Search

Your search keyword '"Dosset, Magalie"' showing total 148 results
Start Over Author "Dosset, Magalie"
148 results on '"Dosset, Magalie"'

1. Transcriptional analysis links B cells and TERT expression to favorable prognosis in head and neck cancer

Author

Xian, Su, Dosset, Magalie, Castro, Andrea, Carter, Hannah, and Zanetti, Maurizio

Subjects
Rare Diseases, Dental/Oral and Craniofacial Disease, Cancer, Genetics, B cells, head and neck cancer, telomerase, tertiary lymphoid structures, transcriptomics
Abstract

Telomerase reverse transcriptase (TERT) is a conserved self-tumor antigen overexpressed in ∼85% of tumor cells and is immunogenic in cancer patients. The effect of TERT expression on the regulation of intratumor adaptive immunity has not yet been investigated. We used RNA sequencing data from The Cancer Genome Atlas (TCGA) in 11 solid tumor types to investigate potential interactions between TERT expression, and B and T cell infiltrate in the tumor microenvironment. We found a positive correlation between TERT expression, B and T cells in four cancer types with the strongest association in head and neck squamous cell carcinoma (HSNCC). In HNSCC a Bhigh/TERThigh signature was associated with improved progression-free survival (PFS) (P = 0.0048). This effect was independent of HPV status and not shared in comparable analysis by other conserved tumor antigens (NYESO1, MUC1, MAGE, and CEA). Bhigh/TERThigh HNSCC tumors also harbored evidence of tertiary lymphoid structure (TLS) such as signatures for germinal center (GC) and switched memory B cells, central memory CD4 and effector memory CD8 T cells. Bhigh/TERThigh HNSCC tumors also showed an up-regulation of genes and pathways related to B and T cell activation, proliferation, migration, and cytotoxicity, while factors associated with immunosuppression and cancer cell invasiveness were down-regulated. In summary, our study uncovers a new association between high TERT expression and high B cell infiltrate in HNSCC, suggesting a potential benefit from therapeutic strategies that invigorate intratumor TERT-mediated T-B cooperation.

Published
2023

2. The Unfolded Protein Response at the Tumor-Immune Interface

Author

Zanetti, Maurizio, Xian, Su, Dosset, Magalie, and Carter, Hannah

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Immunization, Cancer, Genetics, Vaccine Related, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Aneuploidy, Humans, Myeloid Cells, Neoplasms, Tumor Microenvironment, Unfolded Protein Response, unfolded protein response, myeloid cells, T cells, aneuploidy, transcellular stress, Medical Microbiology, Biochemistry and cell biology
Abstract

The tumor-immune interface has surged to primary relevance in an effort to understand the hurdles facing immune surveillance and cancer immunotherapy. Reports over the past decades have indicated a role for the unfolded protein response (UPR) in modulating not only tumor cell fitness and drug resistance, but also local immunity, with emphasis on the phenotype and altered function of immune cells such as myeloid cells and T cells. Emerging evidence also suggests that aneuploidy correlates with local immune dysregulation. Recently, we reported that the UPR serves as a link between aneuploidy and immune cell dysregulation in a cell nonautonomous way. These new findings add considerable complexity to the organization of the tumor microenvironment (TME) and the origin of its altered function. In this review, we summarize these data and also discuss the role of aneuploidy as a negative regulator of local immunity.

Published
2022

3. The unfolded protein response links tumor aneuploidy to local immune dysregulation

Author

Xian, Su, Dosset, Magalie, Almanza, Gonzalo, Searles, Stephen, Sahani, Paras, Waller, T Cameron, Jepsen, Kristen, Carter, Hannah, and Zanetti, Maurizio

Subjects
Genetics, Human Genome, Cancer, Rare Diseases, 2.1 Biological and endogenous factors, Aetiology, Aneuploidy, Humans, Neoplasms, Tumor Microenvironment, Unfolded Protein Response, aneuploidy, macrophages, T cells, tumor immune microenvironment, unfolded protein response, Biochemistry and Cell Biology, Developmental Biology
Abstract

Aneuploidy is a chromosomal abnormality associated with poor prognosis in many cancer types. Here, we tested the hypothesis that the unfolded protein response (UPR) mechanistically links aneuploidy and local immune dysregulation. Using a single somatic copy number alteration (SCNA) score inclusive of whole-chromosome, chromosome arm, and focal alterations in a pan-cancer analysis of 9,375 samples in The Cancer Genome Atlas (TCGA) database, we found an inverse correlation with a cytotoxicity (CYT) score across disease stages. Co-expression patterns of UPR genes changed substantially between SCNAlow and SCNAhigh groups. Pathway activity scores showed increased activity of multiple branches of the UPR in response to aneuploidy. The PERK branch showed the strongest association with a reduced CYT score. The conditioned medium of aneuploid cells transmitted XBP1 splicing and caused IL-6 and arginase 1 transcription in receiver bone marrow-derived macrophages and markedly diminished the production of IFN-γ and granzyme B in activated human T cells. We propose the UPR as a mechanistic link between aneuploidy and immune dysregulation in the tumor microenvironment.

Published
2021

4. Telomerase Reverse Transcriptase in Humans: From Biology to Cancer Immunity

Author

Dosset, Magalie, Castro, Andrea, Xian, Su, Carter, Hannah, Zanetti, Maurizio, Rezaei, Nima, Series Editor, Ahmed, Atif A., Editorial Board Member, Aguiar, Rodrigo, Editorial Board Member, Ambrosio, Maria R., Editorial Board Member, Artac, Mehmet, Editorial Board Member, Augustine, Tanya N., Editorial Board Member, Bambauer, Rolf, Editorial Board Member, Bhat, Ajaz Ahmad, Editorial Board Member, Bertolaccini, Luca, Editorial Board Member, Bianchini, Chiara, Editorial Board Member, Cavic, Milena, Editorial Board Member, Chakrabarti, Sakti, Editorial Board Member, Cho, William C. S., Editorial Board Member, Czarnecka, Anna M., Editorial Board Member, Domingues, Cátia, Editorial Board Member, Eşkazan, A. Emre, Editorial Board Member, Fares, Jawad, Editorial Board Member, Fonseca Alves, Carlos E., Editorial Board Member, Fru, Pascaline, Editorial Board Member, Da Gama Duarte, Jessica, Editorial Board Member, García, Mónica C., Editorial Board Member, Gener, Melissa A.H., Editorial Board Member, Estrada Guadarrama, José Antonio, Editorial Board Member, Hargadon, Kristian M., Editorial Board Member, Holvoet, Paul, Editorial Board Member, Jurisic, Vladimir, Editorial Board Member, Kabir, Yearul, Editorial Board Member, Katsila, Theodora, Editorial Board Member, Kleeff, Jorg, Editorial Board Member, Liang, Chao, Editorial Board Member, Tan, Mei Lan, Editorial Board Member, Li, Weijie, Editorial Board Member, Prado López, Sonia, Editorial Board Member, Macha, Muzafar A., Editorial Board Member, Malara, Natalia, Editorial Board Member, Orhan, Adile, Editorial Board Member, Prado-Garcia, Heriberto, Editorial Board Member, Pérez-Velázquez, Judith, Editorial Board Member, Rashed, Wafaa M., Editorial Board Member, Sanguedolce, Francesca, Editorial Board Member, Sorrentino, Rosalinda, Editorial Board Member, Shubina, Irina Zh., Editorial Board Member, de Araujo, Heloisa Sobreiro Selistre, Editorial Board Member, Torres-Suárez, Ana Isabel, Editorial Board Member, Włodarczyk, Jakub, Editorial Board Member, Yeong, Joe Poh Sheng, Editorial Board Member, Toscano, Marta A., Editorial Board Member, Wong, Tak-Wah, Editorial Board Member, Yin, Jun, Editorial Board Member, and Yu, Bin, Editorial Board Member

