TGFβ signaling in the pancreatic tumor microenvironment promotes fibrosis and immune evasion to facilitate tumorigenesis

Daniel R. Principe, Brian DeCant, Emman Mascariñas, Elizabeth A. Wayne, Andrew M. Diaz, Naomi Akagi, Rosa Hwang, Boris Pasche, David W. Dawson, Deyu Fang, David J. Bentrem, Hidayatullah G. Munshi, Barbara Jung, Paul J. Grippo*

*Corresponding author for this work

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

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 ex vivo, and adoptive transfer 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 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.

Original languageEnglish (US)
Pages (from-to)2525-2539
Number of pages15
JournalCancer Research
Volume76
Issue number9
DOIs
StatePublished - May 1 2016

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Principe, D. R., DeCant, B., Mascariñas, E., Wayne, E. A., Diaz, A. M., Akagi, N., Hwang, R., Pasche, B., Dawson, D. W., Fang, D., Bentrem, D. J., Munshi, H. G., Jung, B., & Grippo, P. J. (2016). TGFβ signaling in the pancreatic tumor microenvironment promotes fibrosis and immune evasion to facilitate tumorigenesis. Cancer Research, 76(9), 2525-2539. https://doi.org/10.1158/0008-5472.CAN-15-1293