Enrichment of a neutrophil-like monocyte transcriptional state in glioblastoma myeloid suppressor cells

Abstract Glioblastomas (GBM) are lethal central nervous system cancers associated with tumor and systemic immunosuppression. Heterogeneous monocyte myeloid-derived suppressor cells (M-MDSC) are implicated in the altered immune response in GBM, but M-MDSC ontogeny and definitive phenotypic markers are unknown. Using single-cell transcriptomics, we revealed heterogeneity in blood M-MDSC from GBM subjects and an enrichment in a transcriptional state reminiscent of neutrophil-like monocytes (NeuMo), a newly described pathway of monopoiesis in mice. Human NeuMo gene expression and Neu-like deconvolution fraction algorithms were created to quantitate the enrichment of this transcriptional state in GBM subjects. NeuMo populations were also observed in M-MDSCs from lung and head and neck cancer subjects. Dexamethasone (DEX) and prednisone exposures increased the usage of Neu-like states, which were inversely associated with tumor purity and survival in isocitrate dehydrogenase wildtype (IDH WT) gliomas. Anti-inflammatory ZC3HA12/Regnase-1 transcripts were highly correlated with NeuMo expression in tumors and in blood M-MDSC from GBM, lung, and head and neck cancer subjects. Additional novel transcripts of immune-modulating proteins were identified. Collectively, these findings provide a framework for understanding the heterogeneity of M-MDSCs in GBM as cells with different clonal histories and may reshape approaches to study and therapeutically target these cells.