Childhood brain tumors instruct cranial hematopoiesis and immunotolerance

doi:10.1038/s41588-025-02499-2

Childhood brain tumors instruct cranial hematopoiesis and immunotolerance

2026-02-01

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AI

Rocio Jimenez-Guerrero

K

Katherine E. Masih

K

Katherine Wickham Rahrmann

Valar Nila Roamio Franklin

Timotheus Y. F. Halim

Richard J. Gilbertson *

DOI：10.1038/s41588-025-02499-2

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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.

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Childhood brain tumors instruct cranial hematopoiesis and immunotolerance

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