PLA2G2A+cancer-associated fibroblasts mediate pancreatic cancer immune escape via impeding antitumor immune response of CD8+cytotoxic T cells
PLA2G2A+cancer-associated fibroblasts mediate pancreatic cancer immune escape via impeding antitumor immune response of CD8+cytotoxic T cells
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DOI：
10.1016/j.canlet.2023.216095
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发表时间：
2023-02-24
期刊：
影响因子：
9.7
通讯作者：
Wang, Liwei
中科院分区：
文献类型：
--
作者：
Ge, Weiyu;Yue, Ming;Wang, Liwei
我们之前的研究定义了一种新型代谢癌相关成纤维细胞亚群 (meCAF)，其富含松散型胰腺导管腺癌 (PDAC)，且与 CD8+ T 细胞积累相关。一致地，meCAF 的丰度与 PDAC 患者的不良预后相关，但与更好的免疫治疗反应相关。然而，meCAF 的代谢特征及其与 CD8+ T 细胞的串扰仍有待阐明。在这项研究中，我们将 PLA2G2A 确定为 meCAF 的标记。特别是，PLA2G2A+ meCAF 的丰度与总 CD8+ T 细胞的积累呈正相关，与 PDAC 患者的临床结果和瘤内 CD8+ T 细胞的浸润呈负相关。我们证明 PLA2G2A+ meCAF 显着减弱肿瘤浸润 CD8+ T 细胞的抗肿瘤能力，并促进 PDAC 中的肿瘤免疫逃逸。从机制上讲，PLA2G2A 作为关键的可溶性介质通过 MAPK/Erk 和 NF-kappa B 信号通路调节 CD8+ T 细胞的功能。总之，我们的研究确定了 PLA2G2A+ meCAF 通过阻碍 CD8+ T 细胞的抗肿瘤免疫功能来促进肿瘤免疫逃逸的未被认识的作用，并强烈建议 PLA2G2A 作为 PDAC 免疫治疗的有前景的生物标志物和治疗靶点。
Our previous research defined a novel metabolic cancer associated fibroblasts subset (meCAFs) enriched in loosetype pancreatic ductal adenocarcinoma (PDAC) and related to CD8+ T cells accumulation. Consistently, the abundance of meCAFs was associated with poor prognosis but better immunotherapy responses in PDAC patients. However, the metabolic characteristic of meCAFs and its cross-talk with CD8+ T cells remain to be elucidated. In this study, we identified PLA2G2A as a marker of meCAFs. In particular, the abundance of PLA2G2A+ meCAFs was positively related to the accumulation of total CD8+ T cells and negatively correlated with clinical outcomes of PDAC patients and infiltration of intratumoral CD8+ T cells. We demonstrated that PLA2G2A+ meCAFs substantially attenuated the antitumor ability of tumor infiltrating CD8+ T cells and facilitated tumor immune escape in PDAC. Mechanistically, PLA2G2A regulated the function of CD8+ T cells as a pivotal soluble mediator via MAPK/Erk and NF-kappa B signaling pathways. In conclusion, our study identified the unrecognized role of PLA2G2A+ meCAFs in promoting tumor immune escape by impeding the antitumor immune function of CD8+ T cells, and strongly suggested PLA2G2A as a promising biomarker and therapeutic target for immunotherapy in PDAC.