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

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 t...

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Main Authors: Xu, Shihao (Author) , Chaudhary, Omkar (Author) , Rodríguez-Morales, Patricia (Author) , Sun, Xiaoli (Author) , Chen, Dan (Author) , Zappasodi, Roberta (Author) , Xu, Ziyan (Author) , Pinto, Antonio F. M. (Author) , Williams, April (Author) , Schulze, Isabell (Author) , Farsakoglu, Yagmur (Author) , Varanasi, Siva Karthik (Author) , Low, Jun Siong (Author) , Tang, Wenxi (Author) , Wang, Haiping (Author) , McDonald, Bryan (Author) , Tripple, Victoria (Author) , Downes, Michael (Author) , Evans, Ronald M. (Author) , Abumrad, Nada A. (Author) , Merghoub, Taha (Author) , Wolchok, Jedd D. (Author) , Shokhirev, Maxim N. (Author) , Ho, Ping-Chih (Author) , Witztum, Joseph L. (Author) , Emu, Brinda (Author) , Cui, Guoliang (Author) , Kaech, Susan M. (Author)
Format: Article (Journal)
Language:English
Published: 7 June 2021
In: Immunity
Year: 2021, Volume: 54, Issue: 7, Pages: 1561-1577, e1-e7
ISSN:1097-4180
DOI:10.1016/j.immuni.2021.05.003
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.immuni.2021.05.003
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S1074761321002090
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Author Notes:Shihao Xu, Omkar Chaudhary, Patricia Rodríguez-Morales, Xiaoli Sun, Dan Chen, Roberta Zappasodi, Ziyan Xu, Antonio F.M. Pinto, April Williams, Isabell Schulze, Yagmur Farsakoglu, Siva Karthik Varanasi, Jun Siong Low, Wenxi Tang, Haiping Wang, Bryan McDonald, Victoria Tripple, Michael Downes, Ronald M. Evans, Nada A. Abumrad, Taha Merghoub, Jedd D. Wolchok, Maxim N. Shokhirev, Ping-Chih Ho, Joseph L. Witztum, Brinda Emu, Guoliang Cui, and Susan M. Kaech
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Summary: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.
Item Description:Im Titel ist das Pluszeichen hochgestellt
Gesehen am 27.10.2021
Physical Description:Online Resource
ISSN:1097-4180
DOI:10.1016/j.immuni.2021.05.003

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