PD-1 signaling limits expression of phospholipid phosphatase 1 and promotes intratumoral CD8+ T cell ferroptosis

  • Immunity. 2024 Sep 10;57(9):2122-2139.e9. doi: 10.1016/j.immuni.2024.08.003.
Yu Ping  1 ,  Jiqi Shan  1 ,  Haiming Qin  2 ,  Feng Li  1 ,  Jiao Qu  1 ,  Ru Guo  1 ,  Dong Han  1 ,  Wei Jing  1 ,  Yaqing Liu  1 ,  Jinyan Liu  1 ,  Zhangnan Liu  1 ,  Jieyao Li  3 ,  Dongli Yue  3 ,  Feng Wang  3 ,  Liping Wang  3 ,  Bin Zhang  4 ,  Bo Huang  5 ,  Yi Zhang  6
Affiliations
  • 1. Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • 2. Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; School of Public Health, Zhengzhou University, Zhengzhou, Henan, China.
  • 3. Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • 4. Robert H. Lurie Comprehensive Cancer Center, Department of Medicine, Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
  • 5. Department of Immunology & National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College, Beijing, China.
  • 6. Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; School of Public Health, Zhengzhou University, Zhengzhou, Henan, China; State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, Henan, China; School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, China; Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China. Electronic address: [email protected].
PMID: 39208806 DOI: 10.1016/j.immuni.2024.08.003
Abstract

The tumor microenvironment (TME) promotes metabolic reprogramming and dysfunction in immune cells. Here, we examined the impact of the TME on phospholipid metabolism in CD8+ T cells. In lung Cancer, phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were lower in intratumoral CD8+ T cells than in circulating CD8+ T cells. Intratumoral CD8+ T cells exhibited decreased expression of phospholipid Phosphatase 1 (PLPP1), which catalyzes PE and PC synthesis. T cell-specific deletion of Plpp1 impaired antitumor immunity and promoted T cell death by Ferroptosis. Unsaturated fatty acids in the TME stimulated Ferroptosis of Plpp1-/- CD8+ T cells. Mechanistically, programmed death-1 (PD-1) signaling in CD8+ T cells induced GATA1 binding to the promoter region Plpp1 and thereby suppressed Plpp1 expression. PD-1 blockade increased Plpp1 expression and restored CD8+ T cell antitumor function but did not rescue dysfunction of Plpp1-/- CD8+ T cells. Thus, PD-1 signaling regulates phospholipid metabolism in CD8+ T cells, with therapeutic implications for immunotherapy.

Keywords
CD8(+) T cell; PD-1 signaling; PLPP1; anti-PD-1 therapy; antitumor immunity; ferroptosis; lipid peroxidation; phospholipid metabolism; tumor microenvironment; unsaturated fatty acid.
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