Glioma-induced DNMT3A reduction in microglia promotes an anti-tumoral phenotype

Glioblastoma, IDH1 wildtype, aggressive primary brain tumors with a dismal prognosis, promote the recruitment of microglia, brain resident innate immune cells, and ultimately their activation toward a tumor-supportive phenotype that increases gliomal proliferation and invasion capability. Here, we report that upon stimulation by glioma cells, microglia transit via a reactive state holding anti-tumoral properties coupled to reduced DNA methyltransferase 3 A (DNMT3A) chromatin occupancy and DNA demethylation that promote the expression of gene sets related to the transforming growth factor beta (TGF-β)-dependent microglial homeostasis and the microglial sensome. We find that upon repression of Dnmt3a expression in microglia, those cells maintain anti-tumoral attributes in vitro and in vivo. In a syngeneic immunocompetent glioblastoma mouse model, brain delivery of antisense oligonucleotide targeting Dnmt3a expression led to microglial activation and reduced tumor growth. Taken together, our results reveal the involvement of DNA demethylation in the control of glioma cells-induced microglia activation and indicate that microglial DNMT3A is a potentially therapeutic target to treat brain neoplasms such as glioblastoma that include a microglial component.