CXCR6 is required for antitumor efficacy of intratumoral CD8(+) T cell

BACKGROUND: Increasing infiltration of CD8(+) T cells within tumor tissue predicts a better prognosis and is essential for response to checkpoint blocking therapy. Furthermore, current clinical protocols use unfractioned T cell populations as the starting point for transduction of chimeric antigen receptors (CARs)-modified T cells, but the optimal T cell subtype of CAR-modified T cells remains unclear. Thus, accurately identifying a group of cytotoxic T lymphocytes with high antitumor efficacy is imperative. Inspired by the theory of yin and yang, we explored a subset of CD8(+) T cell in cancer with the same phenotypic characteristics as highly activated inflammatory T cells in autoimmune diseases. METHODS: Combination of single-cell RNA sequencing, general transcriptome sequencing data and multiparametric cytometric techniques allowed us to map CXCR6 expression on specific cell type and tissue. We applied Cxcr6(−/−) mice, immune checkpoint therapies and bone marrow chimeras to identify the function of CXCR6(+)CD8(+) T cells. Transgenic Cxcr6(−/−) OT-I mice were employed to explore the functional role of CXCR6 in antigen-specific antitumor response. RESULTS: We identified that CXCR6 was exclusively expressed on intratumoral CD8(+) T cell. CXCR6(+)CD8(+) T cells were more immunocompetent, and chimeras with specific deficiency on CD8(+) T cells showed weaker antitumor activity. In addition, Cxcr6(−/−) mice could not respond to anti-PD-1 treatment effectively. High tumor expression of CXCR6 was not mainly caused by ligand-receptor chemotaxis of CXCL16/CXCR6 but induced by tumor tissue self. Induced CXCR6(+)CD8(+) T cells possessed tumor antigen specificity and could enhance the effect of anti-PD-1 blockade to retard tumor progression. CONCLUSIONS: This study may contribute to the rational design of combined immunotherapy. Alternatively, CXCR6 may be used as a biomarker for effective CD8(+) T cell state before adoptive cell therapy, providing a basis for tumor immunotherapy.