TGFβ Signaling in the Pancreatic Tumor Microenvironment Promotes Fibrosis and Immune Evasion to Facilitate Tumorigenesis

In early pancreatic carcinogenesis, TGF beta acts as a tumor suppressor due to its growth-inhibitory effects in epithelial cells. However, in advanced disease, TGF beta appears to promote tumor progression. Therefore, to better understand the contributions of TGF beta signaling to pancreatic carcinogenesis, we generated mouse models of pancreatic cancer with either epithelial or systemic TGFBR deficiency. We found that epithelial suppression of TGF beta signals facilitated pancreatic tumorigenesis, whereas global loss of TGF beta signaling protected against tumor development via inhibition of tumor-associated fibrosis, stromal TGF beta 1 production, and the resultant restoration of antitumor immune function. Similarly, TGFBR-deficient T cells resisted TGF beta-induced inactivation ex vivo, and adoptive trans-fer of TGFBR-deficient CD8(+)T cells led to enhanced infiltration and granzyme B-mediated destruction of developing tumors. These findings paralleled our observations in human patients, where TGF beta expression correlated with increased fibrosis and associated negatively with expression of granzyme B. Collectively, our findings suggest that, despite opposing the proliferation of some epithelial cells, TGF beta may promote pancreatic cancer development by affecting stromal and hematopoietic cell function. Therefore, the use of TGFBR inhibition to target components of the tumor microenvironment warrants consideration as a potential therapy for pancreatic cancer, particularly in patients who have already lost tumor-suppressive TGF beta signals in the epithelium. (C) 2016 AACR.