Regulatory T cell depletion alters the tumor microenvironment and accelerates pancreatic carcinogenesis.

Regulatory T cells (Tregs) are abundant ion human and mouse pancreatic cancer. To understand the contribution to the immunosuppressive microenvironment, we depleted Tregs in a mouse model of pancreatic cancer. Contrary to our expectations, Treg depletion failed to relieve immunosuppression, and led to accelerated tumor progression. We show that Tregs are a key source of TGFβ ligands and, accordingly, their depletion reprogramed the fibroblast population, with loss of tumor-restraining, smooth muscle actin-expressing fibroblasts (myCAFs). Conversely, we observed an increase in chemokines Ccl3, Ccl6, and Ccl8 leading to increased myeloid cell recruitment, restoration of immune suppression and promotion of carcinogenesis, an effect that was inhibited by blockade of the common CCL3/6/8 receptor CCR1. Further, Treg depletion unleashed pathological CD4+ Tcell responses. Our data points to new mechanisms regulating fibroblast differentiation in pancreatic cancer and supports the notion that fibroblasts are a heterogeneous population with different and opposing functions in pancreatic carcinogenesis.