A functional subpopulation of human glioma associated macrophages linked to malignant glioma progression

Malignant gliomas are aggressive brain cancers with poor prognosis. Pro-tumorigenic glioma associated macrophages (GAM) have been implicated in disease progression; however, identification of pathogenic functional subsets is lacking. Macrophage functional specification is driven by transcription factor-associated gene regulatory networks, yet the core regulatory transcription factors that govern GAM functions remain unclear. Here we apply gene regulatory network analyses to derive the imprint of the glioma tumor microenvironment on GAM transcriptional program specification. We identify cell surface markers to prospectively isolate a functionally distinct subpopulation of GAMs in human high-grade gliomas irrespective of IDH mutation status. This subset of GAMs, termed malignancy associated GAMs (mGAMs) spatially localize to hypoxic metabolic niches, possess a multitude of pro-tumorigenic functions and are likely involved in low-grade to high-grade glioma progression. mGAMs also share mitochondrial somatic mutations with monocytes, suggesting a common bone marrow origin. mGAMs therefore represent a functional subset of GAMs in human high-grade glioma and a potential therapeutic target.