Abstract SY30-03: Reversing brain tumor immunotolerance: A new therapeutic approach for childhood brain tumors

Abstract Brain tumours kill more children than any other cancer. Although immunotherapies have proved effective against treatment-resistant adult cancers and some leukamias, they have proved less effective against brain tumours. This is due in part to a poor understanding of how the immune system operates within the central nervous system (CNS), hindered further by a long-held belief that the brain is an immunoprivileged site, devoid of immune activity. Recent research challenges this view, revealing active immunosurveillance within the CNS. Using a novel genetically engineered mouse model of ZFTA-RELA ependymoma-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 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, normalising haematopoiesis with 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 findings uncover a skull bone marrow-tumour immunological interface and suggest that modulating local supply of myeloid cells may offer a less-toxic therapeutic strategy for aggressive childhood brain tumours. Citation Format: Richard J. Gilbertson. Reversing brain tumor immunotolerance: A new therapeutic approach for childhood brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr SY30-03.