Saillard et al. demonstrated the clinical potential of TCR-engineered CD4+ T cells targeting a broad range of NY-ESO-1–expressing tumors in HLA-DRB3*02:02-positive cancers. HLA-DRB3*02:02–restricted NYESO-1-specific CD4+ T cells exhibited high cytotoxicity, strong T helper 1 polarization, and a dominant TCRαβ usage across patients and anatomical sites. These cytotoxic TCR-biased CD4+ T cells were also present in other NY-ESO-1-expressing cancers. Adoptive T cell therapy using engineered CD4+ T cells with these conserved TCR chain pairs showed robust antigen-specific cytotoxicity in vitro and in vivo against HLA-matched xenograft tumors.
Contributed by Shishir Pant
ABSTRACT: 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.
Author Info: (1) Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland. Ludwig Institute for Cancer Research, Lausanne, Switzerland. Department of Pathology and Immuno
Author Info: (1) 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. (2) 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. (3) Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland. Ludwig Institute for Cancer Research, Lausanne, Switzerland. (4) Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland. Ludwig Institute for Cancer Research, Lausanne, Switzerland. (5) 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. (6) Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland. Ludwig Institute for Cancer Research, Lausanne, Switzerland. (7) Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland. Ludwig Institute for Cancer Research, Lausanne, Switzerland. (8) Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland. Ludwig Institute for Cancer Research, Lausanne, Switzerland. (9) Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland. Ludwig Institute for Cancer Research, Lausanne, Switzerland. (10) Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland. Ludwig Institute for Cancer Research, Lausanne, Switzerland. (11) Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland. Ludwig Institute for Cancer Research, Lausanne, Switzerland. SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland. (12) Division of Nephrology, Geneva University Hospitals, Geneva, Switzerland. Division of Transplantation Immunology, Geneva University Hospitals, Geneva, Switzerland. (13) Pediatric Hematology-Oncology Unit, Division of Pediatrics, Department "Woman-Mother-Child," University Hospital and Lausanne University, Lausanne, Switzerland. (14) Molecular Modeling Group, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland. Department of Oncology, Geneva University Hospitals, Geneva, Switzerland. (15) 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. (16) Plateforme clinique et translationnelle, Centre des thrapies exprimentales, University Hospital and Lausanne University, Lausanne, Switzerland. (17) Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland. Ludwig Institute for Cancer Research, Lausanne, Switzerland. (18) Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland. (19) Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland. Ludwig Institute for Cancer Research, Lausanne, Switzerland. (20) Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland. Ludwig Institute for Cancer Research, Lausanne, Switzerland. SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland. (21) Universit Bourgogne Franche-Comt, INSERM, EFS BFC, UMR1098, Interactions Hte-Greffon-Tumeur/Ingnierie Cellulaire et Gnique, Besanon, France. (22) Pediatric Hematology-Oncology Unit, Division of Pediatrics, Department "Woman-Mother-Child," University Hospital and Lausanne University, Lausanne, Switzerland. (23) Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland. Ludwig Institute for Cancer Research, Lausanne, Switzerland. (24) Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland. Ludwig Institute for Cancer Research, Lausanne, Switzerland. (25) 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.
