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

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.

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.

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.

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.