郑州大学张毅团队发现，PD-1信号通路限制磷脂磷酸酶1的表达并促进肿瘤内CD8⁺ T细胞的铁死亡。近日，国际知名学术期刊《免疫》在线发表了这一成果。

研究人员报道了肿瘤微环境（TME）对CD8⁺ T细胞中磷脂代谢的影响。在肺癌中，肿瘤内CD8⁺ T细胞中的磷脂酰胆碱（PC）和磷脂酰乙醇胺（PE）水平低于循环中的CD8⁺ T细胞。肿瘤内CD8⁺ T细胞表现出磷脂磷酸酶1（PLPP1）表达的下降，而PLPP1催化PE和PC的合成。

T细胞特异性敲除Plpp1会削弱抗肿瘤免疫力，并通过铁死亡促进T细胞死亡。TME中的不饱和脂肪酸刺激Plpp1^−/− CD8⁺ T细胞发生铁死亡。

在机制上，程序性死亡受体1（PD-1）信号通路通过诱导GATA1与Plpp1启动子区域结合，从而抑制Plpp1的表达。PD-1阻断增加了Plpp1的表达，并恢复了CD8⁺ T细胞的抗肿瘤功能，但未能挽救Plpp1^−/− CD8⁺ T细胞的功能障碍。因此，PD-1信号通路调节CD8⁺ T细胞中的磷脂代谢，这对于免疫治疗具有重要的治疗意义。

据介绍，TME促使免疫细胞发生代谢重编程和功能障碍。

附：英文原文

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

Author: Yu Ping, Jiqi Shan, Haiming Qin, Feng Li, Jiao Qu, Ru Guo, Dong Han, Wei Jing, Yaqing Liu, Jinyan Liu, Zhangnan Liu, Jieyao Li, Dongli Yue, Feng Wang, Liping Wang, Bin Zhang, Bo Huang, Yi Zhang

Issue&Volume:

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.

DOI: 10.1016/j.immuni.2024.08.003

Source: https://www.cell.com/immunity/abstract/S1074-7613(24)00376-5