Published
2023
Full Text
View/download PDF

5. Telomerase and CD4 T Cell Immunity in Cancer.

Author

Dosset, Magalie, Castro, Andrea, Carter, Hannah, and Zanetti, Maurizio

Subjects
CD4 T cells, MHC-II, TERT, cancer, immune checkpoint therapy, immune monitoring, immune surveillance, prognostic-predictive biomarker, telomerase, vaccine, Oncology and Carcinogenesis
Abstract

Telomerase reverse transcriptase (TERT) is a conserved self-tumor antigen which is overexpressed in most tumors and plays a critical role in tumor formation and progression. As such, TERT is an antigen of great relevance to develop widely applicable immunotherapies. CD4 T cells play a major role in the anti-cancer response alone or with other effector cells such as CD8 T cells and NK cells. To date, efforts have been made to identify TERT peptides capable of stimulating CD4 T cells that are also able to bind diverse MHC-II alleles to ease immune status monitoring and immunotherapies. Here, we review the current status of TERT biology, TERT/MHC-II immunobiology, and past and current vaccine clinical trials. We propose that monitoring CD4 T cell immunity against TERT is a simple and direct way to assess immune surveillance in cancer patients and a new way to predict the response to immune checkpoint inhibitors (ICPi). Finally, we present the initial results of a systematic discovery of TERT peptides able to bind the most common HLA Class II alleles worldwide and show that the repertoire of MHC-II TERT peptides is wider than currently appreciated.

Published
2020

8. Distinct prognostic value of circulating anti-telomerase CD4+ Th1 immunity and exhausted PD-1+/TIM-3+ T cells in lung cancer

Author

Laheurte, Caroline, Dosset, Magalie, Vernerey, Dewi, Boullerot, Laura, Gaugler, Béatrice, Gravelin, Eléonore, Kaulek, Vincent, Jacquin, Marion, Cuche, Laurie, Eberst, Guillaume, Jacoulet, Pascale, Fabre, Elizabeth, Le Pimpec-Barthes, Françoise, Tartour, Eric, De Carvalho Bittencourt, Marcelo, Westeel, Virginie, and Adotévi, Olivier

Published
2019
Full Text
View/download PDF

12. Supplementary Material and Methods from Immunoregulation and Clinical Implications of ANGPT2/TIE2+ M-MDSC Signature in Non–Small Cell Lung Cancer

Author

Lauret Marie Joseph, Elodie, primary, Laheurte, Caroline, primary, Jary, Marine, primary, Boullerot, Laura, primary, Asgarov, Kamal, primary, Gravelin, Eléonore, primary, Bouard, Adeline, primary, Rangan, Laurie, primary, Dosset, Magalie, primary, Borg, Christophe, primary, and Adotévi, Olivier, primary

Published
2023
Full Text
View/download PDF

13. Supplementary Figure 1 from Universal Cancer Peptide-Based Therapeutic Vaccine Breaks Tolerance against Telomerase and Eradicates Established Tumor

Author

Dosset, Magalie, primary, Godet, Yann, primary, Vauchy, Charline, primary, Beziaud, Laurent, primary, Lone, Yu Chun, primary, Sedlik, Christine, primary, Liard, Christelle, primary, Levionnois, Emeline, primary, Clerc, Bertrand, primary, Sandoval, Federico, primary, Daguindau, Etienne, primary, Wain-Hobson, Simon, primary, Tartour, Eric, primary, Langlade-Demoyen, Pierre, primary, Borg, Christophe, primary, and Adotévi, Olivier, primary

Published
2023
Full Text
View/download PDF

14. Supplementary Figure 4 from Universal Cancer Peptide-Based Therapeutic Vaccine Breaks Tolerance against Telomerase and Eradicates Established Tumor

Author

Dosset, Magalie, primary, Godet, Yann, primary, Vauchy, Charline, primary, Beziaud, Laurent, primary, Lone, Yu Chun, primary, Sedlik, Christine, primary, Liard, Christelle, primary, Levionnois, Emeline, primary, Clerc, Bertrand, primary, Sandoval, Federico, primary, Daguindau, Etienne, primary, Wain-Hobson, Simon, primary, Tartour, Eric, primary, Langlade-Demoyen, Pierre, primary, Borg, Christophe, primary, and Adotévi, Olivier, primary

Published
2023
Full Text
View/download PDF

15. Supplementary Data from Cleaved Caspase-3 Transcriptionally Regulates Angiogenesis-Promoting Chemotherapy Resistance

Author

Bernard, Antoine, primary, Chevrier, Sandy, primary, Beltjens, Françoise, primary, Dosset, Magalie, primary, Viltard, Etienne, primary, Lagrange, Anaïs, primary, Derangère, Valentin, primary, Oudot, Alexandra, primary, Ghiringhelli, François, primary, Collin, Bertrand, primary, Apetoh, Lionel, primary, Feron, Olivier, primary, Chen, Suzie, primary, Arnould, Laurent, primary, Végran, Frédérique, primary, and Boidot, Romain, primary

Published
2023
Full Text
View/download PDF

16. Supplementary Table Legend from Analysis of Spontaneous Tumor-Specific CD4 T-cell Immunity in Lung Cancer Using Promiscuous HLA-DR Telomerase-Derived Epitopes: Potential Synergistic Effect with Chemotherapy Response

