CD36 Activity Causes Ferroptosis in Tumor-Infiltrating CD8⁺ T Cells

Tumor-infiltrating cytotoxic T cells can contribute to antitumor immune responses, but they often become dysfunctional due to the immunosuppressive tumor microenvironment (TME), limiting their effector functions and reducing the efficacy of immunotherapies. In tumor-infiltrating CD8⁺ T cells from patients with melanoma or multiple myeloma, Ma, Xiao, Liu, and colleagues discovered that higher expression of the transmembrane fatty acid transporter CD36 was correlated with shorter survival. Additionally, in mouse models of melanoma and multiple myeloma, CD36 expression on CD8⁺ T cells increased with tumor progression, an effect that depended on the presence of cholesterol in the TME. Notably, in the mouse melanoma model, CD36-depleted CD8⁺ T cells exhibited superior antitumor activity and lengthened survival relative to wild-type (WT) CD8⁺ T cells. In tumor-infiltrating CD8⁺ T cells from both patients and mice, CD36 expression was negatively correlated with the production of cytotoxic cytokines, and CD36-depleted CD8⁺ T cells exhibited greater antitumor effects in the mouse melanoma model than WT CD8⁺ T cells. In the mouse melanoma model and in patients with melanoma, CD36-deficient tumor-infiltrating CD8⁺ T cells had lower expression of genes associated with lipid peroxidation and ferroptosis, an iron- and lipid peroxide–triggered form of programmed cell death, and direct measures of levels of lipid peroxides, iron, and cell death in vivo confirmed that CD36 deficiency was associated with reduced ferroptosis of tumor-infiltrating CD8⁺ T cells. Further investigation revealed that ferroptosis promoted by T cell–expressed CD36 was the cause of the reduction in the T cell–generated cytotoxic cytokines IFNγ and TNFα described previously. Mechanistically, CD36-mediated uptake of TME-derived fatty acids—particularly arachidonic acid, an omega-6 polyunsaturated fatty acid—was found to underlie the observed T-cell ferroptosis. Importantly, CD8⁺ T cells treated with a ferroptosis inhibitor or depleted of CD36, both of which were confirmed to reduce ferroptosis, improved the T cells' antitumor immune function, particularly when combined with anti–PD-1. Together, these results show that CD36-mediated ferroptosis of tumor-infiltrating CD8⁺ T cells limits antitumor immunity and suggest that blocking this pathway may enhance antitumor immune function alone or in combination with immune checkpoint blockade.

Ma X, Xiao L, Liu L, Ye L, Su P, Bi E, et al. CD36-mediated ferroptosis dampens intratumoral CD8+ T cell effector function and impairs their antitumor ability. Cell Metab 2021 Mar 9 [Epub ahead of print].

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