in a phase II study with Melan-A-specific T-cell clones generated from patient blood. During the period required for T-cell clone generation, the patients were treated by dacarbazine. Every patient received a T-cell clone suspension followed by subcutaneous injections of interleukin 2 and interferon alpha. Patients were monitored until disease progression occurred. We succeeded in obtaining autologous Melan-A-specific cytotoxic T lymphocyte clones, which were highly reactive against tumor cells for all the patients. Of the 14 patients treated, six (43%) experienced an objective response (CR þ PR) with long-term complete remission for two patients (1 CR for 5 years and 1 CR for 28 months). Furthermore, we showed that all the clinical responses were significantly associated with in vivo expansion of the Melan-A-specific T-cell repertoire. This phenomenon appeared to be significantly associated with clinical responses. Thus, over the course of an adoptive cell transfer, monitoring this melanoma-specific T-cell expansion in patient blood appears crucial for predicting the clinical efficiency of such an immunological approach.
Published: 2009

38. MELOE-1 is a new antigen overexpressed in melanomas and involved in adoptive T cell transfer efficiency

Author: Y Guilloux, Yann Godet, Virginie Vignard, Amir Khammari, Brigitte Dréno, Agnès Moreau-Aubry, Francine Jotereau, Nathalie Labarrière, 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), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN), Service de dermatologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), and LABARRIERE, Nathalie
Subjects: Adoptive cell transfer, DNA, Complementary, [SDV.IMM] Life Sciences [q-bio]/Immunology, T cell, Lymphocyte, medicine.medical_treatment, Immunology, Clone (cell biology), Oligonucleotides, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Lymphocytes, Tumor-Infiltrating, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigen, Antigens, Neoplasm, Recurrence, Chlorocebus aethiops, medicine, Immunology and Allergy, Cytotoxic T cell, Animals, Humans, Melanoma, 030304 developmental biology, DNA Primers, 0303 health sciences, Immunomagnetic Separation, Immunotherapy, Articles, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, Adoptive Transfer, 3. Good health, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, 030220 oncology & carcinogenesis, COS Cells, Cancer research, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, Melanoma-Specific Antigens, T-Lymphocytes, Cytotoxic
Abstract: International audience; A cytotoxic T lymphocyte (CTL) clone was derived from a tumor-infiltrating lymphocyte (TIL) population infused to a melanoma patient who remained relapse free for 10 yr after this adoptive transfer. This clone recognized all melanoma cell lines tested and, to a lower extent, melanocytes, in the context of human histocompatibility leukocyte antigen A2 (HLA-A2), but it did not recognize other tumor cell types. The gene coding for the antigen recognized by this clone was identified by the screening of a melanoma complementary DNA expression library. This antigen is overexpressed in melanomas, compared with other cancer cell lines and healthy tissues, and was thus called melanoma-overexpressed antigen (meloe). Remarkably, the structure of meloe was unusual, with multiple short open reading frames (ORFs). The peptide recognized by the CTL clone was encoded by one of these ORFs, called MELOE-1. Using a specific HLA-A2/peptide tetramer, we showed a correlation between the infusion of TILs containing MELOE-1-specific T cells and relapse prevention in HLA-A2 patients. Indeed, 5 out of 9 patients who did not relapse were infused with TILs that contained MELOE-1-specific T cells, whereas 0 out of the 21 patients who relapsed was infused with such TIL-containing lymphocytes. Overall, our results suggest that this new antigen is involved in immunosurveillance and, thus, represents an attractive target for immunotherapy protocols of melanoma.
Published: 2008

