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

Immunity. 2021 Jul 13;54(7):1561-1577.e7. doi: 10.1016/j.immuni.2021.05.003. Epub 2021 Jun 7.

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.

Keywords: CD36; CD8(+) T cells; lipid peroxidation; oxidized lipids; tumor microenvironment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Transport / physiology
  • CD36 Antigens / metabolism*
  • CD8-Positive T-Lymphocytes / metabolism*
  • Cell Line, Tumor
  • HEK293 Cells
  • Humans
  • Leukocytes, Mononuclear / metabolism
  • Lipid Peroxidation / physiology*
  • Lipoproteins, LDL / metabolism*
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neoplasms / metabolism*
  • Receptors, Scavenger / metabolism*
  • Tumor Microenvironment / physiology

Substances

  • CD36 Antigens
  • Lipoproteins, LDL
  • Receptors, Scavenger
  • oxidized low density lipoprotein