ID2-ETS2 axis regulates the transcriptional acquisition of pro-tumoral microglia phenotype in glioma

Glioblastoma is a highly aggressive brain tumour that creates an immunosuppressive microenvironment.Microglia, the brain's resident immune cells, play a crucial role in this environment. Glioblastoma cells canreprogram microglia to create a supportive niche that promotes tumour growth. However, the mechanismscontrolling the acquisition of a transcriptome-associated with a tumour-supportive microglial reactive state arenot fully understood. In this study, we investigated changes in the transcriptional profile of BV2 microgliaexposed to C6 glioma cells. RNA sequencing analysis revealed a significant upregulation of microglial inhibitorof DNA binding 1 (Id1) and Id2, helix-loop-helix negative transcription regulatory factors. The concomitantregulation of microglial ETS proto-oncogene 2, transcription factor (ETS2)-target genes, i.e., Dusp6, Fli1, Jun,Hmox1, and Stab1, led us to hypothesize that ETS2 could be regulated by ID proteins. In fact, ID2-ETS2 proteininteractions increased in microglia exposed to glioma cells. In addition, perturbation of the ID2-ETS2transcriptional axis influenced the acquisition of a microglial tumour-supportive phenotype. ID2 and ETS2 geneswere found to be expressed by the tumour-associated microglia isolated from human glioblastoma tumourbiopsies. Furthermore, ID2 and ETS2 gene expressions exhibited inverse prognostic values in patients withglioma in cohorts from The Cancer Genome Atlas. Collectively, our findings indicate that the regulation of ETS2by ID2 plays a role in the transcriptional regulation of microglia in response to stimuli originating fromglioblastoma cells, information that could lead to developing therapeutic strategies to manipulate microglialtumour-trophic functions.