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.

中文翻译：

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癌症中 PLA2G10 上调会损害 T 细胞浸润，从而抑制免疫力

在自发诱导免疫和治疗性免疫治疗期间，即使存在功能性 T 细胞募集趋化因子系统，人类癌症组织中也常常不存在 T 细胞，这表明存在损害浸润的 T 细胞排除机制。使用全基因组体外筛选平台，我们确定了磷脂酶 A2 10 族 (PLA2G10) 蛋白在 T 细胞排斥中的作用。 PLA2G10 上调在人类癌症中广泛存在，并且与肿瘤组织中 T 细胞浸润不良有关。 PLA2G10 在免疫原性小鼠肿瘤中过度表达，排除了 T 细胞的浸润，导致对抗 PD-1 免疫疗法的抵抗。 PLA2G10 可以将磷脂水解成小的脂质代谢物，从而抑制趋化因子介导的 T 细胞迁移性。 PLA2G10 酶活性的消除增强了 T 细胞浸润，并使 PLA2G10 过表达的肿瘤对免疫疗法敏感。我们的研究暗示了 PLA2G10 在 T 细胞排除肿瘤中的作用，并提出了癌症免疫治疗的潜在靶点。