Hubei Province Key Laboratory of Occupational Hazard Identification and Control, Wuhan University of Science and Technology, Wuhan 430065, China.
New Medicine Innovation and Development Institute, Department of Pharmacy, College of Medicine, Wuhan University of Science and Technology, Wuhan 430065, China.
Mol Cells. 2021 Sep 30;44(9):647-657. doi: 10.14348/molcells.2021.0145.
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 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 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.
作为一种胰腺炎症标志物，再生胰岛衍生蛋白 3A（Reg3A）通过促进细胞增殖、抑制细胞凋亡以及调节癌细胞迁移和侵袭，在炎症相关的胰腺癌发生中发挥关键作用。本研究旨在揭示 Reg3A 调节胰腺癌（PC）进展过程中促瘤反应的一种新的免疫调节机制。在允许人外周血衍生树突状细胞（DC）与 Reg3A 过表达/沉默的人 PC 细胞直接共培养的 Transwell 系统中，发现 PC 细胞来源的 Reg3A 下调了成熟 DC 表面的 CD80、CD83 和 CD86 的表达，增加了 DC 的内吞作用，抑制了 DC 诱导的 T 淋巴细胞增殖，减少了 IL-12p70 的产生，并增强了 DC 产生的 IL-23。通过将这些经肿瘤衍生的 Reg3A 诱导的人 DC 细胞经腹腔内转移到用人 T 细胞重建的 PC 植入的严重联合免疫缺陷（SCID）小鼠中，证实了肿瘤来源的 Reg3A 诱导的人 DC 对 PC 进展的正向作用。在接受 Reg3A 诱导的 DC 中鉴定出了 Reg3A-JAK2/STAT3 正反馈回路。总之，作为一种肿瘤源性因子，Reg3A 阻断了最重要的抗原呈递细胞 DC 的分化和成熟，使其限制了潜在的抗肿瘤反应，从而促进了 PC 的逃逸和进展。
