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 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.

Automated summary

The accumulation of lipids in the tumor microenvironment is associated with dysfunction of CD8(+) T cells, mediated in part by the CD36 receptor and its promotion of lipid uptake and peroxidation. Inhibiting p38 kinase or resolving lipid peroxidation may restore effector T cell functions and provide a potential therapeutic avenue for immunotherapies.