Journal Article

DKFZ-2021-01275

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8+ T cells in tumors.

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.DKFZ* ; Kaech, S. M.

2021
Elsevier New York, NY

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Please use a persistent id in citations: doi:10.1016/j.immuni.2021.05.003

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.

Keyword(s): CD36 ; CD8(+) T cells ; lipid peroxidation ; oxidized lipids ; tumor microenvironment

Note: 2021 Jul 13;54(7):1561-1577.e7

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Contributing Institute(s):

1. T-Zell-Metabolismus (D140)
2. T-Zell-Metabolismus (D192)

Research Program(s):

1. 314 - Immunologie und Krebs (POF4-314) (POF4-314)

Appears in the scientific report 2021

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 20 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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