@article{ab0d72b507bf4f2c97aa4bf05c26b93b,
title = "CXCR6 positions cytotoxic T cells to receive critical survival signals in the tumor microenvironment",
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.",
keywords = "CCR7 dendritic cells, CTL, CXCL16, CXCR6, IL-15, TCF-1, TCGA, multiphoton intravital microscopy, scRNA-seq, tumor microenvironment",
author = "{Di Pilato}, Mauro and Raphael Kfuri-Rubens and Pruessmann, {Jasper N.} and Ozga, {Aleksandra J.} and Marius Messemaker and Cadilha, {Bruno L.} and Ramya Sivakumar and Chiara Cianciaruso and Warner, {Ross D.} and Francesco Marangoni and Esteban Carrizosa and Stefanie Lesch and James Billingsley and Daniel Perez-Ramos and Fidel Zavala and Esther Rheinbay and Luster, {Andrew D.} and Gerner, {Michael Y.} and Sebastian Kobold and Pittet, {Mikael J.} and Mempel, {Thorsten R.}",
note = "Funding Information: We thank the Harvard Single Cell Core, the Harvard Chan Bioinformatics Core (supported in part by a Harvard Medical School Foundry award), and Allon Klein for assistance in the scRNA-seq as well as TCGA survival analyses. Funding was through National Institutes of Health (NIH) grants R01 AI123349 (to T.R.M.), P01-CA240239 (to T.R.M. and M.J.P.), R01 AI084880 , R01 CA218579 , R01 AI123349 , R01 CA206890 (to M.J.P), R01 CA204028 (to A.D.L.), R01 AI134713 , R21AI142667 (to M.Y.G.), the BMBF project Oncoattract, the MSC network for Optimizing Adoptive T Cell Therapy of Cancer funded by the H2020 Program of the European Union (grant 955575 ), the Bavarian Ministry for Economic Affairs (CARMOUFLAGE), ERC grant 756017 , and i-Target: Immunotargeting of Cancer funded by the Elite Network of Bavaria (to S.K). T.R.M. was also supported by a Melanoma Research Alliance Established Investigator Award (award # 827872 ) and by a research grant from the Melanoma Research Foundation , M.J.P. in part by the ISREC Foundation , M.D.P. by an EMBO fellowship ( ALTF534-2015 ) and a Marie Curie Global Fellowship ( 750973 ), J.N.P. by DFG research fellowships ( PR 1652/1-1 and PR 1652/2-1 ), R.K.-R. by the German Academic Scholarship Foundation and by a LMU Prosa Scholarship, A.J.O. by the Swiss National Science Foundation Early Postdoctoral Mobility Award ( P3BEP3_165406 ) and the American Association for Cancer Research Basic Science Fellowship Program ( 18-40-01-OZGA ), and D.P.-R. and F.Z. by the Bloomberg Philanthropies . Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = aug,
day = "19",
doi = "10.1016/j.cell.2021.07.015",
language = "English (US)",
volume = "184",
pages = "4512--4530.e22",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "17",
}