Uptake of oxidized lipids from the tumor microenvironment by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8 T cells

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 over-expression 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. Lipid accumulation is a common metabolic alteration in the tumor microenvironment. Xu et al. show that intratumoral CD8 + T cells adapt to increased lipid concentrations by increasing expression of the scavenger receptor CD36. This in turn leads to intracellular accumulation of oxidized lipid and T cell dysfunction downstream of lipid peroxidation.