CD8(+) T cell–Dependent Remodeling of the Tumor Microenvironment Overcomes Chemoresistance

The therapeutic efficacy of chemotherapy is in part a result of its ability to enhance adaptive antitumor immune responses. However, tumor cells exploit various evasion mechanisms to escape the immune attack and blunt chemosensitivity. Herein, we report that through single-cell profiling of the tumor immune microenvironment, we identified a subset of CD161-overexpressing CD8(+) T cells enriched in chemoresistant tumors. CD161 engagement repressed the calcium influx and cytolytic capacity of CD8(+) T cells through acid sphingomyelinase activation and ceramide generation. Targeting CD161 in adoptively transferred cytotoxic T lymphocytes enhanced antitumor immunity and reversed chemoresistance in patient-derived xenografts in vivo. Clinically, CD161 expression on CD8(+) T cells was associated with chemoresistance and shortened patient survival. Our findings provide insights into novel immunosuppressive mechanisms in chemoresistance and highlight targeting CD161 as a potential therapeutic strategy.