39. Infusion of Melan-A/Mart-1 speciWc tumor-inWltrating lymphocytes enhanced relapse-free survival of melanoma patients

Author: Houssem Benlalam, Annabelle Bonnin, Francine Jotereau, Nathalie Labarrière, Brigitte Dréno, Yann Godet, Virginie Vignard, Amir Khammari, Marie-Christine Pandolfino, LABARRIERE, Nathalie, Recherches en cancérologie, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre hospitalier universitaire de Nantes (CHU Nantes)
Subjects: Oncology, Cancer Research, T-Lymphocytes, medicine.medical_treatment, Disease, Immunotherapy, Adoptive, 0302 clinical medicine, Chlorocebus aethiops, Immunology and Allergy, Melanoma, Lymph node, 0303 health sciences, hemic and immune systems, 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, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, chemical and pharmacologic phenomena, [SDV.CAN]Life Sciences [q-bio]/Cancer, Transplantation, Autologous, Relapse free survival, Disease-Free Survival, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, MART-1 Antigen, Antigen, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigens, Neoplasm, Internal medicine, HLA-A2 Antigen, medicine, Animals, Humans, 030304 developmental biology, Tumor-infiltrating lymphocytes, business.industry, Cancer, Immunotherapy, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, Survival Analysis, business, 030215 immunology
Abstract: International audience; Adoptive therapy of cancer has been mostly tested in advanced cancer patients using tumor-inWl-trating lymphocytes (TIL). Following discouraging results likely due to poor tumor-speciWcity of TIL and/ or high tumor burden, recent studies reiterate the enormous potential of this therapy, particularly in mel-anoma. We had performed a phase II/III randomised trial on 88 stage III melanoma patients, who received autologous TIL plus IL-2 or IL-2 alone, after complete tumour resection. We reported previously clinical and immunological results supporting the ability of tumor reactive TIL infusion to prevent further development of the melanoma disease and to increase overall survival of patients bearing only one tumor invaded lymph node. The absence of correlation between overall and disease-free survival and the amount of infused tumor-speciWc TIL suggested that therapeutic eYciency might depend on other parameters such as antigen speciWcity, function or persistence of TIL. Here we studied the recognition of a panel of 38 shared tumor-associated antigens (TAA) by TIL infused to the patients included in this assay, in order to determine if treatment outcome could correlate with particular antigen speciWcities of infused TIL. Results show that the infusion of Melan-A/MART-1 reactive TIL appears to be associated with a longer relapse-free survival for HLA-A2 patients. These results further support the relevance of Melan-A/MART-1 antigen as a prime target for immunotherapy protocols in melanoma.
Published: 2007

40. Immunologic and Clinical Effects of Injecting Mature Peptide- Loaded Dendritic Cells by Intralymphatic and Intranodal Routes in Metastatic Melanoma Patients

Author: Louis Toujas, Irène Philip, André Carsin, Mohamed Chokri, Thierry Lesimple, Virginie Vignard, Gilles Clapisson, Delphine Monnier, Véronique Quillien, Henri Adamski, Nathalie Labarrière, Claudia Lefeuvre, Brigitte Collet, Brigitte Birebent, Eve-Marie Neidhard, Centre Eugène Marquis (CRLCC), Centre Léon Bérard [Lyon], Recherches en cancérologie, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), CHU Pontchaillou [Rennes], Etablissement français du sang [Rennes] (EFS Bretagne), IDM (Immuno-Designed Molecules), IDM S.A., and LABARRIERE, Nathalie
Subjects: Male, Cancer Research, Pathology, Skin Neoplasms, medicine.medical_treatment, Immunotherapy, Adoptive, 0302 clinical medicine, Melanoma, Aged, 80 and over, 0303 health sciences, Immunity, Cellular, biology, Middle Aged, 3. Good health, Neoplasm Proteins, Lymphatic system, Treatment Outcome, Oncology, 030220 oncology & carcinogenesis, Lymphatic Metastasis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, Adult, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cancer Vaccines, Disease-Free Survival, 03 medical and health sciences, MART-1 Antigen, Antigen, [SDV.CAN] Life Sciences [q-bio]/Cancer, Immunity, Antigens, Neoplasm, medicine, Humans, 030304 developmental biology, Aged, business.industry, Injections, Intralymphatic, Immunotherapy, Dendritic cell, Dendritic Cells, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, Survival Analysis, Immunology, Antibody Formation, biology.protein, business, Peptides, CD8, Keyhole limpet hemocyanin
Abstract: Purpose: A phase I/II trial was conducted to evaluate clinical and immunologic responses after intralymphatic and intranodal injections of mature dendritic cells.Experimental Design: Fourteen patients with a metastatic melanoma received matured dendritic cells, loaded with Melan-A/MART-1 and/or NA17-A peptides and keyhole limpet hemocyanin. The cells were matured overnight with Ribomunyl, a toll-like receptor ligand, and IFN-γ, which ensured the production of high levels of interleukin-12p70. Dendritic cells were injected at monthly intervals, first into an afferent lymphatic and then twice intranodally. Immunologic responses were monitored by tetramer staining of circulating CD8+ lymphocytes and delayed-type hypersensitivity tests.Results: Dendritic cell vaccination induced delayed-type hypersensitivity reactivity toward NA17-A-pulsed, keyhole limpet hemocyanin–pulsed, and Melan-A-pulsed dendritic cells in 6 of 10, 4 of 11, and 3 of 9 patients, respectively. Four of the 12 patients analyzed by tetramer staining showed a significantly increased frequency of Melan-A-specific T cells, including one patient vaccinated only with NA17-A-pulsed dendritic cells. Furthermore, 2 of the 12 analyzed patients had a significant increase of NA17-A-specific T cells, including one immunized after an optional additional treatment course. No objective clinical response was observed. Two patients were stabilized at 4 and 10 months and three patients are still alive at 30, 39, and 48 months.Conclusions: Injections into the lymphatic system of mature peptide-loaded dendritic cells with potential TH1 polarization capacities did not result in marked clinical results, despite immunologic responses in some patients. This highlights the need to improve our understanding of dendritic cell physiology.
Published: 2006

