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

Immunity (Cambridge, Mass.), 2021-07, Vol.54 (7), p.1561-1577.e7 [Peer Reviewed Journal]

2021 Elsevier Inc. ;Copyright © 2021 Elsevier Inc. All rights reserved. ;2021. Elsevier Inc. ;ISSN: 1074-7613 ;EISSN: 1097-4180 ;DOI: 10.1016/j.immuni.2021.05.003 ;PMID: 34102100

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Title:
Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8+ T cells in tumors
Author: Xu, Shihao ; Chaudhary, Omkar ; Rodríguez-Morales, Patricia ; Sun, Xiaoli ; Chen, Dan ; Zappasodi, Roberta ; Xu, Ziyan ; Pinto, Antonio F.M. ; Williams, April ; Schulze, Isabell ; Farsakoglu, Yagmur ; Varanasi, Siva Karthik ; Low, Jun Siong ; Tang, Wenxi ; Wang, Haiping ; McDonald, Bryan ; Tripple, Victoria ; Downes, Michael ; Evans, Ronald M. ; Abumrad, Nada A. ; Merghoub, Taha ; Wolchok, Jedd D. ; Shokhirev, Maxim N. ; Ho, Ping-Chih ; Witztum, Joseph L. ; Emu, Brinda ; Cui, Guoliang ; Kaech, Susan M.
Subjects: Accumulation ; Animals ; Antigens ; Atherosclerosis ; Biological Transport - physiology ; Cancer ; CD36 ; CD36 antigen ; CD36 Antigens - metabolism ; CD8 antigen ; CD8+ T cells ; CD8-Positive T-Lymphocytes - metabolism ; Cell Line, Tumor ; Cholesterol ; Cytokines ; Effector cells ; Fatty acids ; Flow cytometry ; Gene expression ; Glutathione ; Glutathione peroxidase ; HEK293 Cells ; Homeostasis ; Humans ; Immunotherapy ; Kinases ; Leukocytes, Mononuclear - metabolism ; Lipid peroxidation ; Lipid Peroxidation - physiology ; Lipids ; Lipoproteins ; Lipoproteins, LDL - metabolism ; Lymphocytes ; Lymphocytes T ; Lymphocytes, Tumor-Infiltrating - metabolism ; Metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Neoplasms - metabolism ; oxidized lipids ; Peroxidase ; Peroxidation ; Receptors ; Receptors, Scavenger - metabolism ; Scavenger receptors ; Tumor microenvironment ; Tumor Microenvironment - physiology ; Tumor necrosis factor-TNF ; Tumors
Is Part Of: Immunity (Cambridge, Mass.), 2021-07, Vol.54 (7), p.1561-1577.e7
Description: 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. [Display omitted] •The tumor microenvironment is enriched with lipids and oxidized lipids•Dysfunctional CD8+ TILs increase CD36 expression and OxLDL uptake•OxLDL uptake via CD36 inhibits T cell effector functions through lipid peroxidation•GPX4 overexpression promotes CD8+ TIL functionality Lipid accumulation is a common metabolic alteration in the tumor microenvironment. Xu et al. show that intratumoral CD8+ T cells adapt to increased lipid concentrations by increasing expression of the scavenger receptor CD36. This, in turn, leads to intracellular accumulation of oxidized lipid and T cell dysfunction downstream of lipid peroxidation.
Publisher: United States: Elsevier Inc
Language: English
Identifier: ISSN: 1074-7613
EISSN: 1097-4180
DOI: 10.1016/j.immuni.2021.05.003
PMID: 34102100
Source: MEDLINE
Open Access: Cell Press Free Archives

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

2021 Elsevier Inc. ;Copyright © 2021 Elsevier Inc. All rights reserved. ;2021. Elsevier Inc. ;ISSN: 1074-7613 ;EISSN: 1097-4180 ;DOI: 10.1016/j.immuni.2021.05.003 ;PMID: 34102100

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