Dual receptor T cells mediate effective antitumor immune responses via increased recognition of tumor antigens

BACKGROUND: Discovery that ~16% of T cells naturally co-express two T-cell receptor (TCR) clonotypes prompts examining the role of dual TCR cells in immune functions. METHODS: Using TCRα-reporter transgenic mice, enabling unambiguous identification of single-TCR and dual-TCR cells, we tested the role of dual TCR cells in antitumor immune responses against immune-responsive syngeneic 6727 sarcoma and immune-resistant B16F10 melanoma. RESULTS: Dual TCR cells were specifically increased among tumor-infiltrating lymphocytes (TILs) in both models, indicating selective advantage in antitumor responses. Phenotype and single-cell gene expression analyses identified dual TCR are predominant during the effective antitumor response, demonstrating selectively increased activation in the TIL compartment and skewing toward an effector memory phenotype. Absence of dual TCR cells impaired immune response to B16F10 but not 6727, suggesting that dual TCR cells may be more influential in responses against poorly immunogenic tumors. Dual TCR cells demonstrated an advantage in recognition of B16F10-derived neoantigens in vitro, providing a mechanistic basis for their antitumor reactivity. CONCLUSIONS: These results discover an unrecognized role for dual TCR cells in protective immune function and identify these cells and their TCRs as a potential resource for antitumor immunotherapy.