4.8 Article

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

Journal

JOURNAL OF CLINICAL INVESTIGATION
Volume 132, Issue 7, Pages -

Publisher

AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI153247

Keywords

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Funding

  1. National Cancer Institute (NCI) [R01 CA200539, R01 CA239255]
  2. Cancer Prevention & Research Institute of Texas Recruitment of Established Investigator Award [RR180044]
  3. NCI [R01 CA211073, R01 CA214811]

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This study reveals that lipid peroxidation regulates the longevity and antitumor effects of Tc9 cells through the IL-9/STAT3/fatty acid oxidation pathway. Modulating T cell lipid peroxidation can be utilized to enhance T cell-based immunotherapy in human cancer.
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.

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