Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8(+) T cells in tumors Journal Article
| Authors: | Xu, S.; Chaudhary, O.; Rodríguez-Morales, P.; Sun, X.; Chen, D.; Zappasodi, R.; Xu, Z.; Pinto, A. F. M.; Williams, A.; Schulze, I.; Farsakoglu, Y.; Varanasi, S. K.; Low, J. S.; Tang, W.; Wang, H.; McDonald, B.; Tripple, V.; Downes, M.; Evans, R. M.; Abumrad, N. A.; Merghoub, T.; Wolchok, J. D.; Shokhirev, M. N.; Ho, P. C.; Witztum, J. L.; Emu, B.; Cui, G.; Kaech, S. M. |
| Article Title: | Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8(+) T cells in tumors |
| Abstract: | 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. © 2021 Elsevier Inc. |
| Keywords: | lipid peroxidation; tumor microenvironment; cd8+ t cells; cd36; oxidized lipids |
| Journal Title: | Immunity |
| Volume: | 54 |
| Issue: | 7 |
| ISSN: | 1074-7613 |
| Publisher: | Cell Press |
| Date Published: | 2021-01-01 |
| Start Page: | 1561 |
| End Page: | 1577.e7 |
| Language: | English |
| DOI: | 10.1016/j.immuni.2021.05.003 |
| PUBMED: | 34102100 |
| PROVIDER: | scopus |
| PMCID: | PMC9273026 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 August 2021 -- Source: Scopus |
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