Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8 + T cells in tumors.

Autor:	Xu S; NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA., Chaudhary O; Section of Infectious Diseases, Yale School of Medicine, New Haven, CT 06510, USA., Rodríguez-Morales P; NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA., Sun X; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA., Chen D; NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA., Zappasodi R; Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA., Xu Z; NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA., Pinto AFM; Mass Spectrometry Core for Proteomics and Metabolomics, Salk Institute for Biological Studies, La Jolla, CA 92037, USA., Williams A; The Razavi Newman Integrative Genomics and Bioinformatics Core Facility, Salk Institute for Biological Studies, La Jolla, CA 92037, USA., Schulze I; Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA., Farsakoglu Y; NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA., Varanasi SK; NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA., Low JS; Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA; Fondazione per l'istituto di ricerca in biomedicina, Bellinzona, Switzerland., Tang W; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA., Wang H; Department of Fundamental Oncology, Ludwig Institute for Cancer Research at University of Lausanne, Lausanne, Switzerland., McDonald B; NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA., Tripple V; NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA., Downes M; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA., Evans RM; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA., Abumrad NA; Division of Geriatrics and Nutritional Science, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA., Merghoub T; Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Wolchok JD; Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Shokhirev MN; The Razavi Newman Integrative Genomics and Bioinformatics Core Facility, Salk Institute for Biological Studies, La Jolla, CA 92037, USA., Ho PC; Department of Fundamental Oncology, Ludwig Institute for Cancer Research at University of Lausanne, Lausanne, Switzerland., Witztum JL; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA., Emu B; Section of Infectious Diseases, Yale School of Medicine, New Haven, CT 06510, USA., Cui G; T Cell Metabolism Group (D140), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany. Electronic address: g.cui@dkfz-heidelberg.de., Kaech SM; NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: skaech@salk.edu.
Jazyk:	angličtina
Zdroj:	Immunity [Immunity] 2021 Jul 13; Vol. 54 (7), pp. 1561-1577.e7. Date of Electronic Publication: 2021 Jun 07.
DOI:	10.1016/j.immuni.2021.05.003
Abstrakt:	A common metabolic alteration in the tumor microenvironment (TME) is lipid accumulation, a feature associated with immune dysfunction. Here, we examined how CD8 + tumor infiltrating lymphocytes (TILs) respond to lipids within the TME. We found elevated concentrations of several classes of lipids in the TME and accumulation of these in CD8 + TILs. Lipid accumulation was associated with increased expression of CD36, a scavenger receptor for oxidized lipids, on CD8 + TILs, which also correlated with progressive T cell dysfunction. Cd36 -/- T cells retained effector functions in the TME, as compared to WT counterparts. Mechanistically, CD36 promoted uptake of oxidized low-density lipoproteins (OxLDL) into T cells, and this induced lipid peroxidation and downstream activation of p38 kinase. Inhibition of p38 restored effector T cell functions in vitro, and resolution of lipid peroxidation by overexpression of glutathione peroxidase 4 restored functionalities in CD8 + TILs in vivo. Thus, an oxidized lipid-CD36 axis promotes intratumoral CD8 + T cell dysfunction and serves as a therapeutic avenue for immunotherapies. Competing Interests: Declaration of interests G.C. receives research funding from Bayer AG and Boehringer Ingelheim, but the funding is not relevant to the current study. J.L.W. and X.S. are named inventors on patent applications or patents related to the use of oxidation-specific antibodies held by UCSD. R.Z. is an inventor on patent applications related to work on GITR, PD-1, and CTLA-4. R.Z. is a consultant for Leap Therapeutics and iTEOS. T.M. is a cofounder and holds equity in IMVAQ Therapeutics. T.M. is a consultant for Immunos Therapeutics, Pfizer, and Immunogenesis. T.M. has research support from Bristol-Myers Squibb; Surface Oncology; Kyn Therapeutics; Infinity Pharmaceuticals, Inc.; Peregrine Pharmaceuticals, Inc.; Adaptive Biotechnologies; Leap Therapeutics, Inc.; and Aprea. T.M. has patents on applications related to work on oncolytic viral therapy, alpha virus-based vaccines, neoantigen modeling, CD40, GITR, OX40, PD-1, and CTLA-4. J.D.W. is a consultant for Adaptive Biotech, Amgen, Apricity, Ascentage Pharma, Astellas, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Chugai, Elucida, Eli Lilly, F Star, Georgiamune, Imvaq, Kyowa Hakko Kirin, Linneaus, Merck Pharmaceuticals, Neon Therapeutics, Polynoma, Psioxus, Recepta, Takara Bio, Trieza, Truvax, Sellas Life Sciences, Serametrix, Surface Oncology, Syndax, Syntalogic, and Werewolf Therapeutics. J.D.W. reports grants from Bristol Myers Squibb and Sephora. J.D.W. has equity in Tizona Pharmaceuticals, Adaptive Biotechnologies, Imvaq, Beigene, Linneaus, Apricity, Arsenal IO, and Georgiamune. J.D.W. is an inventor on patent applications related to work on DNA vaccines in companion animals with cancer, assays for suppressive myeloid cells in blood, oncolytic viral therapy, alphavirus-based vaccines, neo-antigen modeling, CD40, GITR, OX40, PD-1, and CTLA-4. (Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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