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

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