Engineered CD4 TCR T cells with conserved high-affinity TCRs targeting NY-ESO-1 for advanced cellular therapies in cancer

Article Article scientifique Article Engineered CD4 TCR T cells with conserved high-affinity TCRs targeting NY-ESO-1 for advanced cellular therapies in cancer eng 2025-06-27 2025-06-27 author Saillard Margaux 0000-0001-9467-1830 Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research, Lausanne, Switzerland.,Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.,Translational Research Centre in Onco-Hematology (CRTOH), University of Geneva, Geneva, Switzerland.,Geneva Centre for Inflammation Research (GCIR), University of Geneva, Geneva, Switzerland. 936887 author Cenerenti Mara 0000-0001-6630-0557 Ludwig Institute for Cancer Research, Lausanne, Switzerland.,Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.,Translational Research Centre in Onco-Hematology (CRTOH), University of Geneva, Geneva, Switzerland.,Geneva Centre for Inflammation Research (GCIR), University of Geneva, Geneva, Switzerland. 943132 author Reichenbach Patrick 0009-0000-8673-1936 Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research, Lausanne, Switzerland. author Guillaume Philippe Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research, Lausanne, Switzerland. author Su Ziyang Ludwig Institute for Cancer Research, Lausanne, Switzerland.,Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.,Translational Research Centre in Onco-Hematology (CRTOH), University of Geneva, Geneva, Switzerland.,Geneva Centre for Inflammation Research (GCIR), University of Geneva, Geneva, Switzerland. 402588 Département de pathologie et immunologie (PATIM) author Hafezi Morteza 0009-0005-2494-449X Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research, Lausanne, Switzerland. author Schmidt Julien Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research, Lausanne, Switzerland. author Cesbron Julien 0009-0004-3930-2273 Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research, Lausanne, Switzerland. author Genolet Raphaël 0000-0001-9335-3945 Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research, Lausanne, Switzerland. 631340 author Queiroz Lise Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research, Lausanne, Switzerland. author Racle Julien 0000-0002-0100-0323 Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research, Lausanne, Switzerland.,SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland. author Villard Jean 0000-0003-2667-7506 Division of Nephrology, Geneva University Hospitals, Geneva, Switzerland.,Division of Transplantation Immunology, Geneva University Hospitals, Geneva, Switzerland. 29595 Département de médecine (DEMED) author Renella Raffaele 0000-0002-5041-2308 Pediatric Hematology-Oncology Unit, Division of Pediatrics, Department "Woman-Mother-Child," University Hospital and Lausanne University, Lausanne, Switzerland. author Michielin Olivier 0000-0003-4926-6355 Molecular Modeling Group, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.,Department of Oncology, Geneva University Hospitals, Geneva, Switzerland. 903944 Département de médecine (DEMED) author Zoete Vincent 0000-0002-2336-6537 Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research, Lausanne, Switzerland.,Molecular Modeling Group, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland. author Rivals Jean-Paul 0000-0002-5525-1435 Plateforme clinique et translationnelle, Centre des thérapies expérimentales, University Hospital and Lausanne University, Lausanne, Switzerland. author Irving Melita 0000-0002-6849-7194 Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research, Lausanne, Switzerland. author Speiser Daniel E 0000-0003-2031-3250 Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland. author Harari Alexandre Max-Albert 0000-0002-1055-2090 Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research, Lausanne, Switzerland. 