J Clin Invest. 2022 Apr 1;132(7). doi: 10.1172/JCI153247.
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.
CD8+T 细胞的代谢活性决定其寿命，在癌症免疫治疗中起着重要作用。虽然体外极化的分泌白细胞介素-9（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功效，但其中的机制仍不清楚。在这里，我们发现几种小鼠模型中，肿瘤浸润的 Tc9 细胞的脂质过氧化水平明显低于 Tc1 细胞，这与它们的持久性密切相关。通过 RNA 测序和功能验证，我们发现 Tc9 细胞表现出独特的脂质代谢程序。Tc9 细胞衍生的 IL-9 激活了 STAT3，上调了脂肪酸氧化和线粒体活性，使 Tc9 细胞减少了脂质过氧化，并在肿瘤微环境中对肿瘤或 ROS 诱导的铁死亡具有抗性。IL-9 信号缺失、抑制 STAT3 或脂肪酸氧化增加了 Tc9 细胞的脂质过氧化和铁死亡，导致其寿命缩短和抗肿瘤能力受损。同样，黑色素瘤患者肿瘤浸润的 CD8+T 细胞中表达的 IL9 较低，脂质过氧化和铁死亡相关基因较高，而循环 CD8+T 细胞中表达的 IL9 较低，脂质过氧化和铁死亡相关基因较高。这项研究表明，脂质过氧化通过 IL-9/STAT3/脂肪酸氧化途径调节 Tc9 细胞的寿命和抗肿瘤作用，调节 T 细胞的脂质过氧化可以用于增强人类癌症的基于 T 细胞的免疫治疗。
