TCR sensitivity shapes recognition of tumor antigen presented by host cells and TCR-T cell efficacy in solid tumors

Abstract

Despite advances in adoptive T cell therapy, therapeutic efficacy in solid tumors remains inconsistent, and the mechanistic determinants of treatment failure are incompletely understood. Increasing evidence suggests that effective antitumor responses depend not only on direct recognition of malignant cells but also on interactions with the tumor microenvironment, including non-malignant host cells that cross-present tumor antigens. Using an HLA-A2-transgenic syngeneic mouse cancer model that enables near-physiological presentation of human tumor antigens by both malignant and host cells, we investigated how TCR antigen sensitivity relates to therapeutic outcome. We compared T cell receptor-engineered (TCR-)T cells with different antigen sensitivities directed against the same HLA-A2-restricted melanoma antigen. Although high- and low-sensitivity TCR-T cells recognized tumor cells comparably in vitro, only high-sensitivity TCR-T cells mediated durable tumor regression in vivo. Improved tumor control correlated with enhanced recognition of cross-presented tumor antigen on tumor-associated CD11b+ myeloid cells and increased intratumoral effector activity. IFN-γ levels in tumor tissue and peripheral blood reflected intratumoral T cell activity and correlated with therapeutic response. Together, these findings identify host cell antigen recognition as a sensitivity-dependent functional correlate of TCR-T cell efficacy and provide a mechanistic explanation for the superior activity of higher-sensitivity TCRs in solid tumors.