Engineered CD4 TCR T cells with conserved high-affinity TCRs targeting NY-ESO-1 for advanced cellular therapies in cancer
Copyright policy )Engineered CD4 TCR T cells with conserved high-affinity TCRs targeting NY-ESO-1 for advanced cellular therapies in cancer
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-1 123–137 / 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.
- University of Geneva Switzerland
- SIB Swiss Institute of Bioinformatics Switzerland
- Ludwig Institute for Cancer Research United States
- Université Bourgogne Franche-Comté France
- University of Lausanne Switzerland
CD4-Positive T-Lymphocytes / metabolism, Antigens, Neoplasm / genetics, Melanoma / immunology, Cell- and Tissue-Based Therapy / methods, Receptors, Antigen, T-Cell / immunology, 616.07, Melanoma / therapy, Immunotherapy, Adoptive, Receptors, Antigen, T-Cell, alpha-beta / immunology, Mice, CD4-Positive T-Lymphocytes / immunology, Cell Line, Tumor, 616, Humans, Animals, Receptors, Antigen, T-Cell / genetics, Membrane Proteins / genetics, Receptors, Antigen, T-Cell, alpha-beta / genetics, Neoplasms / therapy, Neoplasms / immunology, Membrane Proteins / immunology, Membrane Proteins / metabolism, Antigens, Neoplasm / immunology, Receptors, Antigen, T-Cell / metabolism, 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, Biomedicine and Life Sciences
CD4-Positive T-Lymphocytes / metabolism, Antigens, Neoplasm / genetics, Melanoma / immunology, Cell- and Tissue-Based Therapy / methods, Receptors, Antigen, T-Cell / immunology, 616.07, Melanoma / therapy, Immunotherapy, Adoptive, Receptors, Antigen, T-Cell, alpha-beta / immunology, Mice, CD4-Positive T-Lymphocytes / immunology, Cell Line, Tumor, 616, Humans, Animals, Receptors, Antigen, T-Cell / genetics, Membrane Proteins / genetics, Receptors, Antigen, T-Cell, alpha-beta / genetics, Neoplasms / therapy, Neoplasms / immunology, Membrane Proteins / immunology, Membrane Proteins / metabolism, Antigens, Neoplasm / immunology, Receptors, Antigen, T-Cell / metabolism, 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, Biomedicine and Life Sciences
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