IL-9/STAT3/fatty acid oxidation-mediated lipid peroxidation contributes to Tc9 cell longevity and enhanced antitumor activity.
IL-9/STAT3/fatty acid oxidation-mediated lipid peroxidation contributes to Tc9 cell longevity and enhanced antitumor activity.
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DOI：
10.1172/jci153247
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发表时间：
2022-04-01
期刊：
影响因子：
--
通讯作者：
Yi Q
中科院分区：
文献类型：
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作者：
Xiao L;Ma X;Ye L;Su P;Xiong W;Bi E;Wang Q;Xian M;Yang M;Qian J;Yi Q
代谢活性调节CD8+T细胞寿命在肿瘤免疫治疗中具有重要作用。尽管在体外极化下，转导的分泌IL-9的CD8+Tc9(细胞毒性T淋巴细胞亚群9)细胞比Tc1细胞具有更强的持久性和抗肿瘤效果，但其潜在机制尚不清楚。在这里，我们表明，肿瘤浸润性Tc9细胞在几个小鼠模型中表现出明显低于Tc1细胞的脂质过氧化，这与它们的持久性密切相关。利用RNA测序和功能验证，我们发现Tc9细胞表现出独特的脂代谢程序。TC9细胞来源的IL-9激活STAT3，上调脂肪酸氧化和线粒体活性，使TC9细胞减少脂质过氧化，并在肿瘤微环境中抵抗肿瘤或ROS诱导的铁下垂。IL-9信号转导缺陷、抑制STAT3或脂肪酸氧化增加Tc9细胞的脂质过氧化和铁下垂，导致Tc9细胞的寿命和抗肿瘤能力受损。同样，在黑色素瘤患者中，人Tc9细胞比Tc1细胞表现出更低的脂质过氧化反应，肿瘤浸润性CD8+T细胞比循环CD8+T细胞表达更低的IL9和更高的脂质过氧化和铁下垂相关基因。本研究表明，脂质过氧化通过IL-9/STAT3/脂肪酸氧化途径调节Tc9细胞寿命和抗肿瘤效应，调节T细胞脂质过氧化可用于加强T细胞免疫治疗。
CD8+ T cell longevity regulated by metabolic activity plays important roles in cancer immunotherapy. Although in vitro–polarized, transferred IL-9–secreting CD8+ Tc9 (cytotoxic T lymphocyte subset 9) cells exert greater persistence and antitumor efficacy than Tc1 cells, the underlying mechanism remains unclear. Here, we show that tumor-infiltrating Tc9 cells display significantly lower lipid peroxidation than Tc1 cells in several mouse models, which is strongly correlated with their persistence. Using RNA-sequence and functional validation, we found that Tc9 cells exhibited unique lipid metabolic programs. Tc9 cell–derived IL-9 activated STAT3, upregulated fatty acid oxidation and mitochondrial activity, and rendered Tc9 cells with reduced lipid peroxidation and resistance to tumor- or ROS-induced ferroptosis in the tumor microenvironment. IL-9 signaling deficiency, inhibiting STAT3, or fatty acid oxidation increased lipid peroxidation and ferroptosis of Tc9 cells, resulting in impaired longevity and antitumor ability. Similarly, human Tc9 cells also exhibited lower lipid peroxidation than Tc1 cells and tumor-infiltrating CD8+ T cells expressed lower IL9 and higher lipid peroxidation– and ferroptosis-related genes than circulating CD8+ T cells in patients with melanoma. This study indicates that lipid peroxidation regulates Tc9 cell longevity and antitumor effects via the IL-9/STAT3/fatty acid oxidation pathway and regulating T cell lipid peroxidation can be used to enhance T cell–based immunotherapy in human cancer.