Wen Jiexia, Xuan Bin, Gao Yunhuan, Liu Yang, Wang Liwei, He Li, Meng Xiangcai, Zhou Tao, Tao Yang, Guo Kening, Wang Yimin
Department of Central Laboratory, The First Hospital of Qinhuangdao, Hebei Medical University, Qinhuangdao, Hebei, China.
Department of General Surgery, The First Hospital of Qinhuangdao, Hebei Medical University, Qinhuangdao, Hebei, China.
Cell Immunol. 2023 Mar;385:104676. doi: 10.1016/j.cellimm.2023.104676. Epub 2023 Feb 3.
Myeloid-derived suppressor cells (MDSCs) are a population of immature bone marrow cells that accumulate in large numbers in the spleen, peripheral blood, bone marrow, lymph nodes, and local and metastatic foci of tumors. C/EBP homologous protein (CHOP) and CCAAT/enhancer binding protein β (C/EBPβ) play key roles in regulating the immunosuppressive function and differentiation of MDSCs. Our study revealed that the long noncoding RNA Lnc-17Rik was able to promote immunosuppression in tumors by facilitating the activation and expression of key genes involved in MDSC differentiation. Lnc-17Rik was shown to directly interact with CHOP and C/EBPβ LIP to facilitate their dissociation from the transcriptional repressor complex involving C/EBP LAP/LIP/CHOP. Moreover, Lnc-17Rik increased the association of WD repeat-containing protein 5 (WDR5) with C/EBP LAP, promoting H3K4me3 enrichment in the promoter regions of arginase 1 (Arg-1), cyclooxygenase 2 (COX2), nitric oxide synthase 2 (NOS2) and NADPH oxidase 2 (NOX2) to enhance the expression of these genes. Furthermore, using a CD45 chimeric model we confirmed that Lnc-17Rik promoted the differentiation of monocytic (M)-MDSCs in vivo with the introduction of Lnc-17Rik-overexpressing MDSCs shown to promote tumor growth as a result of enhancing their immunosuppressive function. Notably, human Lnc-17Rik is highly homologous to mouse Lnc-17Rik and fulfills similar functions in human MDSC-like cells. In addition, we also found a high level of Lnc-17Rik in peripheral blood MDSC of patients with esophageal cancer. These findings suggest that Lnc-17Rik plays an important role in controlling the immunosuppressive function of MDSCs in the tumor environment and may further serve as a potential therapeutic target for patients with esophageal cancer.
髓源性抑制细胞（MDSCs）是一群未成熟的骨髓细胞，大量积聚于脾脏、外周血、骨髓、淋巴结以及肿瘤的局部和转移灶中。C/EBP同源蛋白（CHOP）和CCAAT/增强子结合蛋白β（C/EBPβ）在调节MDSCs的免疫抑制功能和分化中起关键作用。我们的研究表明，长链非编码RNA Lnc-17Rik能够通过促进参与MDSC分化的关键基因的激活和表达来促进肿瘤中的免疫抑制。研究显示Lnc-17Rik直接与CHOP和C/EBPβ LIP相互作用，促进它们与涉及C/EBP LAP/LIP/CHOP的转录抑制复合物解离。此外，Lnc-17Rik增加了含WD重复蛋白5（WDR5）与C/EBP LAP的结合，促进精氨酸酶1（Arg-1）、环氧化酶2（COX2）、一氧化氮合酶2（NOS2）和NADPH氧化酶2（NOX2）启动子区域的H3K4me3富集，以增强这些基因的表达。此外，使用CD45嵌合模型，我们证实Lnc-17Rik在体内促进单核细胞（M）-MDSCs的分化，引入过表达Lnc-17Rik的MDSCs可增强其免疫抑制功能，从而促进肿瘤生长。值得注意的是，人Lnc-17Rik与小鼠Lnc-17Rik高度同源，并且在人MDSC样细胞中发挥类似功能。此外，我们还发现食管癌患者外周血MDSC中Lnc-17Rik水平较高。这些发现表明，Lnc-17Rik在控制肿瘤环境中MDSCs的免疫抑制功能方面发挥重要作用，并且可能进一步成为食管癌患者的潜在治疗靶点。
