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

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...

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Bibliographic Details
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
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Summary: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.
ISSN:2470-9468
2470-9468
DOI:10.1126/sciimmunol.adh2334