Author

Godet, Yann, primary, Fabre, Elizabeth, primary, Dosset, Magalie, primary, Lamuraglia, Michele, primary, Levionnois, Emeline, primary, Ravel, Patrice, primary, Benhamouda, Nadine, primary, Cazes, Aurélie, primary, Le Pimpec-Barthes, Françoise, primary, Gaugler, Beatrice, primary, Langlade-Demoyen, Pierre, primary, Pivot, Xavier, primary, Saas, Philippe, primary, Maillère, Bernard, primary, Tartour, Eric, primary, Borg, Christophe, primary, and Adotévi, Olivier, primary

Published
2023
Full Text
View/download PDF

17. Supplementary Figure 3 from Universal Cancer Peptide-Based Therapeutic Vaccine Breaks Tolerance against Telomerase and Eradicates Established Tumor

Author

Dosset, Magalie, primary, Godet, Yann, primary, Vauchy, Charline, primary, Beziaud, Laurent, primary, Lone, Yu Chun, primary, Sedlik, Christine, primary, Liard, Christelle, primary, Levionnois, Emeline, primary, Clerc, Bertrand, primary, Sandoval, Federico, primary, Daguindau, Etienne, primary, Wain-Hobson, Simon, primary, Tartour, Eric, primary, Langlade-Demoyen, Pierre, primary, Borg, Christophe, primary, and Adotévi, Olivier, primary

Published
2023
Full Text
View/download PDF

18. Supplementary Figure 5 from Universal Cancer Peptide-Based Therapeutic Vaccine Breaks Tolerance against Telomerase and Eradicates Established Tumor

Author

Dosset, Magalie, primary, Godet, Yann, primary, Vauchy, Charline, primary, Beziaud, Laurent, primary, Lone, Yu Chun, primary, Sedlik, Christine, primary, Liard, Christelle, primary, Levionnois, Emeline, primary, Clerc, Bertrand, primary, Sandoval, Federico, primary, Daguindau, Etienne, primary, Wain-Hobson, Simon, primary, Tartour, Eric, primary, Langlade-Demoyen, Pierre, primary, Borg, Christophe, primary, and Adotévi, Olivier, primary

Published
2023
Full Text
View/download PDF

19. Supplementary Table 1 from Analysis of Spontaneous Tumor-Specific CD4 T-cell Immunity in Lung Cancer Using Promiscuous HLA-DR Telomerase-Derived Epitopes: Potential Synergistic Effect with Chemotherapy Response

Author

Godet, Yann, primary, Fabre, Elizabeth, primary, Dosset, Magalie, primary, Lamuraglia, Michele, primary, Levionnois, Emeline, primary, Ravel, Patrice, primary, Benhamouda, Nadine, primary, Cazes, Aurélie, primary, Le Pimpec-Barthes, Françoise, primary, Gaugler, Beatrice, primary, Langlade-Demoyen, Pierre, primary, Pivot, Xavier, primary, Saas, Philippe, primary, Maillère, Bernard, primary, Tartour, Eric, primary, Borg, Christophe, primary, and Adotévi, Olivier, primary

Published
2023
Full Text
View/download PDF

20. Supplementary Methods and Figure Legend from Universal Cancer Peptide-Based Therapeutic Vaccine Breaks Tolerance against Telomerase and Eradicates Established Tumor

Author

Dosset, Magalie, primary, Godet, Yann, primary, Vauchy, Charline, primary, Beziaud, Laurent, primary, Lone, Yu Chun, primary, Sedlik, Christine, primary, Liard, Christelle, primary, Levionnois, Emeline, primary, Clerc, Bertrand, primary, Sandoval, Federico, primary, Daguindau, Etienne, primary, Wain-Hobson, Simon, primary, Tartour, Eric, primary, Langlade-Demoyen, Pierre, primary, Borg, Christophe, primary, and Adotévi, Olivier, primary

Published
2023
Full Text
View/download PDF

21. Supplementary Figure 2 from Universal Cancer Peptide-Based Therapeutic Vaccine Breaks Tolerance against Telomerase and Eradicates Established Tumor

Author

Dosset, Magalie, primary, Godet, Yann, primary, Vauchy, Charline, primary, Beziaud, Laurent, primary, Lone, Yu Chun, primary, Sedlik, Christine, primary, Liard, Christelle, primary, Levionnois, Emeline, primary, Clerc, Bertrand, primary, Sandoval, Federico, primary, Daguindau, Etienne, primary, Wain-Hobson, Simon, primary, Tartour, Eric, primary, Langlade-Demoyen, Pierre, primary, Borg, Christophe, primary, and Adotévi, Olivier, primary

Published
2023
Full Text
View/download PDF

22. Landscape analysis of urothelial carcinoma (UC) by telomerase reverse transcriptase (TERT) alterations.

Author

Stewart, Tyler F., primary, Dosset, Magalie, additional, Brodskiy, Pavel, additional, Xiu, Joanne, additional, Rezazadeh, Arash, additional, Mar, Nataliya, additional, Darabi, Sourat, additional, Demeure, Michael J., additional, Barata, Pedro C., additional, Geynisman, Daniel M., additional, Ghatalia, Pooja, additional, Joshi, Monika, additional, Ramamurthy, Chethan, additional, Nabhan, Chadi, additional, Heath, Elisabeth I., additional, Carter, Hannah, additional, Zanetti, Maurizio, additional, and McKay, Rana R., additional

Published
2022
Full Text
View/download PDF

25. Chemoradiation triggers antitumor Th1 and tissue resident memory-polarized immune responses to improve immune checkpoint inhibitors therapy

Author

Lauret Marie Joseph, Elodie, Kirilovsky, Amos, Lecoester, Benoît, El Sissy, Carine, Boullerot, Laura, Rangan, Laurie, Marguier, Amélie, Tochet, Florent, Dosset, Magalie, Boustani, Jihane, Ravel, Patrice, Boidot, Romain, Spehner, Laurie, Haicheur-Adjouri, Nacilla, Marliot, Florence, Pallandre, Jean-René, Bonnefoy, Francis, Scripcariu, Viorel, Van den Eynde, Marc, Cornillot, Emmanuel, Mirjolet, Céline, Pages, Franck, Adotevi, Olivier, UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, UCL - (SLuc) Centre du cancer, UCL - (SLuc) Service de gastro-entérologie, and UCL - (SLuc) Unité d'oncologie médicale

Subjects
Cancer Research, Immunology, Mice, Tumor Microenvironment, Immunology and Allergy, Animals, Humans, Immune Checkpoint Inhibitors, radiotherapy, RC254-282, Pharmacology, combination, Immunity, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Basic Tumor Immunology, adaptive immunity, Chemoradiotherapy, Th1 Cells, drug therapy, Disease Models, Animal, Oncology, Molecular Medicine, Female, Immunotherapy
Abstract

