Tumour-Derived Reg3A Educates Dendritic Cells to Promote Pancreatic Cancer Progression
Jie Guo 1,2,3, Mengfan Liao 1,2,3, Xianmin Hu 1,2,3, and Jun Wang 1,2,*
1Hubei Province Key Laboratory of Occupational Hazard Identification and Control, Wuhan University of Science and Technology, Wuhan 430065, China, 2New Medicine Innovation and Development Institute, Department of Pharmacy, College of Medicine, Wuhan University of Science and Technology, Wuhan 430065, China, 3These authors contributed equally to this work.
Received May 27, 2021; Revised July 9, 2021; Accepted July 22, 2021.; Published online September 10, 2021.
© Korean Society for Molecular and Cellular Biology. All rights reserved.

ABSTRACT
As a pancreatic inflammatory marker, regenerating islet-derived protein 3A (Reg3A) plays a key role in inflammation-associated pancreatic carcinogenesis by promoting cell proliferation, inhibiting apoptosis, and regulating cancer cell migration and invasion. This study aimed to reveal a novel immuno-regulatory mechanism by which Reg3A modulates tumour-promoting responses during pancreatic cancer (PC) progression. In an in vitro Transwell system that allowed the direct co-culture of human peripheral blood-derived dendritic cells (DCs) and Reg3A-overexpressing/ silenced human PC cells, PC cell-derived Reg3A was found to downregulate CD80, CD83 and CD86 expression on educated DCs, increase DC endocytic function, inhibit DC-induced T lymphocyte proliferation, reduce IL-12p70 production, and enhance IL-23 production by DCs. The positive effect of tumour-derived Reg3A-educated human DCs on PC progression was demonstrated in vivo by intraperitoneally transferring them into PC-implanted severe combined immunodeficiency (SCID) mice reconstituted with human T cells. A Reg3A-JAK2/STAT3 positive feedback loop was identified in DCs educated with Reg3A. In conclusion, as a tumour-derived factor, Reg3A acted to block the differentiation and maturation of the most important antigen-presenting cells, DCs, causing them to limit their potential anti-tumour responses, thus facilitating PC escape and progression.
Keywords: dendritic cells, immunosuppressive tumour microenvironment, inflammation-linked pancreatic carcinogenesis, pancreatic cancer, regenerating islet-derived protein 3A
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31 August 2021 Volume 44,
Number 8, pp. 541~625
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