Sun Jin-Ping, Ge Quan-Xing, Ren Zheng, Sun Xin-Fang, Xie Shu-Ping
Department of Gastroenterology, Huaihe Hospital of Henan University, Kaifeng 475000, China,
Onco Targets Ther. 2018 Dec 28;12:309-317. doi: 10.2147/OTT.S185422. eCollection 2019.
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of cells derived from bone marrow, which has a significant ability in inhibition of immune cell response. In this study, the role of miR-6991-3p in regulating function of MDSCs was investigated.
MDSCs were isolated from different tissues of the control and hepatoma-bearing mice, and then expression of miR-6991-3p was detected with qPCR. Then, the miR-6991-3p mimic and inhibitor were respectively transfected into MDSCs, and behaviors of MDSCs were evaluated, including expansion, apoptosis, and production of inflammatory factors. Furthermore, we explored the underlying mechanism from which miR-6991-3p regulated MDSC functions.
Expression miR-6991-3p was markedly decreased in the MDSCs derived from spleen and further decreased in the MDSCs derived from the tumor tissue. MiR-6991-3p mimic transfection suppressed expansion and promoted apoptosis of MDSCs, accompanied by a significant decrease in the production of IL-6 and GM-CSF that are identified as stimulators in MDSC expansion. In contrast, miR-6991-3p inhibitor transfection displayed the opposite effect. miR-6991-3p bound with and negatively regulated expression of LGALS9, a newly identified immune checkpoint gene and activator of STAT3, suppressing production of multiple factors that were customarily used to characterize the activation of MDSCs. MiR-6991-3p-accommodated MDSCs displayed less suppression on T cells, while miR-6991-3p inhibitor enhanced the suppression of MDSCs on T cells.
MiR-6991-3p is identified as a novel suppressor in the expansion and activation of myeloid-derived suppressor cells, which may be regarded as a promising target for modulating the function of MDSCs.
髓源性抑制细胞（MDSCs）是一类源自骨髓的异质性细胞群，具有显著抑制免疫细胞反应的能力。本研究探讨了miR-6991-3p在调节MDSCs功能中的作用。
从对照小鼠和荷肝癌小鼠的不同组织中分离出MDSCs，然后用qPCR检测miR-6991-3p的表达。接着，将miR-6991-3p模拟物和抑制剂分别转染到MDSCs中，并评估MDSCs的行为，包括增殖、凋亡和炎症因子的产生。此外，我们还探究了miR-6991-3p调节MDSC功能的潜在机制。
脾脏来源的MDSCs中miR-6991-3p的表达明显降低，肿瘤组织来源的MDSCs中miR-6991-3p的表达进一步降低。miR-6991-3p模拟物转染抑制了MDSCs的增殖并促进其凋亡，同时伴随着IL-6和GM-CSF产生的显著减少，这两种因子被确定为MDSC增殖的刺激因子。相反，miR-6991-3p抑制剂转染则表现出相反的效果。miR-6991-3p与新鉴定的免疫检查点基因LGALS9结合并负向调节其表达，LGALS9是STAT3的激活剂，抑制了多种通常用于表征MDSCs激活的因子的产生。miR-6991-3p处理的MDSCs对T细胞的抑制作用较小，而miR-6991-3p抑制剂增强了MDSCs对T细胞的抑制作用。
miR-6991-3p被确定为髓源性抑制细胞增殖和激活的新型抑制剂，有望成为调节MDSCs功能的靶点。
