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

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. und Mempel, Thorsten R. (2021): CXCR6 positions cytotoxic T cells to receive critical survival signals in the tumor microenvironment. In: Cell, Bd. 184, Nr. 17, e22: S. 4512-4530

Abstract

Cytotoxic T lymphocyte (CTL) responses against tumors are maintained by stem-like memory cells that selfrenew 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0092-8674
• Sprache: Englisch