BACKGROUND: Multiple synergistic combination approaches with cancer drugs are developed to overcome primary resistance to immunotherapy; however, the mechanistic rationale to combine chemoradiotherapy (CRT) with immune checkpoint inhibitors remains elusive. METHODS: This study described the immunological landscape of tumor microenvironment (TME) exposed to CRT. Tumor samples from patients with rectal cancer (n=43) treated with neoadjuvant CRT or radiotherapy were analyzed by nanostring and immunohistochemistry. Studies in mice were performed using three syngeneic tumors (TC1, CT26 and MC38). Tumor-bearing mice were treated either with platinum-based CRT, radiotherapy or chemotherapy. Anti-CTLA-4 and/or anti-Programmed Cell Death Receptor-1 (PD-1) therapy was used in combination with CRT. The therapy-exposed TME was screened by RNA sequencing and flow cytometry and tumor-infiltrating T lymphocyte functionality was evaluated by interferon (IFN)-γ ELIspot and intracellular cytokine staining. RESULTS: Front-to-front comparison analysis revealed the synergistic effect of CRT to establish a highly inflamed and Th1-polarized immune signature in the TME of patients and mice. In both settings, CRT-exposed TMEs were highly enriched in newly-infiltrated tumor-specific CD8+ T cells as well as tissue resident memory CD103+CD8+ T cells. In mice, CD8 T cells were involved in the antitumor response mediated by CRT and were primed by CRT-activated CD103+ dendritic cells. In the three tumor models, we showed that concurrent combination of CRT with a dual CTLA-4 and PD-1 blockade was required to achieve an optimal antitumor effect and to establish a broad and long-lasting protective antitumor T cell immunity. CONCLUSIONS: Our results highlight the ability of CRT to stimulate strong antitumor T-cell-mediated immunity and tissue resident memory T activation in TME, to foster immune checkpoint inhibitors action. These findings have implications in clinic for the design clinical trials combining chemoradiation with immunotherapy.

Published
2021

29. Cleaved Caspase-3 Transcriptionally Regulates Angiogenesis-Promoting Chemotherapy Resistance

Author

Bernard, Antoine, primary, Chevrier, Sandy, additional, Beltjens, Françoise, additional, Dosset, Magalie, additional, Viltard, Etienne, additional, Lagrange, Anaïs, additional, Derangère, Valentin, additional, Oudot, Alexandra, additional, Ghiringhelli, François, additional, Collin, Bertrand, additional, Apetoh, Lionel, additional, Feron, Olivier, additional, Chen, Suzie, additional, Arnould, Laurent, additional, Végran, Frédérique, additional, and Boidot, Romain, additional

Published
2019
Full Text
View/download PDF

30. PD-1/PD-L1 pathway: an adaptive immune resistance mechanism to immunogenic chemotherapy in colorectal cancer

Author

Dosset, Magalie, Vargas, Thaiz Rivera, Lagrange, Anaïs, Boidot, Romain, Végran, Frédérique, Roussey, Aurélie, Chalmin, Fanny, Dondaine, Lucile, Paul, Catherine, Marie-Joseph, Elodie Lauret, Martin, François, Ryffel, Bernhard, Borg, Christophe, Adotévi, Olivier, Ghiringhelli, François, Apetoh, Lionel, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (HOTE GREFFON), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Université de Franche-Comté (UFC), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer (LabEx LipSTIC), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC)-Université de Montpellier (UM), Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), University of Cape Town, Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Service d'Oncologie Médicale [CHRU Besançon], Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC), 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), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Montpellier (UM), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Plateforme de transfert en biologie cancérologique [Dijon], Centre d'épidémiologie des populations (CEP), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Equipe CADIR (LNC - U1231), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), ERT Géomatériaux, Géosciences Environnement Toulouse (GET), Centre National d'Études Spatiales [Toulouse] (CNES)-Observatoire Midi-Pyrénées (OMP), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Observatoire Midi-Pyrénées (OMP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS), Département d'oncologie médicale [Centre Georges-François Leclerc], Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), and UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC)

Subjects
lcsh:Immunologic diseases. Allergy, [SDV]Life Sciences [q-bio], CD8 T cells, colorectal cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, chemotherapy, lcsh:RC254-282, digestive system diseases, cd8 t cells, colorectal cancer, adaptive immune resistance, immunotherapy, PD-1/PD-L1 pathway, lcsh:RC581-607, adaptive immune resistance, ComputingMilieux_MISCELLANEOUS, Original Research
Abstract

IF 5.503 (2017); International audience; Background: Chemotherapy is currently evaluated in order to enhance the efficacy of immune checkpoint blockade (ICB) therapy in colorectal cancer. However, the mechanisms by which these drugs could synergize with ICB remains unclear. The impact of chemotherapy on the PD-1/PD-L1 pathway and the resulting anticancer immune responses was assessed in two mouse models of colorectal cancer and validated in tumor samples from metastatic colorectal cancer patients that received neoadjuvant treatment. We demonstrated that 5-Fluorouracil plus Oxaliplatin (Folfox) drove complete tumor cure in mice when combined to anti-PD-1 treatment, while each monotherapy failed. This synergistic effect relies on the ability of Folfox to induce tumor infiltration by activated PD-1+ CD8 T cells in a T-bet dependent manner. This effect was concomitantly associated to the expression of PD-L1 on tumor cells driven by IFN-γ secreted by PD-1+ CD8 T cells, indicating that Folfox triggers tumor adaptive immune resistance. Finally, we observed an induction of PD-L1 expression and high CD8 T cell infiltration in the tumor microenvironment of colorectal cancer patients treated by Folfox regimen. Our study delineates a molecular pathway involved in Folfox-induced adaptive immune resistance in colorectal cancer. The results strongly support the use of immune checkpoint blockade therapy in combination with chemotherapies like Folfox.

