Department of Infection, Guizhou Provincial People's Hospital, Guiyang 550002, PR China.
Department of General Surgery, Guizhou Provincial people's Hospital, Guiyang 550002, PR China; Department of Cell Biology, School of Life Sciences, Central South University, Changsha 410013, PR China.
Int Immunopharmacol. 2023 Nov;124(Pt A):110868. doi: 10.1016/j.intimp.2023.110868. Epub 2023 Aug 30.
Exosomes can help to effectively regulate the crosstalk between cancer cells and normal cells in the tumor microenvironment. They also regulate cancer cell proliferation and apoptosis by virtue of their cargo molecules. Transmission electron microscopy (TEM) together with differential ultracentrifugation served for verifying the presence of exosomes. In vivo and in vitro assays served for determining the role of exosomal circ_001264. RNA pull-down and dual-luciferase reporter assays assisted in the classification of the mechanism of exosomal circ_001264-mediated regulation of the crosstalk between Acute myeloid leukemia (AML) cells and M2 macrophages. Furthermore, we adopted a programmed death ligand 1 antibody (aPD-L1) in combination with exosomal circ_001264 siRNA for antitumor treatment in vitro and in vivo mouse models served for validating the in vivo outcomes. Out study illustrated the aberrant overexpression of circ_001264 in AML patients and its correlation with poor patient prognosis. AML cell-derived exosomal circ_001264 regulated the RAF1 expression and activated the p38-STAT3 signaling pathway, thereby inducing the M2 macrophage polarization. Polarized M2 macrophages can induce PD-L1 overexpression by secreting PD-L1. Here, a programmed death ligand (aPD-L1) was adopted for preventing the immunosuppression, which was able to achieve the desired therapeutic effect at the tumor site. Indeed, in the mouse model, leukemia tumor load decreased remarkably in the exosomal circ_001264 siRNA plus aPD-L1 combination group. Taken together, our study contributed to a theoretical basis for AML treatment. The co-administration of exosomal circ_001264 siRNA and aPD-L1 exhibited an obvious anti-cancer effectiveness in AML.
外泌体可以帮助有效调节肿瘤微环境中癌细胞与正常细胞之间的串扰。它们还可以通过其携带的分子来调节癌细胞的增殖和凋亡。透射电子显微镜（TEM）和差速超速离心法用于验证外泌体的存在。体内和体外测定用于确定外泌体 circ_001264 的作用。RNA 下拉和双荧光素酶报告基因检测协助分类外泌体 circ_001264 介导调节急性髓系白血病（AML）细胞与 M2 巨噬细胞之间串扰的机制。此外，我们采用程序性死亡配体 1 抗体（aPD-L1）联合外泌体 circ_001264 siRNA 进行体外抗肿瘤治疗，并在体内小鼠模型中验证体内结果。我们的研究表明 circ_001264 在 AML 患者中异常过表达，并且与患者预后不良相关。AML 细胞衍生的外泌体 circ_001264 调节 RAF1 表达并激活 p38-STAT3 信号通路，从而诱导 M2 巨噬细胞极化。极化的 M2 巨噬细胞可以通过分泌 PD-L1 诱导 PD-L1 过表达。在这里，采用程序性死亡配体（aPD-L1）来防止免疫抑制，这可以在肿瘤部位达到预期的治疗效果。事实上，在小鼠模型中，外泌体 circ_001264 siRNA 加 aPD-L1 联合组的白血病肿瘤负荷显著降低。总之，我们的研究为 AML 治疗提供了理论基础。外泌体 circ_001264 siRNA 和 aPD-L1 的联合给药在 AML 中表现出明显的抗癌效果。
