# Childhood brain tumors instruct cranial hematopoiesis and immunotolerance

## TL;DR

Childhood brain tumors interact with skull bone marrow to suppress immune responses, and targeting this interaction can shrink tumors.

## Contribution

The study reveals a novel immune circuit between brain tumors and hematopoietic stem cells in the skull bone marrow.

## Key findings

- Antigen presentation by hematopoietic stem cells promotes myelopoiesis and regulatory T cells, leading to tumor immunotolerance.
- Normalizing hematopoiesis with anti-cytokine antibodies caused significant tumor regression in mouse models of aggressive childhood brain tumors.

## 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.

Antigen presentation in skull bone marrow by hematopoietic stem and progenitor cells induces myelopoiesis and generates CD4+ regulatory T cells in a mouse model of ependymoma, promoting immune tolerance. Treatment with anti-GM-CSF antibody has antitumor effects that are augmented by immunotherapy.