Published
2018

31. Abstract 575: Adaptive CD4 Th1 response against telomerase in blood counteracts T-cell exhaustion in non-small cell lung cancer

Author

Laheurte, Caroline, primary, Dosset, Magalie, additional, Vernerey, Dewi, additional, Joseph, Elodie Lauret Marie, additional, Boullerot, Laura, additional, Kaulec, Vincent, additional, Jacquin, Marion, additional, Cuche, Laurie, additional, Eberst, Guillaume, additional, Jacoulet, Pascale, additional, Westeel, Virginie, additional, and Adotevi, Olivier, additional

Published
2019
Full Text
View/download PDF

32. Personalized identification of tumor-associated immunogenic neoepitopes in hepatocellular carcinoma in complete remission after sorafenib treatment

Author

Vrecko, Sindy, primary, Guenat, David, additional, Mercier-Letondal, Patricia, additional, Faucheu, Hugues, additional, Dosset, Magalie, additional, Royer, Bernard, additional, Galaine, Jeanne, additional, Boidot, Romain, additional, Kim, Stefano, additional, Jary, Marine, additional, Adotévi, Olivier, additional, Borg, Christophe, additional, and Godet, Yann, additional

Published
2018
Full Text
View/download PDF

33. Circulating NKp46+Natural Killer cells have a potential regulatory property and predict distinct survival in Non-Small Cell Lung Cancer

Author

Picard, Emilie, primary, Godet, Yann, additional, Laheurte, Caroline, additional, Dosset, Magalie, additional, Galaine, Jeanne, additional, Beziaud, Laurent, additional, Loyon, Romain, additional, Boullerot, Laura, additional, Lauret Marie Joseph, Elodie, additional, Spehner, Laurie, additional, Jacquin, Marion, additional, Eberst, Guillaume, additional, Gaugler, Béatrice, additional, Le pimpec-Barthes, Françoise, additional, Fabre, Elizabeth, additional, Westeel, Virginie, additional, Caignard, Anne, additional, Borg, Christophe, additional, and Adotévi, Olivier, additional

Published
2018
Full Text
View/download PDF

35. Identification of a novel PD-L1 positive solid tumor transplantable in HLA-A*0201/DRB1*0101 transgenic mice

Author

Rangan, Laurie, primary, Galaine, Jeanne, additional, Boidot, Romain, additional, Hamieh, Mohamad, additional, Dosset, Magalie, additional, Francoual, Julie, additional, Beziaud, Laurent, additional, Pallandre, Jean-René, additional, Joseph, Elodie Lauret Marie, additional, Asgarova, Afag, additional, Borg, Christophe, additional, Al Saati, Talal, additional, Godet, Yann, additional, Latouche, Jean Baptiste, additional, Valmary-Degano, Séverine, additional, and Adotévi, Olivier, additional

Published
2017
Full Text
View/download PDF

36. Distinct prognostic value of circulating anti-telomerase CD4+ Th1 immunity and exhausted PD-1+/TIM-3+ T cells in lung cancer.

Author

Laheurte, Caroline, Dosset, Magalie, Vernerey, Dewi, Boullerot, Laura, Gaugler, Béatrice, Gravelin, Eléonore, Kaulek, Vincent, Jacquin, Marion, Cuche, Laurie, Eberst, Guillaume, Jacoulet, Pascale, Fabre, Elizabeth, Le Pimpec-Barthes, Françoise, Tartour, Eric, De Carvalho Bittencourt, Marcelo, Westeel, Virginie, and Adotévi, Olivier

Abstract

Background: Despite the critical roles of Th1-polarised CD4+ T cells in cancer immunosurveillance, the translation of their potential to clinical use remains challenging. Here, we investigate the clinical relevance of circulating antitumor Th1 immunity in non-small cell lung cancer (NSCLC).Methods: The circulating antitumor Th1 response was assessed by the ELISpot assay in 170 NSCLC patients using a mixture of HLA class II-restricted peptides from telomerase (TERT). Phenotyping of blood immune cells was performed by flow cytometry.Results: TERT-reactive CD4 T-cell response was detected in 35% of NSCLC patients before any treatment. Functional analysis showed that these cells were effector memory and Th1 polarised capable to produce effector cytokines, such as IFN-γ, TNF-α and IL-2. The presence of anti-TERT Th1 response was inversely correlated with the level of exhausted PD-1+/TIM-3+CD4 T cells. The level of these two immune parameters differentially affected the survival, so that increased level of anti-TERT Th1 response and low rate of exhausted PD-1+TIM-3+CD4+ T cells were associated with a better prognosis.Conclusions: Systemic anti-TERT Th1 response plays a strong antitumor protective role in NSCLC. This study underlines the potential interest of monitoring circulating antitumor Th1 response for patients' stratification and therapy decision. [ABSTRACT FROM AUTHOR]

Published
2019
Full Text
View/download PDF

37. Immunoprevalence and magnitude of HLA-DP4 versus HLA-DR-restricted spontaneous CD4+Th1 responses against telomerase in cancer patients

Author

Laheurte, Caroline, primary, Galaine, Jeanne, additional, Beziaud, Laurent, additional, Dosset, Magalie, additional, Kerzerho, Jerome, additional, Jacquemard, Claire, additional, Gaugler, Béatrice, additional, Ferrand, Christophe, additional, Dormoy, Anne, additional, Aubin, François, additional, Jacoulet, Pascale, additional, Westeel, Virginie, additional, Borg, Christophe, additional, Tartour, Eric, additional, Godet, Yann, additional, Maillère, Bernard, additional, and Adotévi, Olivier, additional

Published
2016
Full Text
View/download PDF

38. Caractérisation et influence des lymphocytes T CD4 anti-télomérase dans les cancers

Author

Dosset, Magalie, 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), Université de Franche-Comté, Olivier Adotevi, and STAR, ABES

Subjects
[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, [SDV.IMM] Life Sciences [q-bio]/Immunology, Peptide helper restreint HLA-DR, CTL, [SDV.IMM]Life Sciences [q-bio]/Immunology, CD4 helper T cells, HLA-DR restricted peptide, Tumeur, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Cancer, Lymphocytes T CD4, Télomerase
Abstract

