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
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Animals
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B7-H1 Antigen / genetics
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B7-H1 Antigen / immunology
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / pathology
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Carcinogenesis / genetics
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Carcinogenesis / immunology
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Carcinogenesis / pathology
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Caspase 3 / genetics
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Caspase 3 / immunology
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Cell Movement
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Dendritic Cells / immunology
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Dendritic Cells / pathology
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ErbB Receptors / genetics
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ErbB Receptors / immunology
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Gene Expression Regulation, Neoplastic / immunology*
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Heme Oxygenase-1 / genetics
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Heme Oxygenase-1 / immunology
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Histocompatibility Antigens Class I / genetics
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Histocompatibility Antigens Class I / immunology
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Immunocompromised Host*
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Janus Kinase 2 / genetics*
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Janus Kinase 2 / immunology
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Ki-67 Antigen / genetics
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Ki-67 Antigen / immunology
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Male
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Membrane Proteins / genetics
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Membrane Proteins / immunology
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Pancreatic Neoplasms / genetics*
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Pancreatic Neoplasms / immunology
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Pancreatic Neoplasms / pathology
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Pancreatitis-Associated Proteins / deficiency
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Pancreatitis-Associated Proteins / genetics*
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Pancreatitis-Associated Proteins / immunology
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Programmed Cell Death 1 Receptor / genetics
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Programmed Cell Death 1 Receptor / immunology
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STAT3 Transcription Factor / genetics*
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STAT3 Transcription Factor / immunology
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Signal Transduction
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T-Lymphocytes, Regulatory / immunology
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T-Lymphocytes, Regulatory / pathology
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Tumor Cells, Cultured
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Tumor Microenvironment / genetics
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Tumor Microenvironment / immunology*
Substances
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B7-H1 Antigen
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Cd274 protein, mouse
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Histocompatibility Antigens Class I
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Ki-67 Antigen
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Membrane Proteins
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Pancreatitis-Associated Proteins
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Pdcd1 protein, mouse
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Programmed Cell Death 1 Receptor
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Reg3g protein, mouse
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STAT3 Transcription Factor
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Stat3 protein, mouse
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Heme Oxygenase-1
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Hmox1 protein, mouse
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EGFR protein, mouse
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ErbB Receptors
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Jak2 protein, mouse
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Janus Kinase 2
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Casp3 protein, mouse
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Caspase 3