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 termed antigen-presenting CAFs (apCAFs), characterized by the expression of major histocompatibility complex class 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 find that apCAFs are derived from mesothelial cells. During pancreatic cancer progression, mesothelial cells form apCAFs by downregulating mesothelial features and gaining fibroblastic features, a process induced by interleukin-1 and transforming growth factor β. apCAFs directly ligate and induce naive CD4+ T cells into regulatory T cells (Tregs) in an antigen-specific manner. Moreover, treatment with an antibody targeting the mesothelial cell marker mesothelin can effectively inhibit mesothelial cell to apCAF transition and Treg formation induced by apCAFs. Taken together, our study elucidates how mesothelial cells may contribute to immune evasion in pancreatic cancer and provides insight on strategies to enhance cancer immune therapy. [Display omitted] •Mesothelial cells are the cell of origin of apCAFs•apCAFs induce Treg formation in pancreatic cancer•Anti-mesothelin antibody can inhibit mesothelial cell-apCAF transition Huang et al. discover that antigen-presenting cancer-associated fibroblasts (apCAFs) are derived from mesothelial cells in pancreatic cancer. apCAFs directly ligate and induce naive CD4+ T cells into regulatory T cells in an antigen-specific manner. They also demonstrate that mesothelial cell-apCAF transition can be inhibited by an anti-mesothelin monoclonal antibody.