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
Affiliations
Andrea M. Griesinger
Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children’s Hospital Colorado, Aurora, CO 80045, USA; Department of Pediatrics, University of Colorado Denver, Aurora, CO 80045, USA; Colorado Clinical and Translational Sciences Institute, University of Colorado Denver, Aurora, CO 80045, USA
Kent Riemondy
RNA Bioscience Initiative, University of Colorado Denver, Aurora, CO 80045, USA
Nithyashri Eswaran
Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children’s Hospital Colorado, Aurora, CO 80045, USA; Department of Pediatrics, University of Colorado Denver, Aurora, CO 80045, USA
Andrew M. Donson
Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children’s Hospital Colorado, Aurora, CO 80045, USA; Department of Pediatrics, University of Colorado Denver, Aurora, CO 80045, USA
Nicholas Willard
Department of Pathology, University of Colorado Denver, Aurora, CO 80045, USA
Eric W. Prince
Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children’s Hospital Colorado, Aurora, CO 80045, USA; Department of Neurosurgery, University of Colorado Denver, Aurora, CO 80045, USA
Simon M.L. Paine
Children’s Brain Tumour Research Centre, University of Nottingham Biodiscovery Institute, Nottingham, UK; Nottingham University Hospitals NHS Trust, Queen’s Medical Centre, Derby Road, Nottingham NG7 2UH, UK
Georgia Bowes
Children’s Brain Tumour Research Centre, University of Nottingham Biodiscovery Institute, Nottingham, UK
John Rheaume
IsoPlexis, Branford, CT 06405, USA
Rebecca J. Chapman
Children’s Brain Tumour Research Centre, University of Nottingham Biodiscovery Institute, Nottingham, UK; University of Nottingham Biodiscovery Institute, Nottingham, UK
Judith Ramage
University of Nottingham Biodiscovery Institute, Nottingham, UK
Andrew Jackson
University of Nottingham Biodiscovery Institute, Nottingham, UK
Richard G. Grundy
Children’s Brain Tumour Research Centre, University of Nottingham Biodiscovery Institute, Nottingham, UK; Nottingham University Hospitals NHS Trust, Queen’s Medical Centre, Derby Road, Nottingham NG7 2UH, UK
Nicholas K. Foreman
Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children’s Hospital Colorado, Aurora, CO 80045, USA; Department of Pediatrics, University of Colorado Denver, Aurora, CO 80045, USA; Colorado Clinical and Translational Sciences Institute, University of Colorado Denver, Aurora, CO 80045, USA; Department of Neurosurgery, University of Colorado Denver, Aurora, CO 80045, USA
Timothy A. Ritzmann
Children’s Brain Tumour Research Centre, University of Nottingham Biodiscovery Institute, Nottingham, UK; Nottingham University Hospitals NHS Trust, Queen’s Medical Centre, Derby Road, Nottingham NG7 2UH, UK; Corresponding author
Summary: 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.
