Childhood brain tumors instruct cranial hematopoiesis and immunotolerance.

Abstract:

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+ T cells biased HSPC lineages toward myelopoiesis and polarized CD4+ 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:

E Cooper, DA Posner, CYC Lee, L Hu, S Bonner, JT Taylor, O Baldwin, R Jimenez-Guerrero, KE Masih, KW Rahrmann, J Eigenbrood, G Ngo, VNR Franklin, CS D'Santos, R Mair, T Santarius, C Craven, I Jalloh, J Moreno Vicente, TYF Halim, L Wang, AR Kreigstien, B Wainwright, FJ Swartling, J Khan, MR Clatworthy, RJ Gilbertson

Journal:

Nat Genet

Publication date:

3rd Feb 2026

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