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., Paine, S. M. L., Bowes, G., Rheaume, J., Chapman, R. J., Ramage, J., Jackson, A., Grundy, R. G., Foreman, N. K., & 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: Cell Press
• 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).