CD36-mediated ferroptosis dampens intratumoral CD8+ T-cell effector function and impairs their antitumor ability
By Xingzhe Ma, Liuling Xiao, Lintao Liu, Lingqun Ye, Pan Su, Enguang Bi, Qiang Wang, Maojie Yang, J. Qian, Q. Yi. Cell Metabolism, 2021
834 citations recorded by the source corpus.
SUMMARY Understanding the mechanisms underlying how T cells become dysfunctional in 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 acid 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.
Subfields: Cancer Research, Oncology, Pulmonary and Respiratory Medicine
View Paper: https://www.semanticscholar.org/paper/c476e79182a554433325ef28774a718753ce289e
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Citations in the corpus
- Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research (2022, background): “More importantly, ferroptosis inhibition therapy obtains greater antitumor efficacy when in combination with anti-PD-1 antibodies [346].”
- Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. (2022, positive): “On the other hand, cholesterol in the tumor microenvironment leads to increased CD36 expression on CD8 T cells and causes these cells to take up PUFAs and undergo ferroptosis (Ma et al., 2021).”
- Ferroptosis in cancer: from molecular mechanisms to therapeutic strategies (2024, background): “23,354,449 ; 3) The immunosuppressive activities of ferropto-tic cancer cells promotes the tumor progression.”
- Ferroptosis in infection, inflammation, and immunity (2021, background): “However, CD36-mediated fatty acid uptake promotes ferroptosis in tumor-infiltrating CD8+ T cells, which limits antitumor immunity (Ma et al., 2021).”