Multi-Omic approach identifies hypoxic tumor-associated myeloid cells that drive immunobiology of high risk pediatric ependymoma


SummaryEpendymoma (EPN) is a devastating childhood brain tumor. Single-cell analyses have illustrated the cellular heterogeneity of EPN tumors, identifying multiple neoplastic cell states including a mesenchymal-differentiated subpopulation which characterizes the PFA1 subtype. Here, we characterize the EPN immune environment, in the context of both tumor subtypes and tumor cell subpopulations using single-cell sequencing (scRNAseq, n=27), deconvolution of bulk tumor gene expression (n=299), spatial proteomics (n=54), and single-cell cytokine release assays (n=12). We identify eight distinct myeloid-derived subpopulations from which a group of cells, termed hypoxia myeloid cells, demonstrate features of myeloid-derived suppressor cells, including IL6/STAT3 pathway activation and wound healing ontologies. In PFA tumors, Hypoxia myeloid cells colocalize with mesenchymal-differentiated cells in necrotic and perivascular niches and secrete IL-8, which we hypothesize amplifies the EPN immunosuppressive microenvironment. This myeloid cell driven immunosuppression will need to be targeted for immunotherapy to effective in this difficult to cure childhood brain tumor.


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