Neuro-immune mechanisms in mutant IDH1 gliomas

University Of Michigan At Ann Arbor, Ann Arbor MI

Investigators

Abstract

Molecular profiling of gliomas led to their genetic classification and a better understanding of their pathophysiology. Adult mutant IDH1 gliomas are characterized by a mutation in the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) at active site residue R132. The mutation imparts a gain-of-function catalytic activity which leads to the conversion of α-ketoglutarate (αKG) to (R)-2-hydroxyglutarate (2HG). 2HG is a competitive inhibitor of histone 3 (H3) lysine-specific demethylases (KDMs) and of DNA demethylation by ten-eleven translocation methylcytosine dioxygenases (TETs). KDM and TET inhibition lead to an overall increase in methylation with concurrent epigenetic changes that influence numerous downstream pathways. IDH1 mutation (mIDH1) is an early event in gliomagenesis and imparts favorable prognosis compared to wild-type IDH1 (wt- IDH1). Due to the epigenetic changes mediated by mIDH1 and manifold affected pathways, the survival advantage of mIDH1 patients may arise via several mechanisms, identification of which may, (i) reveal therapeutic interventions for mIDH1, and (ii) by comparison, suggest approaches for wt-IDH1 therapeutics. We developed an immune competent murine mIDH1 glioma model by incorporating genetic lesions into the genomic DNA of neural progenitor cells using the Sleeping Beauty (SB) transposase system. Intracranial tumors develop de novo and exhibit hallmarks of human mIDH1 astrocytoma, including 2HG production, hypermethylation, lower cellular differentiation within the tumor, and longer median survival when compared to wt-IDH1. Total RNAseq followed by gene-set enrichment analysis (GSEA) revealed that tumors harboring mIDH1 exhibited upregulated DNA damage response, upregulated immune response mechanisms and downregulated differentiation in mIDH1. Also, differences arose in cytokines key to immune cell regulation. These mechanisms and signaling pathways were confirmed by analyzing scRNA-seq data from both genetically engineered mouse models (GEMMs) and human samples. Gliomas are known for their immunosuppressive tumor microenvironment (TME), an obstacle to successful immunotherapy. We found substantial recruitment of immature myeloid cells (IMCs) into the TME of both mIDH1 and wt-IDH1. However, our data indicates that mIDH1 IMCs do not exhibit immunosuppressive properties as the wt-IDH1 counterparts do. Thus, we hypothesize that this could account for a functional immune system capable of mounting effective anti-mIDH1 glioma immunity. To uncover neuroimmune mechanisms at play in mIDH1 gliomas, we propose three Specific Aims (SA). SA 1 will uncover the epigenetic and transcriptomic remodeling affecting the myeloid compartment in mIDH1 gliomas. SA2 will uncover the mechanistic and functional impact of combining immunotherapy with mIDH1 inhibition in mIDH1 mouse glioma models. SA 3 will uncover the ontogeny, spatial phenotyping, and cellular and neighborhood interactions within the TME in mIDH1 gliomas, and their reprogramming elicited by treatment with immune- mediated gene therapy and mIDH1 inhibition.