Acceleration of pancreatic tumorigenesis under immunosuppressive microenvironment induced by Reg3g overexpression

Cell Death Dis. 2017 Sep 7;8(9):e3033. doi: 10.1038/cddis.2017.424.

Abstract

Reg3g is a potential risk for pancreatic ductal adenocarcinoma (PDAC). We previously demonstrated that Reg3g promoted pancreatic carcinogenesis via a STAT3 signaling pathway in a murine model of chronic pancreatitis. Whether the immune response is involved in tumorigenesis induced by Reg3g remains unknown. In this study, Reg3g-regulated tumor immunity was evaluated in tumor-implanted murine models, immune cells, and tumor microenvironment. In mice that had been orthotopically or ectopically implanted with Panc02 cells, Reg3g overexpression increased EGFR and Ki67, diminished MHC-I and caspase-3 expression, and accelerated growth of tumors. By interacting with PD-1/PD-L1, Reg3g also promoted differentiation of Tregs and recruitment of MDSC, retarded maturation of DCs and inactivation of CD8+ T cells, and suppressed cross-priming of CD8+ T-cell responses by DCs in tumor-bearing mice. Knockdown of Reg3g delayed tumor development in normal mice, but not in CD8+ T-cell-deficient mice. In vitro, Reg3g upregulated EGFR in DCs, activated heme oxygenase-1 (Hmox1) involved JAK2/STAT3 signaling, raised levels of Th2 cytokines in and suppressed maturation of DCs, and enhanced tumor cell proliferation. These results reveal a novel role of Reg3g as an immunosuppressive promoter that weakens tumor-specific antigenicity and suppresses antitumor effects of CD8+ T cells in a murine model of pancreatic cancer. Reg3g produces these effects by activating the JAK2/STAT3 signaling pathway in DCs, triggering the generation of an immunosuppressive tumor microenvironment.

MeSH terms

  • Animals
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / pathology
  • Carcinogenesis / genetics
  • Carcinogenesis / immunology
  • Carcinogenesis / pathology
  • Caspase 3 / genetics
  • Caspase 3 / immunology
  • Cell Movement
  • Dendritic Cells / immunology
  • Dendritic Cells / pathology
  • ErbB Receptors / genetics
  • ErbB Receptors / immunology
  • Gene Expression Regulation, Neoplastic / immunology*
  • Heme Oxygenase-1 / genetics
  • Heme Oxygenase-1 / immunology
  • Histocompatibility Antigens Class I / genetics
  • Histocompatibility Antigens Class I / immunology
  • Immunocompromised Host*
  • Janus Kinase 2 / genetics*
  • Janus Kinase 2 / immunology
  • Ki-67 Antigen / genetics
  • Ki-67 Antigen / immunology
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / immunology
  • Pancreatic Neoplasms / pathology
  • Pancreatitis-Associated Proteins / deficiency
  • Pancreatitis-Associated Proteins / genetics*
  • Pancreatitis-Associated Proteins / immunology
  • Programmed Cell Death 1 Receptor / genetics
  • Programmed Cell Death 1 Receptor / immunology
  • STAT3 Transcription Factor / genetics*
  • STAT3 Transcription Factor / immunology
  • Signal Transduction
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / pathology
  • Tumor Cells, Cultured
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / immunology*

Substances

  • B7-H1 Antigen
  • Cd274 protein, mouse
  • Histocompatibility Antigens Class I
  • Ki-67 Antigen
  • Membrane Proteins
  • Pancreatitis-Associated Proteins
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Reg3g protein, mouse
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Heme Oxygenase-1
  • Hmox1 protein, mouse
  • EGFR protein, mouse
  • ErbB Receptors
  • Jak2 protein, mouse
  • Janus Kinase 2
  • Casp3 protein, mouse
  • Caspase 3

Supplementary concepts

  • Pancreatic Carcinoma