Department of Neurosurgery, Medical Center-University of Freiburg, Freiburg, Germany.
Laboratory of General Pathology and Immunology, University of Insubria, Varese, Italy.
Commun Biol. 2024 Nov 8;7(1):1472. doi: 10.1038/s42003-024-07144-y.
Glioma associated macrophages/microglia (GAMs) play an important role in glioblastoma (GBM) progression, due to their massive recruitment to the tumor site and polarization to a tumor promoting phenotype. GAMs secrete a variety of cytokines, which facilitate tumor cell growth and invasion, and prevent other immune cells from mounting an immune response against the tumor. Here, we demonstrate that zinc finger and BTB containing domain 18 (ZBTB18), a transcriptional repressor with tumor suppressive function in glioblastoma, impairs the production of key cytokines, which function as chemoattractant for GAMs. Consistently, we observe a reduced migration of GAMs when ZBTB18 is expressed by glioblastoma cells, both in cell culture and in vivo experiments. Moreover, RNA sequencing analysis shows that the presence of ZBTB18 in glioblastoma cells alters the commitment of conditioned microglia, suggesting the loss of the immune-suppressive phenotype and the acquisition of pro-inflammatory features. Thus, therapeutic approaches to increase ZBTB18 expression in GBM cells could represent an effective adjuvant to immune therapy in GBM.
胶质母细胞瘤相关巨噬细胞/小胶质细胞（GAMs）在胶质母细胞瘤（GBM）的进展中起着重要作用，因为它们大量募集到肿瘤部位，并向促进肿瘤的表型极化。GAMs 分泌多种细胞因子，促进肿瘤细胞的生长和侵袭，并阻止其他免疫细胞对肿瘤产生免疫反应。在这里，我们证明锌指和 BTB 结构域蛋白 18（ZBTB18），一种在胶质母细胞瘤中具有肿瘤抑制功能的转录抑制剂，会损害关键细胞因子的产生，这些细胞因子作为 GAMs 的趋化因子发挥作用。一致地，我们观察到当 ZBTB18 由胶质母细胞瘤细胞表达时，GAMs 的迁移减少，无论是在细胞培养还是体内实验中都是如此。此外，RNA 测序分析表明，ZBTB18 在胶质母细胞瘤细胞中的存在改变了条件性小胶质细胞的分化，提示其丧失了免疫抑制表型并获得了促炎特征。因此，增加 GBM 细胞中 ZBTB18 表达的治疗方法可能是 GBM 免疫治疗的有效辅助手段。