Recent advances in immunology have now validated the concept of cancer immunosurveillance and the leading role of adaptative T cell immunity. Until a few years ago, antitumor CD8 T cell responses have been the most studied due to their direct cytotoxic activity on tumor cells. On the other hand, study of antitumor CD4 T cell responses are even more challenging because of the heterogeneity and plasticity of the various CD4 T cells subpopulations described. Among them, CD4 T helper type-1 cells (Th1), mainly characterized by the production of IFN, control the activation of antitumor cellular immunity. Thus, stimulation of specific CD4 Th1 cells may have a major interest for the development of anticancer immunotherapies. During this research thesis, we characterized novel HLA class II epitopes derived from a relevant tumor antigen, telomerase (TERT), and studied their capacities to stimulate specific CD4 Th1 cell responses. Using a method based on predictive immunology, we identified 4 peptides derived from TERT, referred as « Universal Cancer Peptides » (UCPs), enable to bind the most commonly found HLA-DR alleles in human. Using HLA-A2/HLA-DR1 transgenic mouse model, we first evaluated the in vivo immunogenicity of these peptides. Immunization of mice with UCPs induces high avidity specific CD4 T cells. The study of their polarization showed that UCP-specific CD4 T cells do not produce IL-4, -5, -10 or -17 cytokines, excluding a Th1, Treg or Th17 differentiation. In contrast, we measured high amount of IFN and IL-2 which characterize a Th1 pattern. The study of helper role allow us to demonstrate that CD8 peptide-based vaccinations in presence of UCPs enhance the efficacy of tumor specific CTL responses. Indeed, the intensity of these responses is strongly correlated with that of UCP-specific CD4 T cells induced in vivo. Furthermore, the stimulation of UCP-specific CD4 T cells promotes activation and IL-12 release by dendritic cells through a mechanism that involves IFN, GM-CSF and CD40L. We also demonstrated the antitumor efficacy of UCPs during a therapeutic vaccination in mice, as well as their capacity to foster the recruitment of specific CD8 T cells at the tumor site. In addition, the presence of naturally occurring UCP-specific CD4 T cell responses was found in different types of cancers such as leukemia, lung, colorectal or renal cancers. A study conducted in a cohort of 84 metastatic lung cancer patients revealed a synergistic effect of spontaneous UCP-specific CD4 Th1 and chemotherapy-treatment. Altogether, this study provides further evidences that stimulation of antitumor CD4 Th1 cells is a powerful method to improve cancer vaccines and also highlights the interest of TERT-derived UCPs for the innovative monitoring of antitumor CD4 T cell responses, L’histoire naturelle du cancer implique des interactions entre la tumeur et les mécanismes de défense de l’hôte, tout particulièrement avec le système immunitaire adaptatif. Ainsi la transformation de cellules normales en cellules malignes peut engendrer l’expression d’antigènes tumoraux reconnus par les lymphocytes T. Plusieurs sous-populations de lymphocytes T (LT) CD4 contrôlent les réponses antitumorales, parmi elles, les LT CD4 helper de type-1 (Th1) jouent un rôle activateur majeur de l’immunité à médiation cellulaire antitumorale. Ils deviennent actifs grâce à la reconnaissance des peptides de 15 à 20 acides aminés dérivés d’antigènes tumoraux et présentés par les molécules HLA de classe II. Ils sont nécessaires à l’induction et la fonction des cellules effectrices dirigées contre les tumeurs notamment les lymphocytes T CD8 cytotoxiques (CTL). De plus la présence de lymphocytes CD4 Th1 infiltrant les tumeurs est souvent associée à un bon pronostic chez les patients. A l’aide d’un modèle in vitro chez l’homme et in vivo chez des souris transgéniques HLA, nous avons identifié quatre nouveaux peptides CD4 dérivés de la télomérase (TERT) un antigène de tumeur exprimé dans la majorité des cancers humains. Ces peptides appelés «Universal Cancer Peptide, UCP» se lient à la majorité des allèles HLA-DR et sont capables d’activer spécifiquement les LT CD4 de type-1. Des LT CD4 circulants spécifiques des UCP sont naturellement détectables dans plusieurs cancers humains mais absents chez des individus sains. Des clones T CD4 spécifiques des UCP générés à partir des lymphocytes de patients, produisent de forts taux d’IFN, TNF, et d’IL-2, cytokines associées à la polarisation Th1. L’analyse par ELISPOT IFN, de LT CD4 anti-UCP circulants au sein d’une cohorte de 84 patients atteints de cancers bronchiques métastatiques a montré la présence naturelle de ces lymphocytes chez 38 % des patients. De plus un effet bénéfique de la présence de cette réponse sur la survie globale a été observé chez les patients ayant une réponse clinique objective après chimiothérapie (13 vs 10 mois, P< 003). In vivo, l’immunisation de souris transgéniques HLA-A2/HLA-DR1 (Tg A2/DR1) avec les peptides UCP stimule des réponses T CD4 spécifiques caractérisées par une polarisation Th1. Nous avons montré que la présence in vivo de LT CD4 anti-UCP est nécessaire pour l’induction de réponses CTL antitumorales efficaces. Ainsi chez des souris co-immunisées en présence d’un peptide UCP, on observe un accroissement en nombre et de la qualité des réponses CTL proportionnellement à l’aide délivrée par les LT CD4 anti-UCP. L’induction de LT CD4 anti-UCP s’accompagne également d’une activation des cellules dendritiques in vivo via un mécanisme impliquant CD40L, IFN et GM-CSF. Dans un modèle de mélanome transplantable chez les souris Tg A2/DR1 nos résultats ont montré qu’une vaccination thérapeutique comportant un peptide UCP favorise un meilleur recrutement de CTL fonctionnels dans les tumeurs et améliore ainsi l’efficacité antitumorale du vaccin. Ces résultats confirment le rôle antitumoral majeur des lymphocytes CD4 Th1 et soulignent l’intérêt clinique de stimuler des réponses T CD4 spécifiques d’antigènes tumoraux de relevance clinique comme TERT.

Published
2012

39. Characterization and influence of CD4 T lymphocites specific of telomerase in cancers

Author

Dosset, Magalie, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Université de Franche-Comté, and Olivier Adotevi

Subjects
Peptide helper restreint HLA-DR, CTL, [SDV.IMM]Life Sciences [q-bio]/Immunology, CD4 helper T cells, HLA-DR restricted peptide, Tumeur, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Cancer, Lymphocytes T CD4, Télomerase
Abstract

