CXCR6 positions cytotoxic T cells to receive critical survival signals in the tumor microenvironment


Mauro Di Pilato, Raphael Kfuri-Rubens, Jasper N Pruessmann, Aleksandra J Ozga, Marius Messemaker, Bruno L Cadilha, Ramya Sivakumar, Chiara Cianciaruso, Ross D Warner, Francesco Marangoni, Esteban Carrizosa, Stefanie Lesch, James Billingsley, Daniel Perez-Ramos, Fidel Zavala, Esther Rheinbay, Andrew D Luster, Michael Y Gerner, Sebastian Kobold, Mikael J Pittet, and Thorsten R Mempel. 2021. “CXCR6 positions cytotoxic T cells to receive critical survival signals in the tumor microenvironment.” Cell, 184, 17, Pp. 4512-4530.e22.


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 CTLs involves a major chemotactic reprogramming that includes the upregulation of chemokine receptor CXCR6. This receptor positions effector-like CTLs in a discrete perivascular niche of the tumor stroma that is densely occupied by CCR7+ dendritic cells (DCs) expressing the CXCR6 ligand CXCL16. CCR7+ DCs also express and trans-present the survival cytokine interleukin-15 (IL-15). CXCR6 expression and IL-15 trans-presentation are critical for the survival and local expansion of effector-like CTLs 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.