PLA2G2A+ cancer-associated fibroblasts mediate pancreatic cancer immune escape via impeding antitumor immune response of CD8+ cytotoxic T cells

  • Impact factors: 9.756
  • Publication: CANCER LETTERS
  • Author:Weiyu Ge, Ming Yue, Ruirong Lin, Tianhao Zhou, Haiyan Xu, Tiebo Mao, Shumin Li, Xiuqi Wu, Xiaofei Zhang, Yongchao Wang, Jingyu Ma, Yanling Wang, Shengbai Xue, Daiyuan Shentu, Jiujie Cui, Liwei Wang
  • DOI citation-doi:10.1016/j.canlet.2023.216095
  • Date:2023-02-14

Our previous research defined a novel metabolic cancer associated fibroblasts subset (meCAFs) enriched in loose-type pancreatic ductal adenocarcinoma (PDAC) and related toCD8 + 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 withclinical 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-κB 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.

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