apCAFs Are Derived from Mesothelial Cells and Induce Regulatory T Cells

Cancer-associated fibroblasts (CAF) are a large component of pancreatic ductal adenocarcinoma (PDA) tumors, but despite their prevalence, characterization of the heterogenous CAF subtypes and their distinct functions remains necessary. Previous studies have identified the antigen-presenting CAF (apCAF) population that expresses major histocompatibility complex class II molecules (MHC II), but the origin as well as the function of this CAF population in PDA are still undetermined. Therefore, Huang and colleagues sought to answer these questions, demonstrating apCAFs are derived from mesothelial cells with these mesothelial cells expanding during tumor progression and also contributing to the increase observed in desmoplasia. Normal mesothelial cells trended only toward apCAF formation as opposed to inflammatory CAFs (iCAF) or myofibroblastic CAFs (myCAF), which are thought to be derived from resident fibroblasts. Gene signature changes promoted by wound and inflammatory responses from the tumor niche also supported apCAF formation. Functional studies demonstrated that despite apCAFs expressing MHC II molecules that present antigen to CD4⁺ T cells, they lack molecules for costimulation, which was found to in turn lead to efficient induction of regulatory T-cell (T_reg) formation. Further investigation into signaling pathways that drive the transition of mesothelial cells to apCAFs established that the NF-κB and TGFβ signaling pathways, specifically IL1 and TGFβ, contribute to this transition in addition to T_reg induction. As IL1 and TGFβ have also been shown to affect iCAF and myCAF formation, alternative strategies of blocking the mesothelial cell to apCAF transition were sought, with antibodies targeting the mesothelial cell marker mesothelin being used. These antibodies inhibited mesothelial gene downregulation as well as the upregulation of fibroblastic genes, suggesting their use in blocking this transition. Additionally, the induction of T_regs was also inhibited upon use of these antibodies. In summary, this study identified apCAFs as originating from mesothelial cells and detailed their contribution to immunosuppression by inducing T_reg formation. This suggests potential therapeutic strategies that can be used to improve the efficacy of immunotherapy in PDA.

Huang H, Wang Z, Zhang Y, Pradhan RN, Ganguly D, Chandra R, et al. Mesothelial cell-derived antigen-presenting cancer-associated fibroblasts induce expansion of regulatory T cells in pancreatic cancer. Cancer Cell 2022;40:656–73.e7.

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