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

Autor:	Di Pilato M; Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02129, USA; Harvard Medical School, Boston, MA 02115, USA; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA. Electronic address: mdi@mdanderson.org., Kfuri-Rubens R; Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02129, USA; Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, Munich, Germany., Pruessmann JN; Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02129, USA; Harvard Medical School, Boston, MA 02115, USA., Ozga AJ; Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02129, USA; Harvard Medical School, Boston, MA 02115, USA., Messemaker M; Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02115, USA., Cadilha BL; Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, Munich, Germany., Sivakumar R; Department of Immunology, University of Washington, Seattle, WA 98109, USA., Cianciaruso C; Harvard Medical School, Boston, MA 02115, USA; Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02115, USA., Warner RD; Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02129, USA., Marangoni F; Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02129, USA; Harvard Medical School, Boston, MA 02115, USA., Carrizosa E; Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02129, USA; Harvard Medical School, Boston, MA 02115, USA., Lesch S; Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, Munich, Germany., Billingsley J; Harvard Chan Bioinformatics Core, Department of Biostatistics, Harvard School of Public Health, Boston, MA 21205, USA., Perez-Ramos D; Department of Molecular Microbiology and Immunology and Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA., Zavala F; Department of Molecular Microbiology and Immunology and Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA., Rheinbay E; Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02129, USA., Luster AD; Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02129, USA; Harvard Medical School, Boston, MA 02115, USA., Gerner MY; Department of Immunology, University of Washington, Seattle, WA 98109, USA., Kobold S; Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, Munich, Germany; German Center for Translational Cancer Research (DKTK), partner site, Munich, Germany., Pittet MJ; Harvard Medical School, Boston, MA 02115, USA; Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02115, USA; Department of Pathology and Immunology, University of Geneva, Department of Oncology, Geneva University Hospitals, Geneva, Switzerland; Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland., Mempel TR; Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02129, USA; Harvard Medical School, Boston, MA 02115, USA; Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02115, USA. Electronic address: tmempel@mgh.harvard.edu.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2021 Aug 19; Vol. 184 (17), pp. 4512-4530.e22. Date of Electronic Publication: 2021 Aug 02.
DOI:	10.1016/j.cell.2021.07.015
Abstrakt:	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. Competing Interests: Declaration of interests S.K. has filed a patent application (PCT/EP2016/074644) related to the use of CXCR6-transduced T cells in tumor therapy. All other authors declare no competing interests. (Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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