Antigen-presenting cancer-associated fibroblasts in murine pancreatic tumors differentially control regulatory T cell phenotype and function via CXCL9 and CCL22

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a complex tumor microenvironment (TME) including stromal cells that influence resistance to therapy. Recent studies have revealed that stromal cancer-associated fibroblasts (CAFs) are heterogeneous in origin, gene expression, and function. Antigen-presenting CAFs (apCAFs), are defined by major histocompatibility complex (MHC)-II expression and can activate effector CD4+ T cells that have the potential to contribute to the anti-cancer immune response, but also can induce regulatory T cell (Treg) differentiation. Whether apCAFs promote or restrain the antitumor response remains uncertain. Using tumor clones of the KPC murine PDAC model differing in sensitivity to immune checkpoint blockade (ICB), we found that immunosensitive (sKPC) tumors were characterized by higher immune cell and apCAF infiltration than resistant (rKPC) tumors. IMC analysis showed proximity of apCAFs and CD4+ T cells in both sKPC and rKPC tumors implicating interaction within the TME. apCAF-depleted sKPC tumor-bearing mice had diminished sensitivity to ICB. apCAFs from both sKPC and rKPC tumors activated tumor-infiltrating CD4+ T cells and induced Treg differentiation. However, transcriptomic analysis showed that Tregs induced by apCAFs were overexpressed for immunosuppressive genes in rKPCs relative to sKPCs, and that this is associated with differential chemokine signaling from apCAFs depending on tumor origin. Together these data implicate apCAFs as important mediators of the antitumor immune response, modulation of which could facilitate the development of more effective anti-tumor immune based approaches for PDAC patients.