IL-9/STAT3/fatty acid oxidation mediated lipid peroxidation contributes to Tc9 cell longevity and enhanced antitumor activity

Abstract CD8+ T cell longevity regulated by metabolic activity plays important roles in cancer immunotherapy. In vitro polarized IL-9-secreting CD8+ Tc9 cells exert greater persistence and antitumor efficacy than Tc1/CTL cells after adoptive transfer, but 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 resistant to tumor or reactive oxygen species (ROS) induced ferroptosis in TME. IL-9 signal 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 possessed lower lipid peroxidation than Tc1 cells and tumor-infiltrating CD8+ T cells expressed lower IL-9 and higher lipid peroxidation- and ferroptosis-related genes than circulating CD8+ T cells in melanoma patients. This study indicates that lipid peroxidation regulates Tc9 cell longevity and antitumor effects via 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. This work was supported by NCI R01s CA200539 and CA239255, and Cancer Prevention & Research Institute of Texas Recruitment of Established Investigator Award (RR180044).