Recent advances in immunology have now validated the concept of cancer immunosurveillance and the leading role of adaptative T cell immunity. Until a few years ago, antitumor CD8 T cell responses have been the most studied due to their direct cytotoxic activity on tumor cells. On the other hand, study of antitumor CD4 T cell responses are even more challenging because of the heterogeneity and plasticity of the various CD4 T cells subpopulations described. Among them, CD4 T helper type-1 cells (Th1), mainly characterized by the production of IFN, control the activation of antitumor cellular immunity. Thus, stimulation of specific CD4 Th1 cells may have a major interest for the development of anticancer immunotherapies. During this research thesis, we characterized novel HLA class II epitopes derived from a relevant tumor antigen, telomerase (TERT), and studied their capacities to stimulate specific CD4 Th1 cell responses. Using a method based on predictive immunology, we identified 4 peptides derived from TERT, referred as « Universal Cancer Peptides » (UCPs), enable to bind the most commonly found HLA-DR alleles in human. Using HLA-A2/HLA-DR1 transgenic mouse model, we first evaluated the in vivo immunogenicity of these peptides. Immunization of mice with UCPs induces high avidity specific CD4 T cells. The study of their polarization showed that UCP-specific CD4 T cells do not produce IL-4, -5, -10 or -17 cytokines, excluding a Th1, Treg or Th17 differentiation. In contrast, we measured high amount of IFN and IL-2 which characterize a Th1 pattern. The study of helper role allow us to demonstrate that CD8 peptide-based vaccinations in presence of UCPs enhance the efficacy of tumor specific CTL responses. Indeed, the intensity of these responses is strongly correlated with that of UCP-specific CD4 T cells induced in vivo. Furthermore, the stimulation of UCP-specific CD4 T cells promotes activation and IL-12 release by dendritic cells through a mechanism that involves IFN, GM-CSF and CD40L. We also demonstrated the antitumor efficacy of UCPs during a therapeutic vaccination in mice, as well as their capacity to foster the recruitment of specific CD8 T cells at the tumor site. In addition, the presence of naturally occurring UCP-specific CD4 T cell responses was found in different types of cancers such as leukemia, lung, colorectal or renal cancers. A study conducted in a cohort of 84 metastatic lung cancer patients revealed a synergistic effect of spontaneous UCP-specific CD4 Th1 and chemotherapy-treatment. Altogether, this study provides further evidences that stimulation of antitumor CD4 Th1 cells is a powerful method to improve cancer vaccines and also highlights the interest of TERT-derived UCPs for the innovative monitoring of antitumor CD4 T cell responses; L’histoire naturelle du cancer implique des interactions entre la tumeur et les mécanismes de défense de l’hôte, tout particulièrement avec le système immunitaire adaptatif. Ainsi la transformation de cellules normales en cellules malignes peut engendrer l’expression d’antigènes tumoraux reconnus par les lymphocytes T. Plusieurs sous-populations de lymphocytes T (LT) CD4 contrôlent les réponses antitumorales, parmi elles, les LT CD4 helper de type-1 (Th1) jouent un rôle activateur majeur de l’immunité à médiation cellulaire antitumorale. Ils deviennent actifs grâce à la reconnaissance des peptides de 15 à 20 acides aminés dérivés d’antigènes tumoraux et présentés par les molécules HLA de classe II. Ils sont nécessaires à l’induction et la fonction des cellules effectrices dirigées contre les tumeurs notamment les lymphocytes T CD8 cytotoxiques (CTL). De plus la présence de lymphocytes CD4 Th1 infiltrant les tumeurs est souvent associée à un bon pronostic chez les patients. A l’aide d’un modèle in vitro chez l’homme et in vivo chez des souris transgéniques HLA, nous avons identifié quatre nouveaux peptides CD4 dérivés de la télomérase (TERT) un antigène de tumeur exprimé dans la majorité des cancers humains. Ces peptides appelés «Universal Cancer Peptide, UCP» se lient à la majorité des allèles HLA-DR et sont capables d’activer spécifiquement les LT CD4 de type-1. Des LT CD4 circulants spécifiques des UCP sont naturellement détectables dans plusieurs cancers humains mais absents chez des individus sains. Des clones T CD4 spécifiques des UCP générés à partir des lymphocytes de patients, produisent de forts taux d’IFN, TNF, et d’IL-2, cytokines associées à la polarisation Th1. L’analyse par ELISPOT IFN, de LT CD4 anti-UCP circulants au sein d’une cohorte de 84 patients atteints de cancers bronchiques métastatiques a montré la présence naturelle de ces lymphocytes chez 38 % des patients. De plus un effet bénéfique de la présence de cette réponse sur la survie globale a été observé chez les patients ayant une réponse clinique objective après chimiothérapie (13 vs 10 mois, P< 003). In vivo, l’immunisation de souris transgéniques HLA-A2/HLA-DR1 (Tg A2/DR1) avec les peptides UCP stimule des réponses T CD4 spécifiques caractérisées par une polarisation Th1. Nous avons montré que la présence in vivo de LT CD4 anti-UCP est nécessaire pour l’induction de réponses CTL antitumorales efficaces. Ainsi chez des souris co-immunisées en présence d’un peptide UCP, on observe un accroissement en nombre et de la qualité des réponses CTL proportionnellement à l’aide délivrée par les LT CD4 anti-UCP. L’induction de LT CD4 anti-UCP s’accompagne également d’une activation des cellules dendritiques in vivo via un mécanisme impliquant CD40L, IFN et GM-CSF. Dans un modèle de mélanome transplantable chez les souris Tg A2/DR1 nos résultats ont montré qu’une vaccination thérapeutique comportant un peptide UCP favorise un meilleur recrutement de CTL fonctionnels dans les tumeurs et améliore ainsi l’efficacité antitumorale du vaccin. Ces résultats confirment le rôle antitumoral majeur des lymphocytes CD4 Th1 et soulignent l’intérêt clinique de stimuler des réponses T CD4 spécifiques d’antigènes tumoraux de relevance clinique comme TERT.

Published
2012

40. Selective degradation of PU.1 during autophagy represses the differentiation and antitumour activity of TH9 cells.

Author

Thaiz Rivera Vargas, Thaiz Rivera, Zhijian Cai, Yingying Shen, Dosset, Magalie, Benoit-Lizon, Isis, Martin, Tiffany, Roussey, Aurélie, Flavell, Richard A., Ghiringhelli, François, and Apetoh, Lionel

Abstract

Autophagy, a catabolic mechanism that involves degradation of cellular components, is essential for cell homeostasis. Although autophagy favours the lineage stability of regulatory T cells, the contribution of autophagy to the differentiation of effector CD4 T cells remains unclear. Here we show that autophagy selectively represses T helper 9 (TH9) cell differentiation. CD4 T cells lacking Atg3 or Atg5 have increased interleukin-9 (IL-9) expression upon differentiation into TH9 cells relative to Atg3- or Atg5-expressing control cells. In addition, the TH9 cell transcription factor, PU.1, undergoes K63 ubiquitination and degradation through p62-dependent selective autophagy. Finally, the blockade of autophagy enhances TH9 cell anticancer functions in vivo, and mice with T cell-specific deletion of Atg5 have reduced tumour outgrowth in an IL-9-dependent manner. Overall, our findings reveal an unexpected function of autophagy in the modulation of TH9 cell differentiation and antitumour activity, and prompt potential autophagy-dependent modulations of TH9 activity for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Published
2017
Full Text
View/download PDF

41. Immunogenicity Evaluation of a Rationally Designed Polytope Construct Encoding HLA-A*0201 Restricted Epitopes Derived from Leishmania major Related Proteins in HLA-A2/DR1 Transgenic Mice: Steps toward Polytope Vaccine

