CXCR6 Positions Cytotoxic T Cells to Receive Critical Survival Signals in the Tumor Microenvironment

Cytotoxic T lymphocyte (CTL) responses against tumors are maintained by stem-like memory cells that self-renew, but also give rise to effector-like cells. The latter gradually lose their anti-tumor activity and acquire an epigenetically fixed, hypofunctional state, leading to tumor tolerance. Here, we show that the conversion of stem-like into effector-like CTL involves a major chemotactic reprogramming that includes the upregulation of chemokine receptor CXCR6. This receptor positions effector-like CTL in a discrete perivascular niche of the tumor stroma that is densely occupied by CCR7+ dendritic cells (DC) expressing the CXCR6 ligand CXCL16. CCR7+ DC also express and trans-present the survival cytokine IL-15. CXCR6 expression and IL-15 trans-presentation are critical for the survival and local expansion of effector-like CTL in the tumor microenvironment to maximize their anti-tumor activity before progressing to irreversible dysfunction. These observations reveal a cellular and molecular checkpoint that determines the magnitude and outcome of anti-tumor immune responses. We analyzed the single cell transcriptomes of subcutaneous D4M.3A-pOVA, an immunogenic mouse melanoma model (Di Pilato et al., 2019, Nature). Tumor single cell suspensions were enriched for immune cells and rapidly processed for analysis on the inDrops scRNA-seq platform (Klein et al., 2015, Cell). After filtering to exclude putative cell doublets and stressed or dead cells, a total of 8,757 cell transcriptomes from 2 animals were retained for analysis