%0 Journal Article
%A Xu, Shihao
%A Chaudhary, Omkar
%A Rodríguez-Morales, Patricia
%A Sun, Xiaoli
%A Chen, Dan
%A Zappasodi, Roberta
%A Xu, Ziyan
%A Pinto, Antonio F M
%A Williams, April
%A Schulze, Isabell
%A Farsakoglu, Yagmur
%A Varanasi, Siva Karthik
%A Low, Jun Siong
%A Tang, Wenxi
%A Wang, Haiping
%A McDonald, Bryan
%A Tripple, Victoria
%A Downes, Michael
%A Evans, Ronald M
%A Abumrad, Nada A
%A Merghoub, Taha
%A Wolchok, Jedd D
%A Shokhirev, Maxim N
%A Ho, Ping-Chih
%A Witztum, Joseph L
%A Emu, Brinda
%A Cui, Guoliang
%A Kaech, Susan M
%T Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8+ T cells in tumors.
%J Immunity
%V 54
%N 7
%@ 1074-7613
%C New York, NY
%I Elsevier
%M DKFZ-2021-01275
%P 1561-1577.e7
%D 2021
%Z 2021 Jul 13;54(7):1561-1577.e7
%X 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.
%K CD36 (Other)
%K CD8(+) T cells (Other)
%K lipid peroxidation (Other)
%K oxidized lipids (Other)
%K tumor microenvironment (Other)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:34102100
%R 10.1016/j.immuni.2021.05.003
%U https://inrepo02.dkfz.de/record/169133