Childhood brain tumors instruct cranial hematopoiesis and immunotolerance
Recent research has challenged a long-held view of the brain as an immune-privileged organ, revealing active immunosurveillance with therapeutic relevance. Using a new genetically engineered mouse model of ZFTA-RELA ependymoma, a childhood brain tumor, we characterized an immune circuit between the tumor and antigen-presenting hematopoietic stem and progenitor cells (HSPCs) in the skull bone marrow. The presentation of antigens by HSPCs to CD4<sup>+</sup> T cells biased HSPC lineages toward myelopoiesis and polarized CD4<sup>+</sup> T cells to regulatory T cells, culminating in tumor immunotolerance. Remarkably, normalizing hematopoiesis with a single infusion of antibodies directed against cytokines enriched in the cerebrospinal fluid of mice bearing ZFTA-RELA ependymomas, choroid plexus carcinomas or group 3 medulloblastoma-all aggressive childhood brain tumors-disrupted this process and caused profound tumor regression. These findings demonstrate the existence of a skull bone marrow-tumor immunological interface and suggest that modulating the local supply of myeloid cells could represent a less toxic therapeutic strategy for aggressive childhood brain tumors.
Authors
- Annika L. Gable (ORCID: https://orcid.org/0000-0002-8965-0848)
- Katherine E. Masih (ORCID: https://orcid.org/0000-0002-0809-668X)
- Elizabeth Cooper (ORCID: https://orcid.org/0000-0002-6519-4753)
- Ibrahim Jalloh (ORCID: https://orcid.org/0000-0002-5345-5928)
- David A. Posner
- Claudia Craven (ORCID: https://orcid.org/0000-0002-6199-0090)
- Thomas Santarius (ORCID: https://orcid.org/0000-0002-1416-9566)
- Fredrik J. Swartling (ORCID: https://orcid.org/0000-0002-8460-4367)
- Katherine Wickham Rahrmann (ORCID: https://orcid.org/0009-0004-7564-9987)
- Richard J. Gilbertson (ORCID: https://orcid.org/0000-0001-7539-9472)
- Oscar Baldwin
- Valar Nila Roamio Franklin
- Sigourney Bonner
- Colin Y. C. Lee
- Richard Mair
- Rocio Jimenez-Guerrero
- Jason Eigenbrood
- Menna R. Clatworthy
- Li Wang
- Linda Hu
- Jessica T. Taylor
- Arnold R. Kreigstien
- Timotheus Y. F. Halim
- Gina Ngo
- Brandon Wainwright
- Javed Khan
Institutions
- Uppsala University (SE)
- National Institutes of Health (US)
- University of California, San Francisco (US)
- QIMR Berghofer Medical Research Institute (AU)
- University of Cambridge (GB)
- Science for Life Laboratory (SE)
- Broad Center (US)
- Addenbrooke's Hospital (GB)
Publication Details
- Journal
- Nature Genetics
- Published
- 2026-02-01
- DOI
- https://doi.org/10.1038/s41588-025-02499-2
- Primary Topic
- Glioma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00