PLPP1-deficiency-mediated ferroptosis induced by PD-1 signaling impairs antitumor activity of intratumoral CD8+ T cells II

Metabolic programming plays a crucial role in T-cell activation. Herein, we describe how phospholipid metabolism regulates CD8+ T-cell function in patients with cancer. We found that phosphatidylcholine (PC) and phosphatidyl ethanolamine (PE) levels were lower in intratumoral CD8+ T cells than in circulating CD8+ T cells. The expression of phospholipid phosphatase 1 (PLPP1), an enzyme that catalyzes PE and PC synthesis, was also downregulated in CD8+ T cells upon infiltrating tumors. Moreover, unsaturated fatty acid-mediated ferroptosis was a major factor impairing the antitumor function of PLPP1-deficient CD8+ T cells infiltrated in tumors, accompanied by enhanced reactive oxygen species production and lipid peroxidation. The activation of programmed cell death 1 (PD-1) signaling in CD8+ T cells suppressed the PLPP1 expression by increasing GATA1 binding to the promoter region of PLPP1. PLPP1 expression was upregulated after anti-PD-1 therapy. Our findings revealed therapeutic potential of enhancing PLPP1 levels to restore CD8+ T-cell function. Overall design: Female PLPP1fl/fl and Lckcre-PLPP1fl/fl mice were subcutaneously implanted with 5×105 B16 cells into the right flank. Intratumoral CD8+ T cells were sorted on day 14 using mouse CD8a microbeads. RNA-seq and data analyses were conducted by SeqHealth Technology Co., Ltd. (Wuhan, China).

代谢重编程在T细胞活化中发挥关键作用。本研究阐明了磷脂代谢如何调控癌症患者体内CD8+ T细胞的功能。我们发现，肿瘤内CD8+ T细胞中的磷脂酰胆碱（phosphatidylcholine, PC）与磷脂酰乙醇胺（phosphatidylethanolamine, PE）水平低于循环CD8+ T细胞。催化PE与PC合成的酶——磷脂磷酸酶1（phospholipid phosphatase 1, PLPP1），在浸润肿瘤的CD8+ T细胞中表达亦出现下调。此外，不饱和脂肪酸介导的铁死亡是损伤肿瘤浸润性PLPP1缺陷型CD8+ T细胞抗肿瘤功能的主要因素，伴随活性氧生成增强与脂质过氧化反应加剧。CD8+ T细胞中程序性死亡蛋白1（programmed cell death 1, PD-1）信号的激活，通过增强GATA1与PLPP1启动子区域的结合，抑制PLPP1的表达。抗PD-1治疗后，PLPP1的表达会上调。本研究结果揭示了上调PLPP1水平以恢复CD8+ T细胞功能的治疗潜力。研究设计：将雌性PLPP1fl/fl与Lckcre-PLPP1fl/fl小鼠右侧背部皮下接种5×10^5个B16细胞。于接种后第14天，使用小鼠CD8a磁珠分选肿瘤内CD8+ T细胞。RNA测序及数据分析由中国武汉SeqHealth科技有限公司完成。