Oxidized Lipids and CD36-Mediated Lipid Peroxidation in CD8 T Cells Suppress Anti-Tumor Immune Responses

Abstract

T cell metabolic fitness plays a pivotal role in anti-tumor immunity and metabolic deregulation causes T cell dysfunction (i.e., exhaustion) in cancer. We identify that the scavenger receptor CD36 limits anti-tumor CD8+ T cell effector functions through lipid peroxidation. In murine tumors, oxidized phospholipids (OxPLs) were highly abundant and CD8+ TILs increased uptake and accumulation of lipids and lipid peroxidation. Functionally exhausted CD8+ TILs substantially increased CD36 expression and CD36-deficient CD8+ TILs had more robust anti-tumor activity and cytokine production than wild-type cells. We further show that CD36 promotes uptake of oxidized low-density lipoproteins (OxLDL) and induces lipid peroxidation in CD8+ TILs, and OxLDL inhibits CD8+ T cell functions in a CD36-dependent manner. Moreover, glutathione peroxidase 4 (GPX4) over-expression lowers lipid peroxidation and restores functionalities in CD8+ TILs. These results define a key role for an oxidized lipid-CD36 axis in promoting intratumoral CD8+ T cell dysfunction.

Lipid Metabolism and Ferroptosis

“…Exogenous lipids, including PUFAs and MUFAs, absorbed via CD36 induce metabolic and functional reprogramming of tumor-associated myeloid-derived suppressor cells (MDSCs) [ 79 ]. CD36 also directly suppresses the anti-tumor immune function of CD8 + tumor-infiltrating lymphocytes (TILs) by promoting lipid peroxidation through the uptake of oxidized low-density lipoproteins (OxLDL) [ 80 ]. Ferroptosis might be involved in this process, as GPX4 overexpression can rescue CD8 + tumor cell function [ 80 ].…”

“…CD36 also directly suppresses the anti-tumor immune function of CD8 + tumor-infiltrating lymphocytes (TILs) by promoting lipid peroxidation through the uptake of oxidized low-density lipoproteins (OxLDL) [ 80 ]. Ferroptosis might be involved in this process, as GPX4 overexpression can rescue CD8 + tumor cell function [ 80 ]. Since attempts to induce ferroptosis in cancer cells can also suppress anti-tumor immunity, a strategy to induce ferroptosis specifically in tumors based on the difference in ferroptosis mechanisms between cancer cells and immune cells is needed.…”

Distinctly altered lipid components in hepatocellular carcinoma relate to impaired T cell-dependent antitumor immunity

“…For example, cholesterol, free fatty acid and very long-chain fatty acid accumulated in the TME participate in exhaustion of tumor infiltrated CD8 + T cells defined as impaired cytotoxicity and reduced anti-tumor cytokines production [13][14][15]. Upregulated oxidated lipids in tumor contribute to CD8 + T cells lipid peroxidation and dysfunction [16]. In addition, elevated cholesterol uptake in CD8 + T cells promote cellular lipid peroxidation, functional dysregulation and ferroptosis [17].…”