title: TGFβ Signaling in the Pancreatic Tumor Microenvironment Promotes Fibrosis and Immune Evasion to Facilitate Tumorigenesis.
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. Cancer Res; 76(9); 2525-39. ©2016 AACR.
authors.affiliation: University of Illinois College of Medicine, Urbana-Champaign, Illinois.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Principe
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Brian
authors.initials: B
authors.lastname: DeCant
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Emman
authors.initials: E
authors.lastname: Mascariñas
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, Illinois. Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Wayne
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Diaz
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Naomi
authors.initials: N
authors.lastname: Akagi
authors.affiliation: Department of Surgical Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Rosa
authors.initials: R
authors.lastname: Hwang
authors.affiliation: Comprehensive Cancer Center of Wake Forest University, Winston-Salem, North Carolina.
authors.forename: Boris
authors.initials: B
authors.lastname: Pasche
authors.affiliation: Department of Pathology and Laboratory Medicine, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, California.
authors.forename: David W
authors.initials: DW
authors.lastname: Dawson
authors.affiliation: Department of Pathology, Northwestern University, Chicago, Illinois.
authors.forename: Deyu
authors.initials: D
authors.lastname: Fang
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: David J
authors.initials: DJ
authors.lastname: Bentrem
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Department of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Hidayatullah G
authors.initials: HG
authors.lastname: Munshi
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, Illinois. pgrippo@uic.edu bjung@uic.edu.
authors.forename: Barbara
authors.initials: B
authors.lastname: Jung
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, Illinois. pgrippo@uic.edu bjung@uic.edu.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Grippo
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015153:Blotting, Western; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008817:Mice, Mutant Strains; D010190:Pancreatic Neoplasms / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D019139:Tumor Escape / Q000502:physiology*; D059016:Tumor Microenvironment / Q000502:physiology*
chemical_list: D016212:Transforming Growth Factor beta