41. Overexpression of Meloe Gene in Melanomas Is Controlled Both by Specific Transcription Factors and Hypomethylation

Author: Agnès Moreau-Aubry, Mathilde Bobinet, Nathalie Labarrière, François Lang, Laetitia Florenceau, 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), and LABARRIERE, Nathalie
Subjects: Chromatin Immunoprecipitation, [SDV.IMM] Life Sciences [q-bio]/Immunology, Blotting, Western, SOX10, lcsh:Medicine, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Polymerase Chain Reaction, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigens, Neoplasm, medicine, Transcriptional regulation, Humans, RNA, Messenger, lcsh:Science, Luciferases, Melanoma, Transcription factor, DNA Primers, 030304 developmental biology, Regulation of gene expression, 0303 health sciences, Multidisciplinary, biology, SOXE Transcription Factors, lcsh:R, SOX9 Transcription Factor, DNA Methylation, biology.organism_classification, medicine.disease, Molecular biology, Neoplasm Proteins, 3. Good health, Gene Expression Regulation, Neoplastic, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Meloe, Mutagenesis, 030220 oncology & carcinogenesis, DNA methylation, Cancer research, [SDV.IMM]Life Sciences [q-bio]/Immunology, lcsh:Q, Immunotherapy, Chromatin immunoprecipitation, Research Article
Abstract: International audience; The melanoma antigens MELOE-1 and MELOE-2 are encoded by a messenger, called meloe, overexpressed in melanomas compared with other tumour cell types and healthy tissues. They are both able to elicit melanoma-specific T cell responses in melanoma patients, and MELOE-1-specific CD8 T cells have been involved in melanoma immunosurveillance. With the aim to develop immunotherapies targeting this antigen, we investigated the transcriptional mechanisms leading to the preferential expression of meloe messenger in the melanocytic lineage. We defined the minimal promoter region of meloe gene and identified binding motifs for a set of transcription factors. Using mutagenesis, co-transfection experiments and chromatin immunoprecipitation, we showed that transcription factors involved in meloe promoter activity in melanomas were the melanocytic specific SOX9 and SOX10 proteins together with the activated P-CREB protein. Furthermore, we showed that meloe promoter was hypomethylated in melanomas and melanocytes, and hypermethylated in colon cancer cell lines and mesotheliomas, thus explaining the absence of P-CREB binding in these cell lines. This was a second key to explain the overerexpression of meloe messenger in the melanocytic lineage. To our knowledge, such a dual transcriptional control conferring tissue-specificity has never been described for the expression of tumour antigens.
Published: 2013

42. Bi-allelic loss-of-function variants in TMEM147 cause moderate to profound intellectual disability with facial dysmorphism and pseudo-Pelger-Huët anomaly

