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

Abstract

<div>Abstract<p>In early pancreatic carcinogenesis, TGFβ acts as a tumor suppressor due to its growth-inhibitory effects in epithelial cells. However, in advanced disease, TGFβ appears to promote tumor progression. Therefore, to better understand the contributions of TGFβ signaling to pancreatic carcinogenesis, we generated mouse models of pancreatic cancer with either epithelial or systemic TGFBR deficiency. We found that epithelial suppression of TGFβ signals facilitated pancreatic tumorigenesis, whereas global loss of TGFβ signaling protected against tumor development via inhibition of tumor-associated fibrosis, stromal TGFβ1 production, and the resultant restoration of antitumor immune function. Similarly, TGFBR-deficient T cells resisted TGFβ-induced inactivation <i>ex vivo</i>, and adoptive transfer of TGFBR-deficient CD8<sup>+</sup> T cells led to enhanced infiltration and granzyme B–mediated destruction of developing tumors. These findings paralleled our observations in human patients, where TGFβ 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, TGFβ 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 TGFβ signals in the epithelium. <i>Cancer Res; 76(9); 2525–39. ©2016 AACR</i>.</p></div>

VPAC2 receptor signaling promotes pancreatic cancer cell growth and decreases the immunogenicity of the tumor microenvironment

“…Thus, our study presents a novel role for VPAC2 receptor on PDAC cells, promoting T cell exclusion and suppression in the TME in a paracrine fashion via TGFβ-1. TGFβ-1 is a pleiotropic cytokine and can have tumorsuppressing or promoting properties during PDAC progression (46)(47)(48)(49)(50). TGFb signaling on cancer cells can induce apoptosis during the premalignant stage, whereas it promotes EMT transition and metastasis of malignant cancer cells (50).…”

“…TGFb signaling on cancer cells can induce apoptosis during the premalignant stage, whereas it promotes EMT transition and metastasis of malignant cancer cells (50). However, the role of TGFb as a negative regulator in the adaptive or innate immune system is well established and thus reflect an important pathway to control the immunogenicity in the TME (47,48,51).…”