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

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

doi:10.1016/j.isci.2023.107585

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

iScience. 2023 Aug 9;26(9):107585. doi: 10.1016/j.isci.2023.107585. eCollection 2023 Sep 15.

Authors

Andrea M Griesinger^{1

2

3}, Kent Riemondy⁴, Nithyashri Eswaran^{1

2}, Andrew M Donson^{1

2}, Nicholas Willard⁵, Eric W Prince^{1

6}, Simon M L Paine^{7

8}, Georgia Bowes⁷, John Rheaume⁹, Rebecca J Chapman^{7

10}, Judith Ramage¹⁰, Andrew Jackson¹⁰, Richard G Grundy^{7

8}, Nicholas K Foreman^{1

2

3

6}, Timothy A Ritzmann^{7

8}

Affiliations

¹ Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, CO 80045, USA.
² Department of Pediatrics, University of Colorado Denver, Aurora, CO 80045, USA.
³ Colorado Clinical and Translational Sciences Institute, University of Colorado Denver, Aurora, CO 80045, USA.
⁴ RNA Bioscience Initiative, University of Colorado Denver, Aurora, CO 80045, USA.
⁵ Department of Pathology, University of Colorado Denver, Aurora, CO 80045, USA.
⁶ Department of Neurosurgery, University of Colorado Denver, Aurora, CO 80045, USA.
⁷ Children's Brain Tumour Research Centre, University of Nottingham Biodiscovery Institute, Nottingham, UK.
⁸ Nottingham University Hospitals NHS Trust, Queen's Medical Centre, Derby Road, Nottingham NG7 2UH, UK.
⁹ IsoPlexis, Branford, CT 06405, USA.
¹⁰ University of Nottingham Biodiscovery Institute, Nottingham, UK.

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.

Keywords: Biopsy sample; Components of the immune system; Microenvironment; Proteomics; Transcriptomics.

Grants and funding

T15 LM009451/LM/NLM NIH HHS/United States