학술논문
CXCR6 positions cytotoxic T cells to receive critical survival signals in the tumor microenvironment
Document Type
article
Author
Di Pilato, Mauro; Kfuri-Rubens, Raphael; Pruessmann, Jasper N; Ozga, Aleksandra J; Messemaker, Marius; Cadilha, Bruno L; Sivakumar, Ramya; Cianciaruso, Chiara; Warner, Ross D; Marangoni, Francesco; Carrizosa, Esteban; Lesch, Stefanie; Billingsley, James; Perez-Ramos, Daniel; Zavala, Fidel; Rheinbay, Esther; Luster, Andrew D; Gerner, Michael Y; Kobold, Sebastian; Pittet, Mikael J; Mempel, Thorsten R
Source
Cell. 184(17)
Subject
Language
Abstract
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.