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.