Role of ZBTB18 in cytokine production and microglia phenotype in GBM

Glioma associated macrophages (GAMs) are known to play an important role in glioblastoma progression, due to their massive recruitment in the tumor microenvironment and polarization to a tumor promoting phenotype. GAMs secrete a variety of cytokines, which promotes tumor cell growth and invasion while inhibiting an immune tumor response by other immune cells. Here, we demonstrate that ZBTB18, a transcriptional repressor with tumor suppressive function in glioblastoma, impairs the production of key cytokines, which functions as chemoattractant for GAMs. Consequently, we observe a reduced migration of GAMs when ZBTB18 is expressed by GBM cells, both in cell culture and in vivo experiments. Moreover, the presence of ZBTB18 halts GBMs cells-mediated GAMs polarization to a tumor suppressive phenotype characterized by a reduced engage in the oxidative phosphorylation pathway for energy supply. Thus, our findings suggest that therapeutic approaches to increase ZBTB18 expression in GBM cells could have a broad impact on both tumor cells and the surrounding immune microenvironment. Overall design: Comparative gene expression profiling analysis of RNA-seq data from human immortalized microglia conditioned with medium from GBM cells transduced with empty vector (EV), ZBTB18 full lenght (FL) or ZBTB18 Nte-Short form (SF)