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

Griesinger, Andrea M.; Riemondy, Kent; Eswaran, Nithyashri; Donson, Andrew M.; Willard, Nicholas; Prince, Eric W.; Paine, Simon M. L.; Bowes, Georgia; Rheaume, John; Chapman, Rebecca J.; Ramage, Judith; Jackson, Andrew; Grundy, Richard G.; Foreman, Nicholas K.; Ritzmann, Timothy A

Abstract

Ependymoma (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 be effective in this difficult-to-cure childhood brain tumor.

Citation

Griesinger, A. M., Riemondy, K., Eswaran, N., Donson, A. M., Willard, N., Prince, E. W., …Ritzmann, T. A. (2023). Multi-omic approach identifies hypoxic tumor-associated myeloid cells that drive immunobiology of high-risk pediatric ependymoma. iScience, 26(9), Article 107585. https://doi.org/10.1016/j.isci.2023.107585

• Journal Article Type: Article
• Acceptance Date: Aug 4, 2023
• Online Publication Date: Aug 9, 2023
• Publication Date: Sep 15, 2023
• Deposit Date: Oct 24, 2023
• Publicly Available Date: Oct 25, 2023
• Journal: iScience
• Electronic ISSN: 2589-0042
• Publisher: Elsevier BV
• Peer Reviewed: Peer Reviewed
• Volume: 26
• Issue: 9
• Article Number: 107585
• DOI: https://doi.org/10.1016/j.isci.2023.107585
• Keywords: Microenvironment, Transcriptomics, Components of the immune system, Biopsy sample, Proteomics
• Public URL: https://nottingham-repository.worktribe.com/output/25644485
• Publisher URL: https://www.cell.com/iscience/fulltext/S2589-0042(23)01662-0?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2589004223016620%3Fshowall%3Dtrue
• Additional Information: This article is maintained by: Elsevier; Article Title: Multi-omic approach identifies hypoxic tumor-associated myeloid cells that drive immunobiology of high-risk pediatric ependymoma; Journal Title: iScience; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.isci.2023.107585; Content Type: article; Copyright: © 2023 The Author(s).