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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor of the exocrine pancreas
The tumor cells induce the secretion of cytokines, such as IL-10 and tumor growth factor-β (TGF-β),5 which inhibit the maturation of DCs of TBM (DC) and their activity on CD8+ T cells, promoting tumor progression.[6]
Reg3g mice. (f) The expression levels of CD86, MHC-II, CCR7, and PD-L1 on DCs surfaces, and the phagocytic capacity of DCs were measured by fluorescence-activated cell sorting (FACS). (g) Levels of granzyme B, IL-10, interferon-γ (IFN-γ), and tumor growth factor-β (TGF-β) in the serum were detected by enzyme-linked immunosorbent assay (ELISA)
Summary
Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor of the exocrine pancreas. In mice, enhanced Reg3g expression exacerbated pancreatic cancer development in chronic pancreatitis through multiple mechanisms including suppression of T-lymphocyte proliferation and DCs function.[8] The RegIII family comprises three secretion molecules: Reg3α, Reg3β, and Reg3g Their expressions have been reported to be elevated in acute and chronic pancreatitis, inflammatory bowel disease, and liver injury.[9] Recently, increasing attention has been paid to their overexpression in human cancer cells as well. Reg3β is present in PDAC and colorectal carcinoma.[10,11] Reg3β exhibited antiapoptotic effects and induced tumor-related macrophage polarization via activation of STAT3 signaling This facilitated the production of tolerant CD4+ T cells, resulting in systemic tolerance and tumor immune escape.[12,13] We had reported[14] that Reg3g promoted β-cell regeneration and postponed the emergence of type 1 diabetes by inducing Treg differentiation and inhibiting DCs maturation in type 1 diabetes. The results of this study generally support the hypothesis, revealing a novel mechanism for pancreatic tumor promotion by Reg3g
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