2. Academic Validation
  3. PD-1 signaling limits expression of phospholipid phosphatase 1 and promotes intratumoral CD8+ T cell ferroptosis

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

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: yizhang@zzu.edu.cn.
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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