title: Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is associated with marked fibrosis and stromal myofibroblasts, but their functional contribution remains unknown. Transgenic mice with the ability to delete αSMA(+) myofibroblasts in pancreatic cancer were generated. Depletion starting at either noninvasive precursor (pancreatic intraepithelial neoplasia) or the PDAC stage led to invasive, undifferentiated tumors with enhanced hypoxia, epithelial-to-mesenchymal transition, and cancer stem cells, with diminished animal survival. In PDAC patients, fewer myofibroblasts in their tumors also correlated with reduced survival. Suppressed immune surveillance with increased CD4(+)Foxp3(+) Tregs was observed in myofibroblast-depleted mouse tumors. Although myofibroblast-depleted tumors did not respond to gemcitabine, anti-CTLA4 immunotherapy reversed disease acceleration and prolonged animal survival. This study underscores the need for caution in targeting carcinoma-associated fibroblasts in PDAC.
authors.affiliation: Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Berna C
authors.initials: BC
authors.lastname: Özdemir
authors.affiliation: Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
authors.forename: Tsvetelina
authors.initials: T
authors.lastname: Pentcheva-Hoang
authors.affiliation: Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
authors.forename: Julienne L
authors.initials: JL
authors.lastname: Carstens
authors.affiliation: Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
authors.forename: Chia-Chin
authors.initials: CC
authors.lastname: Wu
authors.affiliation: Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
authors.forename: Tyler R
authors.initials: TR
authors.lastname: Simpson
authors.affiliation: Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Hanane
authors.initials: H
authors.lastname: Laklai
authors.affiliation: Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Hikaru
authors.initials: H
authors.lastname: Sugimoto
authors.affiliation: Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Christoph
authors.initials: C
authors.lastname: Kahlert
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Novitskiy
authors.affiliation: Department of Medical Oncology, Johns Hopkins Hospital, Baltimore, MD 21287, USA.
authors.forename: Ana
authors.initials: A
authors.lastname: De Jesus-Acosta
authors.affiliation: Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
authors.forename: Padmanee
authors.initials: P
authors.lastname: Sharma
authors.affiliation: Department of Radiology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Pedram
authors.initials: P
authors.lastname: Heidari
authors.affiliation: Department of Radiology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Umar
authors.initials: U
authors.lastname: Mahmood
authors.affiliation: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
authors.forename: Lynda
authors.initials: L
authors.lastname: Chin
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Harold L
authors.initials: HL
authors.lastname: Moses
authors.affiliation: Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Valerie M
authors.initials: VM
authors.lastname: Weaver
authors.affiliation: Departments of Pathology and Translational Molecular Pathology, Ahmad Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.affiliation: Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Allison
authors.affiliation: Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Valerie S
authors.initials: VS
authors.lastname: LeBleu
authors.affiliation: Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA. Electronic address: rkalluri@mdanderson.org.
authors.forename: Raghu
authors.initials: R
authors.lastname: Kalluri
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000276:immunology / Q000473:pathology*; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000276:immunology / Q000473:pathology*; D005355:Fibrosis / Q000276:immunology / Q000473:pathology*; D006801:Humans; D007108:Immune Tolerance; D051379:Mice; D008822:Mice, Transgenic; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000473:pathology*; D016019:Survival Analysis