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

• Published in: Cancer letters 2023-04, Vol.558, p.216095-216095, Article 216095
• Main Authors: Ge, Weiyu, Yue, Ming, Lin, Ruirong, Zhou, Tianhao, Xu, Haiyan, Wang, Yu, Mao, Tiebo, Li, Shumin, Wu, Xiuqi, Zhang, Xiaofei, Wang, Yongchao, Ma, Jingyu, Wang, Yanling, Xue, Shengbai, Shentu, Daiyuan, Cui, Jiujie, Wang, Liwei
• Format: Article
• Language: English
• Subjects: Cancer-Associated Fibroblasts - metabolism; Carcinoma, Pancreatic Ductal - pathology; CD8+ cytotoxic T cells; CD8-Positive T-Lymphocytes; Group II Phospholipases A2; Humans; Immunity; Metabolic cancer-associated fibroblasts; Pancreatic ductal adenocarcinoma; Pancreatic Neoplasms; Pancreatic Neoplasms - pathology; PLA2G2A; T-Lymphocytes, Cytotoxic - metabolism; Tumor Microenvironment
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2023.216095

Our previous research defined a novel metabolic cancer associated fibroblasts subset (meCAFs) enriched in loose-type 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-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. •PLA2G2A served as a biomarker of meCAFs by comparing the similarity between PLA2G2A+ CAFs and meCAFs.•The conditioned media derived from cultured PLA2G2A+ meCAFs or PLA2G2A protein attenuated antitumor activity of CD8+ T cells.•PLA2G2A regulated the function of CD8+ T cells via MAPK/Erk and NF-κB signaling pathways.