Monocyte-derived tumor-associated macrophages (Mo-TAMs) intensively infiltrate diffuse gliomas with remarkable heterogeneity. Using single-cell transcriptomics, we chart a spatially resolved transcriptional landscape of Mo-TAMs across 51 patients with isocitrate dehydrogenase (IDH)-wild-type glioblastomas or IDH-mutant gliomas. We characterize a Mo-TAM subset that is localized to the peri-necrotic niche and skewed by hypoxic niche cues to acquire a hypoxia response signature. Hypoxia-TAM destabilizes endothelial adherens junctions by activating adrenomedullin paracrine signaling, thereby stimulating a hyperpermeable neovasculature that hampers drug delivery in glioblastoma xenografts. Accordingly, genetic ablation or pharmacological blockade of adrenomedullin produced by Hypoxia-TAM restores vascular integrity, improves intratumoral concentration of the anti-tumor agent dabrafenib, and achieves combinatorial therapeutic benefits. Increased proportion of Hypoxia-TAM or adrenomedullin expression is predictive of tumor vessel hyperpermeability and a worse prognosis of glioblastoma. Our findings highlight Mo-TAM diversity and spatial niche-steered Mo-TAM reprogramming in diffuse gliomas and indicate potential therapeutics targeting Hypoxia-TAM to normalize tumor vasculature.
Adrenomedullin , Brain Neoplasms , Glioblastoma , Tumor-Associated Macrophages , Humans , Glioblastoma/pathology , Glioblastoma/drug therapy , Glioblastoma/blood supply , Glioblastoma/genetics , Glioblastoma/metabolism , Animals , Adrenomedullin/genetics , Adrenomedullin/metabolism , Mice , Brain Neoplasms/drug therapy , Brain Neoplasms/pathology , Brain Neoplasms/blood supply , Brain Neoplasms/genetics , Brain Neoplasms/metabolism , Tumor-Associated Macrophages/metabolism , Neovascularization, Pathologic/genetics , Tumor Microenvironment , Isocitrate Dehydrogenase/genetics , Xenograft Model Antitumor Assays , Cell Line, Tumor , Macrophages/metabolism , Cell Hypoxia
Glioblastoma (GBM) is a highly aggressive primary brain tumour and is resistant to nearly all available treatments, including natural killer (NK) cell immunotherapy. However, the factors mediating NK cell evasion in GBM remain largely unclear. Here, we report that EZH2-92aa, a protein encoded by circular EZH2, is overexpressed in GBM and induces the immune evasion of GBM stem cells (GSCs) from NK cells. Positively regulated by DEAD-box helicase 3 (DDX3), EZH2-92aa directly binds the major histocompatibility complex class I polypeptide-related sequence A/B (MICA/B) promoters and represses their transcription; it also indirectly represses UL16-binding protein (ULBP) transcription by stabilizing EZH2. The downregulation of NK group 2D ligands (NKG2DLs, including MICA/B and ULBPs) in GSCs mediates NK cell resistance. Moreover, stable EZH2-92aa knockdown enhances NK cell-mediated GSC eradication in vitro and in vivo and synergizes with anti-PD1 therapy. Our results highlight the immunosuppressive function of EZH2-92aa in inhibiting the NK cell response in GBM and the clinical potential of targeting EZH2-92aa for NK-cell-directed immune therapy.
Enhancer of Zeste Homolog 2 Protein , Glioblastoma , NK Cell Lectin-Like Receptor Subfamily K , Tumor Escape , Enhancer of Zeste Homolog 2 Protein/genetics , GPI-Linked Proteins/genetics , Glioblastoma/genetics , Histocompatibility Antigens Class I/metabolism , Humans , Ligands , NK Cell Lectin-Like Receptor Subfamily K/genetics , NK Cell Lectin-Like Receptor Subfamily K/metabolism , Receptors, Natural Killer Cell
