Brain Tumor Research Center, Beijing Neurosurgical Institute, Capital Medical University, Beijing, 100070, People's Republic of China.
Department of Neurosurgery, Beijing Tiantan Hospital Affiliated to Capital Medical University, Beijing, 100070, People's Republic of China.
Stem Cell Res Ther. 2022 Jun 28;13(1):284. doi: 10.1186/s13287-022-02968-z.
Glioblastoma (GBM) is a highly immunosuppressive and vascular malignant brain tumor. Current therapeutic strategies targeting tumor cells have limited efficacy because of the immunosuppressive microenvironment and vascularization. Glioma-associated mesenchymal stem cells (GA-MSCs) have been identified as important stromal components of the tumor microenvironment, owing to their contribution to tumor angiogenesis and their potential to drive glioma stem cells. However, there are no reports on the effect of oncolytic Ad5-Ki67/IL-15 on programmed death ligand 1 (PD-L1) expression and angiogenesis induced by GA-MSCs.
Flow cytometry was respectively performed to detect the PD-L1 of glioma cells and programmed death protein 1 (PD-1), CD3, CD4 and CD8 in lymphocytes, as well as distribution of the cell cycle. CCK-8 assay investigated the proliferation of glioma cells and GA-MSCs in vitro. Tumor-bearing nude mice were established with U87-Luc cells and treated with the viruses, and further the IVIS spectrum was utilized to obtain luciferase images. Finally, the expression of PD-L1 in tumor tissues was also investigated using western blotting.
We found that GA-MSCs had potential to induce PD-L1 upregulation and involved in vascular mimicry in vitro. Importantly, Ad5-Ki67/IL-15 reduced PD-L1 expression of glioma cells and neovascularization by targeting GA-MSCs. Furthermore, despite the presence of GA-MSCs, the virus has the ability to generate potent antitumor efficacy in vitro and vivo.
These findings suggest the use of oncolytic Ad5-Ki67/IL-15 targeting GA-MSCs to treat GBM, indicating potential clinical applications.
胶质母细胞瘤（GBM）是一种高度免疫抑制和血管恶性脑肿瘤。由于免疫抑制微环境和血管化，目前针对肿瘤细胞的治疗策略疗效有限。神经胶质瘤相关间充质干细胞（GA-MSCs）已被确定为肿瘤微环境中重要的基质成分，因为它们有助于肿瘤血管生成，并有可能驱动神经胶质瘤干细胞。然而，目前尚无关于溶瘤腺病毒 5-Ki67/IL-15 对 GA-MSCs 诱导的程序性死亡配体 1（PD-L1）表达和血管生成的影响的报道。
采用流式细胞术分别检测胶质瘤细胞和淋巴细胞中程序性死亡蛋白 1（PD-1）、CD3、CD4 和 CD8 的 PD-L1 表达以及细胞周期分布。CCK-8 试验检测胶质瘤细胞和 GA-MSCs 的体外增殖。采用 U87-Luc 细胞建立荷瘤裸鼠模型，并给予病毒治疗，进一步利用 IVIS 光谱获得荧光素酶图像。最后，采用 Western blot 检测肿瘤组织中 PD-L1 的表达。
我们发现 GA-MSCs 具有体外诱导 PD-L1 上调和参与血管拟态的潜力。重要的是，Ad5-Ki67/IL-15 通过靶向 GA-MSCs 降低了胶质瘤细胞的 PD-L1 表达和新生血管形成。此外，尽管存在 GA-MSCs，该病毒仍具有在体外和体内产生强大抗肿瘤疗效的能力。
这些发现表明，使用溶瘤腺病毒 5-Ki67/IL-15 靶向 GA-MSCs 治疗 GBM 具有潜在的临床应用价值。
