G-CSF SECRETED BY EPIGENETICALLY REPROGRAMMED MUTANT IDH1 GLIOMA STEM CELLS REVERSES THE MYELOID CELLS'-MEDIATED IMMUNOSUPPRESSIVE TUMOR MICROENVIRONMENT

Mutation in isocitrate dehydrogenase (mIDH) is a gain of function mutation resulting in the production of the oncometabolite, R-2-hydroxyglutarate, that inhibits DNA and histone demethylases. The resultant hypermethylation phenotype reprograms the glioma cells transcriptome and elicits profound effects on glioma immunity. We report that in mouse models and human gliomas, mIDH1 in the context of ATRX and TP53 inactivation results in global expansion of the granulocytic myeloid cells compartment. Single-cell RNA-sequencing coupled with mass cytometry analysis revealed that these granulocytes are mainly non-immunosuppressive neutrophils and pre-neutrophils; with a small fraction of polymorphonuclear myeloid-derived suppressor cells. The mechanism of mIDH1 mediated pre-neutrophils expansion involves epigenetic reprogramming which leads to enhanced expression of the granulocyte colony-stimulating factor (G-CSF). Blocking G-CSF restored the inhibitory potential of PMN-MDSCs and enhanced tumor progression. Thus, G-CSF induces remodeling of the inhibitory PMN-MDSCs in mIDH1 glioma rendering them non-immunosuppressive; and having significant therapeutic implication