Author

Seyed, Negar, primary, Taheri, Tahereh, additional, Vauchy, Charline, additional, Dosset, Magalie, additional, Godet, Yann, additional, Eslamifar, Ali, additional, Sharifi, Iraj, additional, Adotevi, Olivier, additional, Borg, Christophe, additional, Rohrlich, Pierre Simon, additional, and Rafati, Sima, additional

Published
2014
Full Text
View/download PDF

42. The transcription factor IRF1 dictates the IL-21-dependent anticancer functions of TH9 cells

Author

Végran, Frédérique, primary, Berger, Hélène, additional, Boidot, Romain, additional, Mignot, Grégoire, additional, Bruchard, Mélanie, additional, Dosset, Magalie, additional, Chalmin, Fanny, additional, Rébé, Cédric, additional, Dérangère, Valentin, additional, Ryffel, Bernhard, additional, Kato, Masashi, additional, Prévost-Blondel, Armelle, additional, Ghiringhelli, François, additional, and Apetoh, Lionel, additional

Published
2014
Full Text
View/download PDF

45. Universal Cancer Peptide-Based Therapeutic Vaccine Breaks Tolerance against Telomerase and Eradicates Established Tumor

Author

Dosset, Magalie, primary, Godet, Yann, additional, Vauchy, Charline, additional, Beziaud, Laurent, additional, Lone, Yu Chun, additional, Sedlik, Christine, additional, Liard, Christelle, additional, Levionnois, Emeline, additional, Clerc, Bertrand, additional, Sandoval, Federico, additional, Daguindau, Etienne, additional, Wain-Hobson, Simon, additional, Tartour, Eric, additional, Langlade-Demoyen, Pierre, additional, Borg, Christophe, additional, and Adotévi, Olivier, additional

Published
2012
Full Text
View/download PDF

46. Analysis of Spontaneous Tumor-Specific CD4 T-cell Immunity in Lung Cancer Using Promiscuous HLA-DR Telomerase-Derived Epitopes: Potential Synergistic Effect with Chemotherapy Response

Author

Godet, Yann, primary, Fabre, Elizabeth, additional, Dosset, Magalie, additional, Lamuraglia, Michele, additional, Levionnois, Emeline, additional, Ravel, Patrice, additional, Benhamouda, Nadine, additional, Cazes, Aurélie, additional, Le Pimpec-Barthes, Françoise, additional, Gaugler, Beatrice, additional, Langlade-Demoyen, Pierre, additional, Pivot, Xavier, additional, Saas, Philippe, additional, Maillère, Bernard, additional, Tartour, Eric, additional, Borg, Christophe, additional, and Adotévi, Olivier, additional

Published
2012
Full Text
View/download PDF

49. The transcription factor IRF1 dictates the IL-21-dependent anticancer functions of TH9 cells.

Author

Végran, Frédérique, Berger, Hélène, Boidot, Romain, Mignot, Grégoire, Bruchard, Mélanie, Dosset, Magalie, Chalmin, Fanny, Rébé, Cédric, Dérangère, Valentin, Ryffel, Bernhard, Kato, Masashi, Prévost-Blondel, Armelle, Ghiringhelli, François, and Apetoh, Lionel

Subjects
TRANSCRIPTION factors, INTERFERON regulatory factors, INTERLEUKIN-21, ANTINEOPLASTIC agents, T helper cells, ALLERGY prevention
Abstract

The TH9 subset of helper T cells was initially shown to contribute to the induction of autoimmune and allergic diseases, but subsequent evidence has suggested that these cells also exert antitumor activities. However, the molecular events that account for their effector properties are elusive. Here we found that the transcription factor IRF1 enhanced the effector function of TH9 cells and dictated their anticancer properties. Under TH9-skewing conditions, interleukin 1β (IL-1β) induced phosphorylation of the transcription factor STAT1 and subsequent expression of IRF1, which bound to the promoters of Il9 and Il21 and enhanced secretion of the cytokines IL-9 and IL-21 from TH9 cells. Furthermore, IL-1β-induced TH9 cells exerted potent anticancer functions in an IRF1- and IL-21-dependent manner. Our findings thus identify IRF1 as a target for controlling the function of TH9 cells. [ABSTRACT FROM AUTHOR]

Published
2014
Full Text
View/download PDF

50. Circulating NKp46+ Natural Killer cells have a potential regulatory property and predict distinct survival in Non-Small Cell Lung Cancer.

Author

Picard, Emilie, Godet, Yann, Laheurte, Caroline, Dosset, Magalie, Galaine, Jeanne, Beziaud, Laurent, Loyon, Romain, Boullerot, Laura, Lauret Marie Joseph, Elodie, Spehner, Laurie, Jacquin, Marion, Eberst, Guillaume, Gaugler, Béatrice, Le pimpec-Barthes, Françoise, Fabre, Elizabeth, Westeel, Virginie, Caignard, Anne, Borg, Christophe, and Adotévi, Olivier

Subjects
KILLER cells, NON-small-cell lung carcinoma
Abstract

Natural killer (NK) cells are innate effector lymphocytes widely involved in cancer immunosurveillance. In this study, we described three circulating NK cell subsets in patients with non-small cell lung cancer (NSCLC). Compared to healthy donors (HD), lower rate of the cytotoxic CD56dim CD16+ NK cells was found in NSCLC patients (76.1% vs 82.4%, P = 0.0041). In contrast, the rate of CD56bright NK cells was similar between patients and HD. We showed in NSCLC patients a higher rate of a NK cell subset with CD56dim CD16− phenotype (16.7% vs 9.9% P = 0.0001). The degranulation property and cytokines production were mainly drive by CD56dim CD16− NK cell subset in patients. Analysis of natural cytotoxicity receptors (NCRs) expression identified four distinct clusters of patients with distinct NK cell subset profiles as compared to one major cluster in HD. Notably the cluster characterized by a low circulating level of NKp46+ NK cell subsets was absent in HD. We showed that the rate of circulating NKp46+ CD56dim CD16+ NK cells influenced the patients' survival. Indeed, the median overall survival in patients exhibiting high versus low level of this NK cell subset was 16 and 27 months respectively (P = 0.02). Finally, we demonstrated that blocking NKp46 receptor in vitro was able to restore spontaneous tumor specific T cell responses in NSCLC patients. In conclusion, this study showed a distinct distribution and phenotype of circulating NK cell subsets in NSCLC. It also supports the regulatory role of NKp46+ NK cell subset in NSCLC patients. [ABSTRACT FROM AUTHOR]

Published
2019
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results