CYP4F2-Catalyzed Metabolism of Arachidonic Acid Promotes Stromal Cell-Mediated Immunosuppression in Non–Small Cell Lung Cancer
Xuehan Chen, Yanzhuo Liu, Yang Wang, Chenlong Wang, Xuewei Chen, Yu Xiong, Lilong Liu, Xi Yuan, Honglin Tang, Chong Shu, Jing Zhang, Austin M. Guo, Honglei Chen, Jing Yang
Abstract
Abstract Fatty acid synthesis facilitates tumor cell immune escape and immunotherapy resistance. Cytochrome P450 (CYP) 4A and 4F, the major ω-hydroxylases that convert arachidonic acid (AA) into 20-hydroxyeicosatetraenoic acid (20-HETE), are implicated in inflammation and cancer. However, the role of CYP4 ω-hydroxylases in immune evasion remains unclear. Here, we determined that 20-HETE derived from the CYP4F2 isoenzyme governs immune evasion in non–small cell lung cancer (NSCLC) in a CD8+ T-cell-dependent manner. Mechanistically, CYP4F2 induced expression of immune checkpoint PD-L1 and production of proangiogenic factors IL6 and TGFβ in cancer-associated fibroblasts (CAF) via the 20-HETE-GPR75-STAT3-c-Jun axis. Tumors with high CYP4F2 expression were more resistant to anti-PD-1 treatment, whereas inhibition of CYP4F2 enhanced the efficacy of anti-PD-1 therapy in human NSCLC organoids and mouse models. Collectively, these data delineate that CYP4F2-dependent AA metabolism controls CAF-mediated immune evasion. CYP4F2 inhibition combined with PD-1 antibody represents a promising therapeutic approach for immunotherapy-resistant lung cancer. Significance: The identification of a role for CYP4F2-dependent metabolism in driving immune evasion in non–small cell lung cancer reveals a strategy to improve the efficacy of immunotherapy by inhibiting CYP4F2. See related article by Van Ginderachter, p. 3882