3129 – ROLE OF MICROGLIA IN TP53/IDH1 MUTANT GLIOMAS DEVELOPMENT.

Abstract

The origin of glial macrophages and their role in pathology is debated (Gutmann and Kettenmann 2019). In gliomas, paired TP53/IDH1 mutations are associated with lower immune infiltration and better outcomes (Cancer Genome Atlas Research Network et al. 2015) (Amankulor et al. 2017). In contrast, within isocitrate dehydrogenase 1 (IDH1) non-mutant gliomas, higher amounts of glioma associated macrophages (GAMs) in the tumor core correlated with longer patient survival (Zeiner et al. 2019). Mutant IDH1 produces the 2-hydroxyglutarate, inhibiting activation of the microglia in BV-2 model (Han et al. 2019). In addition, IDH1 mutation induces CpG island methylator phenotype and, together with TP53 mutation, changes the gene expression to repress the immune cells infiltration in a mouse model (Amankulor et al. 2017). However, the relevant models to investigate the effects of IDH1-R132H and p53-R248Q mutations on the activation of human microglia of different origin are not yet established. We aim to establish the primary TP53 or/and IDH1 mutant glioma culture in 3D co-aggregate with subpopulation of human adult CX3CR1/CCR2/CD68/PD-L1 monocytes from umbilical cord blood. Role of GAMs will be assessed by using inhibitors of CSF1R (e.g. GW2850), mTOR (Rapamycin), IGF-1/AKT, AMPK/SIRT, NFkB, and SIRPα-CD47 signalling axis. Single-cell RNAseq analysis will reveal the role of microglia in tumour development. We will focus on the pathology of glioma and its interaction with microglia/macrophages in the mammalian central nervous system pathology in order to facilitate the fundamental understanding of these processes, find targets for anti-cancer therapy, and facilitate drug development. Funding: Russian Science Foundation № 20-15-00378.