Effect of PLA2G10 treatment on activated human primary T cells.

T lymphocytes are frequently excluded from human cancer tissue even if T cell-recruiting chemokines are present. These observations implicate the presence of T cell excluders (TCEs) in the tumor microenvironment. We report here that phospholipase A2 group 10 (PLA2G10) protein is a potent TCE to inhibit chemokine-induced T cell mobility. Overexpression of PLA2G10 is broadly found in human cancers and is associated with poor T cell infiltration in tumor tissues. Secreted PLA2G10 in the blood is correlated with the resistance to anti-programmed cell death (PD) immunotherapy in lung cancer patients. Overexpression of PLA2G10 in immunogenic mouse tumors could exclude T cells leading to their resistance to anti-PD immunotherapy. PLA2G10 hydrolyzes phospholipids into small lipid metabolites that could mediate the inhibition of T cell mobility. Our results discover a functional antagonist of chemokines, a molecular mechanism underpinning T cell exclusion in human cancer, and implicate a potential target for cancer immunotherapy. Overall design: Comparative gene expression profiling analysis of RNA-seq data for activated human T cells treated with CXCL11 (ITAC), PBS, PLA2G10, and CXCL11 plus PLA2G10.