Author: Quentin Thomas, Marialetizia Motta, Thierry Gautier, Maha S. Zaki, Andrea Ciolfi, Julien Paccaud, François Girodon, Odile Boespflug-Tanguy, Thomas Besnard, Jennifer Kerkhof, Haley McConkey, Aymeric Masson, Anne-Sophie Denommé-Pichon, Benjamin Cogné, Eva Trochu, Virginie Vignard, Fatima El It, Lance H. Rodan, Mohammad Ayman Alkhateeb, Rami Abou Jamra, Laurence Duplomb, Emilie Tisserant, Yannis Duffourd, Ange-Line Bruel, Adam Jackson, Siddharth Banka, Meriel McEntagart, Anand Saggar, Joseph G. Gleeson, David Sievert, Hyunwoo Bae, Beom Hee Lee, Kisang Kwon, Go Hun Seo, Hane Lee, Anjum Saeed, Nadeem Anjum, Huma Cheema, Salem Alawbathani, Imran Khan, Jorge Pinto-Basto, Joyce Teoh, Jasmine Wong, Umar Bin Mohamad Sahari, Henry Houlden, Kristina Zhelcheska, Melanie Pannetier, Mona A. Awad, Marion Lesieur-Sebellin, Giulia Barcia, Jeanne Amiel, Julian Delanne, Christophe Philippe, Laurence Faivre, Sylvie Odent, Aida Bertoli-Avella, Christel Thauvin, Bekim Sadikovic, Bruno Reversade, Reza Maroofian, Jérôme Govin, Marco Tartaglia, Antonio Vitobello, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-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), CHU Pontchaillou [Rennes], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de référence Maladies Rares CLAD-Ouest [Rennes], FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), and This work was supported by grants from Dijon University Hospital, the ISITE-BFC (PIA ANR), and the European Union through the FEDER programs, EJP-RD (NSEuroNET), AIRC (IG21614), and Italian Ministry of Health (5x1000). Sequencing for individual 15 was funded by the Institute for Information and Communications Technology Promotion (IITP) grant from the Korean government (MSIT) (2018-0-00861, Intelligent SW Technology Development for Medical Data Analysis). This study makes use of DECIPHER (http://decipher.sanger.ac.uk), which is funded by the Wellcome (www.ddduk.org/access.html).55 This research was made possible through access to the data and findings generated by the 100KGP. The 100KGP is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100KGP is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK, and the Medical Research Council have also funded research infrastructure. The 100KGP uses data provided by individuals and collected by the National Health Service as part of their care and support. Several authors of this publication are members of the European Reference Network for Developmental Anomalies and Intellectual Disability (ERN-ITHACA). The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement no. 779257.
Subjects: Cell Nucleus, [SDV.GEN]Life Sciences [q-bio]/Genetics, DNA methylation, Loss of Heterozygosity, facial dysmorphism, neurodevelopmental disorder, Chromatin, Musculoskeletal Abnormalities, transcriptomics, translocon dysfunction, Pelger-Huët anomaly, intellectual disability, Genetics, LBR, Humans, TMEM147, nuclear envelope instability, Child, Pelger-Huet Anomaly, Genetics (clinical)
Abstract: International audience; The transmembrane protein TMEM147 has a dual function: first at the nuclear envelope, where it anchors lamin B receptor (LBR) to the inner membrane, and second at the endoplasmic reticulum (ER), where it facilitates the translation of nascent polypeptides within the ribosome-bound TMCO1 translocon complex. Through international data sharing, we identified 23 individuals from 15 unrelated families with bi-allelic TMEM147 loss-of-function variants, including splice-site, nonsense, frameshift, and missense variants. These affected children displayed congruent clinical features including coarse facies, developmental delay, intellectual disability, and behavioral problems. In silico structural analyses predicted disruptive consequences of the identified amino acid substitutions on translocon complex assembly and/or function, and in vitro analyses documented accelerated protein degradation via the autophagy-lysosomal-mediated pathway. Furthermore, TMEM147-deficient cells showed CKAP4 (CLIMP-63) and RTN4 (NOGO) upregulation with a concomitant reorientation of the ER, which was also witnessed in primary fibroblast cell culture. LBR mislocalization and nuclear segmentation was observed in primary fibroblast cells. Abnormal nuclear segmentation and chromatin compaction were also observed in approximately 20% of neutrophils, indicating the presence of a pseudo-Pelger-Huët anomaly. Finally, co-expression analysis revealed significant correlation with neurodevelopmental genes in the brain, further supporting a role of TMEM147 in neurodevelopment. Our findings provide clinical, genetic, and functional evidence that bi-allelic loss-of-function variants in TMEM147 cause syndromic intellectual disability due to ER-translocon and nuclear organization dysfunction.
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