Acceleration of pancreatic tumorigenesis under immunosuppressive microenvironment induced by Reg3g overexpression

作者：Liu, Xiulan; Zhou, Zhongshi; Cheng, Qi; Wang, Hongjie; Cao, Hui; Xu, Qianqian; Tuo, Yali; Jiang, Li; Zou, You; Ren, Hongyu^*; Xiang, Ming^*

来源：Cell Death & Disease, 2017, 8(9): e3033.

DOI：10.1038/cddis.2017.424

• HEME OXYGENASE-1 EXPRESSION
• REGULATORY T-CELLS
• TUMOR-GROWTH
• IMMUNE TOLERANCE
• DENDRITIC CELLS
• MURINE MODEL
• CANCER CELLS
• CARCINOMA
• PATHWAY
• DIFFERENTIATION

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.

• 出版日期2017-9
• 单位华中科技大学