Abstract
Understanding the mechanisms underlying how T cells become dysfunctional in a tumor microenvironment (TME) will greatly benefit cancer immunotherapy. We found that increased CD36 expression in tumor-infiltrating CD8+ T cells, which was induced by TME cholesterol, was associated with tumor progression and poor survival in human and murine cancers. Genetic ablation of Cd36 in effector CD8+ T cells exhibited increased cytotoxic cytokine production and enhanced tumor eradication. CD36 mediated uptake of fatty acids by tumor-infiltrating CD8+ T cells in TME, induced lipid peroxidation and ferroptosis, and led to reduced cytotoxic cytokine production and impaired antitumor ability. Blocking CD36 or inhibiting ferroptosis in CD8+ T cells effectively restored their antitumor activity and, more importantly, possessed greater antitumor efficacy in combination with anti-PD-1 antibodies. This study reveals a new mechanism of CD36 regulating the function of CD8+ effector T cells and therapeutic potential of targeting CD36 or inhibiting ferroptosis to restore T cell function.
Original language | English (US) |
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Pages (from-to) | 1001-1012.e5 |
Journal | Cell Metabolism |
Volume | 33 |
Issue number | 5 |
DOIs | |
State | Published - May 4 2021 |
Externally published | Yes |
Keywords
- CD36
- CD8 T cells
- ferroptosis
- lipid peroxidation
ASJC Scopus subject areas
- Physiology
- Molecular Biology
- Cell Biology