CXCR6 Positions Cytotoxic T Cells in a Distinct Niche to Sustain Survival

During antitumor immune responses, cytotoxic T lymphocytes (CTL) exist in states ranging from stem-like memory cells to proliferative effector-like cells to irreversibly exhausted cells. Dendritic cells (DC) regulate CTL function, in part via chemokines, but mechanisms by which chemokine-driven CTL–DC interactions affect CTLs at various stages of differentiation are not completely understood. To investigate the relationship between intratumoral CTLs and DCs, Di Pilato, Kfuri-Rubens, Pruessmann, Ozga, and colleagues characterized chemokine and chemokine receptor gene expression of cells in the tumor microenvironment (TME) in an immunogenic mouse melanoma model, revealing that Cxcr6 was the most highly expressed chemokine receptor gene in CD8⁺ T-cells, with tumor-reactive effector-like CTLs expressing CXCR6 at the highest level. The absence of Cxcr6 in tumor-bearing mice led to increased tumor growth compared with wild-type mice, whereas depletion of CTLs abrogated this difference. To study the function of CXCR6 in CTLs, wild-type and Cxcr6^−/− OT-I cells were adoptively co-transferred into tumor-bearing mice, showing that while wild-type TCF1^neg CX3CR1⁺ CTLs underwent intratumoral expansion, Cxcr6^−/− CTLs failed to accumulate and persist. In addition to supporting CTL expansion, CXCR6 further promoted the function of intratumoral TCF1^neg CTLs by preventing activation-induced cell death. Consistent with a cognate DC–CTL interaction, Cxcl16, encoding the ligand of CXCR6, was most highly expressed by the DC3 state, a recently reported subset of DCs. Intravital imaging analysis revealed that DC3s marked a perivascular niche in the TME in which TCF1^neg CTLs accumulated, whereas Cxcr6^−/− CTLs displayed impaired localization to perivascular DC3 clusters. Examining how DC3s contributed to CTL function, DC3s were found to trans-present IL15 via IL15Rα to CXCR6-expressing CTLs, relaying a critical survival signal. In analysis of patient data from The Cancer Genome Atlas, CXCR6 expression predicted overall survival in melanoma and other solid tumors. In summary, this work highlights CXCR6 as a critical factor positioning CTLs in a distinct niche to enhance an antitumor response.

Di Pilato M, Kfuri-Rubens R, Pruessmann JN, Ozga AJ, Messemaker M, Cadilha BL, et al. CXCR6 positions cytotoxic T cells to receive critical survival signals in the tumor microenvironment. Cell 2021;184:4512–30.

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