Abstract
Isocitrate dehydrogenase (IDH) mutant gliomas are progressive, invariably fatal brain tumors affecting young and middle-age adult patients. Previous single-cell transcriptomic characterization of IDH-mutant gliomas has uncovered heterogeneous cell states, with a hierarchy ranging from neural progenitor-like to differentiated cell states. Despite this understanding, the dynamics of these cell states as tumors undergo grade progression, and the factors that facilitate or restrict cell state transitions remain poorly understood. Here, we characterize the cell states of IDH-mutant gliomas spanning all grades using fresh patient samples and compare them with transcriptional programs of normal brain cells. We find that tumor cell states experience a marked shift as tumors undergo progression. In low-grade tumors, predominant cell states mimic slow-cycling oligodendrocyte progenitor cells (OPCs). With grade progression, cell states transition to resemble highly proliferative neural progenitor cells (NPCs). Additionally, single-cell analyses of accessible chromatin (ATAC-seq) revealed novel cellular states defined in chromatin space, which could facilitate this transition. Genetic analyses identified several molecular alterations in high-grade tumors, including loss of DNA methylation, oncogene amplification, and the deletion of genes associated with the interferon (IFN) response. Lastly, we validate the role of DNA hypomethylation in favoring immune evasion with grade progression using an IDH-mutant glioma organoid model. Overall, our findings provide evidence that tumor progression in IDH-mutant gliomas is driven by an interplay of epigenetic and genetic mechanisms that promote more mitotically active cell states as well as decreased anti-tumoral immune activation.