Mesothelial cell-derived antigen-presenting cancer-associated fibroblasts induce expansion of regulatory T cells in pancreatic cancer

Summary Multiple recent single cell RNA sequencing (scRNA-seq) studies have identified a unique cancer-associated fibroblast (CAF) population in pancreatic ductal adenocarcinoma (PDA) called antigen-presenting CAFs (apCAFs). apCAFs are characterized by the expression of MHC II molecules, suggesting a function in regulating tumor immunity. Here we integrated multiple scRNA-seq studies and found that apCAFs are derived from mesothelial cells. Our data show that during PDA progression, mesothelial cells form apCAFs by down-regulating mesothelial features and gaining the fibroblastic features, a process induced by IL-1 and TGFβ. Moreover, apCAFs directly ligate and induce naïve CD4 + T cells into regulatory T cells (Tregs) in an antigen-specific manner. Our study elucidates an important but neglected cell type in the regulation of PDA immunity and may lead to targeted therapeutic strategies that can overcome immune evasion in PDA.