493 Modulation of the Myeloid Immune Cell Microenvironment Within Gliomas by Mutant IDH

INTRODUCTION: Mutations in isocitrate dehydrogenase (IDH) are a significant prognostic and biological factor leading to slower growth and T cell suppression within diffuse gliomas. However, the effect of IDH and its downstream metabolites specifically on intratumoral myeloid cells remains underexplored. METHODS: Utilizing patient tumor samples, we performed RNA-sequencing and quantitative immunofluorescence on IDH-wildtype glioblastoma and IDH-mutant grade 4 astrocytoma cases. We then engineered the murine GL261 glioma cell line to harbor mutant IDH, comparing transcriptomic and cell-level changes in IDH-wildtype versus IDH-mutant murine tumors. RESULTS: We identified greater hallmarks of productive inflammation in IDH-mutant tumors compared to IDH-wildtype tumors. We also saw transcriptomic enrichment of suppressive macrophage and myeloid-derived suppressor cell (MDSC) signatures in IDH-wildtype tumors, which was confirmed at the cellular level. Furthermore, engineering the IDH mutation into murine tumors appeared sufficient to recapitulate many of the transcriptomic and cellular shifts observed among patient samples. CONCLUSIONS: Our data show that mutant IDH is associated with greater inflammatory signatures and fewer suppressive myeloid cells in human gliomas, and that delivering mutant IDH to murine tumors is sufficient to drive these microenvironment changes. This work advances our understanding of key myeloid cell populations that may be targeted by future immunotherapy strategies.