Biologic and clinical significance of neoplastic and myeloid states in diffuse gliomas.

Abstract INTRODUCTION Interactions between neoplastic cell characteristics and the immune microenvironment is an important yet understudied area in diffuse gliomas. We examined this by analyzing single cell RNAseq data (n=290,738) from 35 glioma patients (in-house and GSE182109) including 24 IDH-wildtype and 11 IDH-mutant tumors at the single cell level. Cells were assigned to specific classes, including neoplastic cell states and myeloid components, based on established methods. We used these data to develop a signature matrix to deconvolve bulk RNAseq data from TCGA diffuse gliomas. RESULTS Clustering of neoplastic cells revealed 4 cell states: proneural, mesenchymal, proliferative and cancer signaling. Elevated proneural cell state was, as expected, positively correlated with IDH-mutant tumors, and elevated mesenchymal cell state was correlated with IDH wildtype tumors (both p< 0.01, chi-square), Among IDH-mutant tumors, 1p/19q co-deletion was associated with the proneural state. Fourteen distinct myeloid cell subtypes were identified, and among them several were enriched for either microglial or macrophage (or both) markers. We examined relationships of neoplastic cell state with myeloid cell type abundance and significant associations were identified in both IDH-mutant tumors and IDH-wildtype tumors between specific myeloid cell states and myeloid clusters. Among IDH-mutant tumors, 1p/19q-co-deletion status was positively associated with abundance of a specific microglial cell cluster but negatively associated with abundance of 3 other myeloid cell clusters, suggesting substantial microenvironmental differences based on 1p/19q status in IDH-mutant tumors. In survival analyses, a specific myeloid cluster group proved interesting, with increased abundance of this group showing improved survival in both IDH-mutant and -wildtype tumors, in a manner that was enriched in specific neoplastic cell states. Overall, results suggest specific interactions between neoplastic cell characteristics, (cell states, IDH- and 1p/19q status), with myeloid cell and highlight the need of further studies understand the biological significance of the immune cell environment in diffuse gliomas.