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

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. AbumradTaha Merghoub, Jedd D. Wolchok, Maxim N. Shokhirev, Ping Chih Ho, Joseph L. Witztum, Brinda Emu, Guoliang Cui, Susan M. Kaech

Research output: Contribution to journalArticlepeer-review

85 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1561-1577.e7
JournalImmunity
Volume54
Issue number7
DOIs
StatePublished - Jul 13 2021
Externally publishedYes

Keywords

  • CD36
  • CD8 T cells
  • lipid peroxidation
  • oxidized lipids
  • tumor microenvironment

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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