Tumor PLA2G10 restrains CD4 T cell activation in lung adenocarcinoma via enhancing arachidonic acid secretion.

Metabolic and immunological disorder of tumor microenvironment (TME) is an essential hallmark of lung adenocarcinoma (LUAD), conducing to tumor initiation and progression. Lipid metabolism exerts an important impact on the TME reprogramming, especially for arachidonic acid (AA). However, the relationship between AA metabolism remodeling and abnormal TME status in LUAD remains unclear. In this study, the LUAD samples were used to perform systematic metabolome and transcriptome analysis, and the result shows AA is a distinctive feature of LUAD, regulated by tumor PLA2G10. Clinical analysis demonstrates that PLA2G10 is highly expressed in LUAD tissues compared to their para-cancerous tissues and high PLA2G10 level predicts poor prognosis in LUAD individuals. Further investigations find that tumor PLA2G10-mediated AA secretion promotes LUAD progression by suppressing CD4 T cell activation while having little impact on the proliferation and migration of tumor cell itself. Mechanistically, high AA level in TME caused by tumor PLA2G10 inhibits the phosphorylation of LCK (Y394) and ZAP70 (Y391), which restrains CD4 T cell activation and facilitates TME immunosuppression. PLA2G10 inhibitor combined with anti-PD-1 antibody exhibits good efficacy in the treatment of lung cancer. Our study uncovers the role of PLA2G10-mediated AA metabolism in TME remodeling via impairing CD4 T cell activation, which highlights the significance of abnormal cell communications in tumor development and provides a promising therapeutic strategy for LUAD by targeting AA metabolism.