Antigen-presenting cancer-associated fibroblasts in pancreatic ductal adenocarcinoma differentially regulate Treg phenotype and function via CXCL9 and CCL22 3293

Abstract Description The complex tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) includes stromal cancer-associated fibroblasts (CAFs) that influence treatment resistance. Recent studies have shown that CAFs are heterogeneous in origin, gene expression, and function. One such population, antigen-presenting CAFs (apCAFs), is defined by MHC-II and can induce both CD4+ T cell activation and regulatory T cell (Treg) differentiation. Using two clones differing in sensitivity to immune checkpoint blockade (ICB) derived from the KPC murine PDAC model, we found that immunosensitive (sKPC) tumors were characterized by higher immune cell and apCAF infiltration than resistant (rKPC) tumors. Imaging mass cytometry shows spatial proximity of apCAFs and CD4+ T cells implicating interaction within the TME. Notably, apCAF-depleted sKPC tumor-bearing mice are less sensitive to ICB. apCAFs activate and induce Treg differentiation of tumor CD4+ T cells, but not production of suppressive cytokines in sKPC tumors. scRNAseq revealed greater induction of Th1-like Treg differentiation by sKPC apCAFs and differential chemokine signaling based on apCAF TME of origin, such that sKPC apCAFs induce Th1-like Tregs via CXCL9 and rKPC apCAFs induce classical Tregs via CCL22. Together these data implicate apCAFs as important mediators of the antitumor response. Modulating apCAF number or function may provide a solution to the unmet need of improved treatments for PDAC patients. Funding Sources Supported by the Conquer Cancer, the ASCO Foundation, and the Three Opinions Foundation Women Who Conquer Cancer Young Investigator Award; the Lustgarten Foundation. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)