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

Recent studies have identified a unique cancer-associated fibroblast (CAF) population called antigen-presenting CAFs (apCAFs). apCAFs are characterized by the expression of MHC II molecules, suggesting a function in regulating tumor immunity. Here by integrating multiple single cell RNA sequencing studies and performing robust lineage tracing assays, we found that apCAFs are derived from mesothelial cells. During pancreatic cancer progression, mesothelial cells form apCAFs by down-regulating mesothelial features and gaining fibroblastic features, a process induced by IL-1 and TGFβ. apCAFs directly ligate and induce naïve CD4+ T cells into regulatory T cells (Tregs) in an antigen-specific manner. Moreover, targeting the mesothelial cell marker mesothelin by a monoclonal antibody can effectively inhibit mesothelial cell to apCAF transition and the Treg formation induced by apCAFs. Taken together, our study elucidates an important but neglected cell type that regulates tumor immunity and may lead to targeted therapies that can overcome immune evasion in cancer. Examination of parental PanMeso cells and sorted PanMeso cells from tumors