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.
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| http://dx.doi.org/10.1016/j.canlet.2023.216095 | DOI Listing |
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