Childhood brain tumours instruct cranial haematopoiesis and immunotolerance

Cooper, E. A.; Posner, D. A.; Lee, C. Y. C.; Hu, L.; Bonner, S.; Taylor, J. T.; Baldwin, O.; Jimenez-Guerrero, R.; Masih, K. E.; Wickham Rahrmann, K.; Eigenbrood, J.; Ngo, G.; Franklin, V. N. R.; D'Santos, C.; Mair, R.; Santarius, T.; Craven, C.; Jalloh, I.; Moreno-Vicente, J.; Halim, T.; Wang, L.; Kriegstein, A.; Swartling, F. J.; Khan, J.; Clatworthy, M. R.; Gilbertson, R. J.

doi:10.1101/2025.09.25.678472

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bioRxiv · 10.1101/2025.09.25.678472

Childhood brain tumours instruct cranial haematopoiesis and immunotolerance

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Abstract

Recent research has revealed a remarkable role for immunosurveillance in healthy and diseased brains, dispelling the notion that this organ is a passive immune-privileged site1-3. Better understanding of how this immunosurveillance operates could improve the treatment of neurological diseases. Here, using a novel genetically engineered mouse model of ZFTA-RELA ependymoma4-a childhood brain tumour-we characterised an immune circuit between the tumour and antigen presenting, haematopoietic stem/progenitor cells (HSPCs) in the skull bone marrow. The presentation of antigens in the cerebrospinal fluid (CSF) by HSPCs to CD4+ T cells, biased HSPC lineages toward myelopoiesis and polarised CD4+ T-cells to regulatory T cells (T- regs), culminating in tumour immunotolerance. Remarkably, a single infusion of antibodies directed against cytokines enriched in the CSF of mice bearing ZFTA-RELA ependymomas, choroid plexus carcinomas or Group-3 medulloblastoma-all aggressive childhood brain tumours-disrupted this process and caused profound tumour regression. These data unmask a mechanism by which skull bone marrow-derived HSPCs and CD4+ T cells cooperate to promote the immunotolerance of childhood brain tumours. Antibodies that disrupt this immunosurveillance could prove an effective therapy for these cancers that are less toxic than current treatments.

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Cooper, E. A., Posner, D. A., Lee, C. Y. C., Hu, L., Bonner, S., Taylor, J. T., Baldwin, O., Jimenez-Guerrero, R., Masih, K. E., Wickham Rahrmann, K., Eigenbrood, J., Ngo, G., Franklin, V. N. R., D'Santos, C., Mair, R., Santarius, T., Craven, C., Jalloh, I., Moreno-Vicente, J., Halim, T., Wang, L., Kriegstein, A., Swartling, F. J., Khan, J., Clatworthy, M. R., Gilbertson, R. J.. 2025-09-26. Childhood brain tumours instruct cranial haematopoiesis and immunotolerance. https://doi.org/10.1101/2025.09.25.678472

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