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

Background: Our previous research identified a novel metabolic cancer associated fibroblasts subset (meCAFs) with a high glycolysis level correlated with poor prognosis and CD8+ T cells accumulation. Consistently, meCAFs were associated with better immunotherapy responses in pancreatic ductal adenocarcinoma (PDAC). However, the molecular characteristic and functional association of meCAFs and CD8+ T cells remain to be elucidated. Methods: We performed ELISA, multicolor flow cytometry, opal multi-colour multiplex analysis, cytotoxicity assay and cytokine release assay to reveal the association with meCAFs and the function of CD8+ T cells in PDAC. Findings: 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 related to clinical outcomes of PDAC patients and infiltration of CD8+ T cells in proximity to cancer 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. Interpretation: 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. Funding Information: NNSF (82272906; 82171824; 81874048; 82103101); SMCHFPG 2018ZHYL0223; SMEDCGFCMGS (20161312); STIPSTCSM (21JC1404300); SHDC (No. SHDC2020CR1035B); IGPSHC (2019CXJQ03);SSP(20YF1424600; 20YF1446400); NKR&DP (2019YFC1315900); CSCOCORF (Y-2019AZZD-0513); SHSMU (SHSMU-ZDCX20210802). Declaration of Interests: The authors declare no potential conflicts of interest. Ethics Approval Statement: All human tissues of PDAC experiments were reviewed and approved by the Ethics Committee of Renji Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine (Shanghai, China) under informed consent from all patients. The ethical approval code is KY [2019]035. Additionally, all animal experiments were approved by the Animal Ethics Committee of Shanghai Renji Hospital, Shanghai Jiao Tong University School of Medicine (Shanghai, China). The ethical approval code is RTMS-20220601 (03).