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. 2024 Apr 26;9(94):eadh2334.
doi: 10.1126/sciimmunol.adh2334. Epub 2024 Apr 26.

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

Tianxiang Zhang  1 , Weiwei Yu  1 , Xiaoxiao Cheng  1 , Jacky Yeung  1   2 , Viviana Ahumada  3 , Paul C Norris  4 , Mackenzie J Pearson  4 , Xuan Yang  1 , Willemijn van Deursen  1 , Christina Halcovich  1 , Ala Nassar  1 , Mathew D Vesely  1   5 , Yu Zhang  1 , Jianping Zhang  1 , Lan Ji  1 , Dallas B Flies  6 , Linda Liu  6 , Solomon Langermann  6 , William J LaRochelle  7 , Rachel Humphrey  7 , Dejian Zhao  8 , Qiuyu Zhang  1 , Jindong Zhang  1 , Runxia Gu  1 , Kurt A Schalper  3 , Miguel F Sanmamed  1   9 , Lieping Chen  1
Affiliations

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

Tianxiang Zhang et al. Sci Immunol. .

Abstract

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.

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