Single-cell profiling of myeloid cells in glioblastoma across species and disease stage reveals macrophage competition and specialization

Glioblastomas are aggressive primary brain cancers that invariably recur as therapy-resistant tumors. Myeloid cells control glioblastoma malignancy, but their dynamics during disease progression remains poorly understood. By relying on single-cell RNA and protein profiling, we mapped the glioblastoma immune landscape in newly diagnosed and recurrent patients and in mouse tumors. This revealed a large and diverse myeloid compartment, with dendritic cell and macrophage populations that were conserved across species and were dynamic across disease stages. Tumor-associated macrophages (TAMs) consisted of microglia- or monocyte-derived populations, with both exhibiting additional heterogeneity, including subsets with conserved lipid and hypoxic signatures. Microglia- and monocyte-derived TAMs (Mo-TAMs) were self-renewing populations that competed for space and could be depleted via CSF1R blockade. Microglia-derived TAMs were predominant in newly diagnosed tumors but were outnumbered by Mo-TAMs upon recurrence, especially in hypoxic tumor environments. Our results unravel the glioblastoma myeloid landscape and provide a framework for future therapeutic interventions. samples of WT mouse GL261 glioblastoma (GBM), samples of CCR2-KO mouse GL261 GBM, samples of WT mouse GL261 tumor-bearing whole brain, samples of human recurrent GBM, samples of human newly diagnosed GBM ***Please note that the human raw data will be deposited to the European Genome-phenome Archive (EGA) with study ID EGAS00001004871, as this is a dataset with restricted access