Article
作者: Ji, Lan ; Schalper, Kurt A ; Norris, Paul C ; Nassar, Ala ; Gu, Runxia ; Yeung, Jacky ; Pearson, Mackenzie J ; Liu, Linda ; Humphrey, Rachel ; Vesely, Mathew D ; LaRochelle, William J ; Cheng, Xiaoxiao ; Yu, Weiwei ; Langermann, Solomon ; Sanmamed, Miguel F ; Zhang, Qiuyu ; Chen, Lieping ; van Deursen, Willemijn ; Zhao, Dejian ; Zhang, Jindong ; Yang, Xuan ; Zhang, Jian-Ping ; Halcovich, Christina ; Zhang, Tianxiang ; Ahumada, Viviana ; Zhang, Yu ; Vesely, Matthew D. ; Flies, Dallas B
T cells are often absent from human cancer tissues during both spontaneously induced immunity and therapeutic immunotherapy, even in the presence of a functional T cell–recruiting chemokine system, suggesting the existence of T cell exclusion mechanisms that impair infiltration. Using a genome-wide in vitro screening platform, we identified a role for phospholipase A2 group 10 (PLA2G10) protein in T cell exclusion. PLA2G10 up-regulation is widespread in human cancers and is associated with poor T cell infiltration in tumor tissues. PLA2G10 overexpression in immunogenic mouse tumors excluded T cells from infiltration, resulting in resistance to anti–PD-1 immunotherapy. PLA2G10 can hydrolyze phospholipids into small lipid metabolites, thus inhibiting chemokine-mediated T cell mobility. Ablation of PLA2G10’s enzymatic activity enhanced T cell infiltration and sensitized PLA2G10-overexpressing tumors to immunotherapies. Our study implicates a role for PLA2G10 in T cell exclusion from tumors and suggests a potential target for cancer immunotherapy.