Up-regulated PLA2G10 in cancer impairs T cell infiltration to dampen immunity

• Published in: Science immunology 2024-04, Vol.9 (94), p.eadh2334
• Main Authors: Zhang, Tianxiang, Yu, Weiwei, Cheng, Xiaoxiao, Yeung, Jacky, Ahumada, Viviana, Norris, Paul C, Pearson, Mackenzie J, Yang, Xuan, van Deursen, Willemijn, Halcovich, Christina, Nassar, Ala, Vesely, Mathew D, Zhang, Yu, Zhang, Jianping, Ji, Lan, Flies, Dallas B, Liu, Linda, Langermann, Solomon, LaRochelle, William J, Humphrey, Rachel, Zhao, Dejian, Zhang, Qiuyu, Zhang, Jindong, Gu, Runxia, Schalper, Kurt A, Sanmamed, Miguel F, Chen, Lieping
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; Female; Humans; Immunotherapy - methods; Lymphocytes, Tumor-Infiltrating - immunology; Mice; Mice, Inbred C57BL; Neoplasms - immunology; Phospholipases A - genetics; Phospholipases A - immunology; Phospholipases A2 - immunology; T-Lymphocytes - immunology; Up-Regulation - immunology
• ISSN: 2470-9468; 2470-9468
• DOI: 10.1126/sciimmunol.adh2334

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.