87597 author Gfeller Christian David 0000-0002-3952-0930 Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research, Lausanne, Switzerland.,SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland. 92696 author Adotevi Olivier Université Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France. author Ceppi Francesco 0000-0002-9665-3190 Pediatric Hematology-Oncology Unit, Division of Pediatrics, Department "Woman-Mother-Child," University Hospital and Lausanne University, Lausanne, Switzerland. author Coukos George 0000-0001-8813-7367 Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research, Lausanne, Switzerland. author Romero Pedro 0000-0002-9688-2882 Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research, Lausanne, Switzerland. author Jandus Camilla 0000-0002-7405-5747 Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research, Lausanne, Switzerland.,Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.,Translational Research Centre in Onco-Hematology (CRTOH), University of Geneva, Geneva, Switzerland.,Geneva Centre for Inflammation Research (GCIR), University of Geneva, Geneva, Switzerland. 932821 Département de pathologie et immunologie (PATIM) eadu5754 10.1126/sciadv.adu5754 40577481 2375-2548 PMC12204177 https://www.science.org/doi/10.1126/sciadv.adu5754 While cancer immunotherapy has primarily focused on CD8 T cells, CD4 T cells are increasingly recognized for their role in antitumor immunity. The HLA-DRB3*02:02 allele is found in 50% of Caucasians. In this study, we screened HLA-DRB3*02:02 patients with melanoma for tumor-specific CD4 T cells and identified robust New York esophageal squamous cell carcinoma 1 (NY-ESO-1)123-137 /HLA-DRB3*02:02 CD4 T cell activity in both peripheral blood and tumor tissue. By analyzing NY-ESO-1123-137 /HLA-DRB3*02:02 -restricted CD4 T cell clones, we uncovered an unexpectedly high cytotoxicity, strong T helper 1 polarization, and recurrent αβ T cell receptor (TCRαβ) usage across patients and anatomical sites. These responses were also present in other NY-ESO-1-expressing cancers. TCRs from these clones, when transduced into primary CD4 T cells, showed direct antitumor efficacy both in vitro and in vivo. Our findings suggest that these TCRs are promising for adoptive T cell transfer therapy, enabling broader targeting of NY-ESO-1-expressing adult and pediatric cancers in clinical settings. Humans CD4-Positive T-Lymphocytes / immunology CD4-Positive T-Lymphocytes / metabolism Membrane Proteins / immunology Membrane Proteins / genetics Membrane Proteins / metabolism Antigens, Neoplasm / immunology Antigens, Neoplasm / genetics Animals Mice Receptors, Antigen, T-Cell / genetics Receptors, Antigen, T-Cell / metabolism Receptors, Antigen, T-Cell / immunology Melanoma / immunology Melanoma / therapy Cell Line, Tumor Immunotherapy, Adoptive Receptors, Antigen, T-Cell, alpha-beta / genetics Receptors, Antigen, T-Cell, alpha-beta / immunology Neoplasms / therapy Neoplasms / immunology Cell- and Tissue-Based Therapy / methods Dewey 616.07 Dewey 616 Swiss National Science Foundation ILC2 functional manipulation at the single cell level for innovative cancer immunotherapy 179727 CH Careers 137 Département de pathologie et immunologie 21F 56 Département de médecine 221 false 1309 Ciblage des lymphocytes sécrétant des cytokines 1015 298 Immunologie de transplantation, immunogénétique et thérapie cellulaire 561 1432 Découverte de biomarqueurs numériques pour l'oncologie de précision 1059 Science advances 11 26 9850be42-94f9-446e-9122-dfd75c9b2270 Article (Published version) Public sciadv.adu5754.pdf 3029880 application/pdf CC BY-NC-4.0 ef3f4e0aeeb9be258e7e2562469b7ba3729ff1f2cebb4975216d2f7d1178c042 1b324b7d-21cf-431d-a588-944d4621e9a9 Appendix Public sciadv.adu5754_sm.pdf 778274 application/pdf 6cc8669fcd4441fc06c8862e8f83ca66b8428fad85d954efad98600600edeed2 openAccess Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie Faculté de médecine / Section de médecine clinique / Département de médecine

Title	Published in	Year	Views	Downloads

Engineered CD4 TCR T cells with conserved high-affinity TCRs targeting NY-ESO-1 for advanced cellular therapies in cancer	Science advances	2025	92	212
Impact of immunotherapy on CD4 T cell phenotypes and function in cancer	Vaccines	2021	262	223

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Saillard, Margaux