Author:

Keywords:

BONE-MARROW, IMMUNE CELLS, INHIBITION, LANDSCAPE, Life Sciences & Biomedicine, NETWORK, Neurosciences, Neurosciences & Neurology, RESPONSES, Science & Technology, SUBSETS, TUMORS, Animals, Brain Neoplasms, Glioblastoma, Humans, Mice, Single-Cell Analysis, Tumor-Associated Macrophages, C14/17/084#54271203, G0I1118N#54551792, IDN/19/039#55225089, 1109 Neurosciences, 1701 Psychology, 1702 Cognitive Sciences, Neurology & Neurosurgery, 3209 Neurosciences, 5202 Biological psychology

Abstract:

Glioblastomas are aggressive primary brain cancers that recur as therapy-resistant tumors. Myeloid cells control glioblastoma malignancy, but their dynamics during disease progression remain poorly understood. Here, we employed single-cell RNA sequencing and CITE-seq to map the glioblastoma immune landscape in mouse tumors and in patients with newly diagnosed disease or recurrence. This revealed a large and diverse myeloid compartment, with dendritic cell and macrophage populations that were conserved across species and 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 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 monocyte-derived TAMs following recurrence, especially in hypoxic tumor environments. Our results unravel the glioblastoma myeloid landscape and provide a framework for future therapeutic interventions.