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Ependymoma instructs cranial haematopoiesis and immunotolerance

ABSTRACT: ZFTA-RELA ependymoma presents a significant clinical challenge due to the lack of effective treatments, driving the need to explore novel immunotherapeutic strategies. Recent studies have identified the skull bone marrow as a source of meningeal immune cells critical for central nervous system (CNS) immunity, yet the role of these cells in childhood CNS tumor surveillance and pathology remains unclear. Here, we demonstrate that intracranial childhood ependymoma tumors harbour a unique myeloid cell population, including hematopoietic stem cells (HSCs) not from the blood, but supplied by adjacent skull bone marrow, ontogenetically distinct from their blood-derived counterparts. Our findings challenge the conventional view of HSCs as passive players in the CNS, revealing that antigen-specific interactions between skull bone marrow-derived HSCs and CD4+ T cells actively promote immunotolerance in childhood brain tumors by enhancing local myelopoiesis and inducing regulatory T cell polarization. This work uncovers a previously unrecognized cellular network linking the skull to brain tumors in children and underscores the therapeutic potential of modulating skull bone marrow haematopoiesis to shift the local immune environment. Targeting this skull-specific immune pathway offers a promising avenue for developing localized immunotherapies to improve treatment outcomes.

ORGANISM(S): Mus musculus

PROVIDER: GSE282337 | GEO | 2025/12/01

REPOSITORIES: GEO

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Ependymoma instructs cranial haematopoiesis and immunotolerance

Project description:ZFTA-RELA ependymoma presents a significant clinical challenge due to the lack of effective treatments, driving the need to explore novel immunotherapeutic strategies. Recent studies have identified the skull bone marrow as a source of meningeal immune cells critical for central nervous system (CNS) immunity, yet the role of these cells in childhood CNS tumour surveillance and pathology remains unclear. Here, we demonstrate that intracranial childhood ependymoma tumours harbour a unique myeloid cell population, including hematopoietic stem cells (HSCs) not from the blood, but supplied by adjacent skull bone marrow, ontogenetically distinct from their blood-derived counterparts. Our findings challenge the conventional view of HSCs as passive players in the CNS, revealing that antigen-specific interactions between skull bone marrow-derived HSCs and CD4+ T cells actively promote immunotolerance in childhood brain tumours by enhancing local myelopoiesis and inducing regulatory T cell polarization. This work uncovers a previously unrecognized cellular network linking the skull to brain tumours in children and underscores the therapeutic potential of modulating skull bone marrow haematopoiesis to shift the local immune environment. Targeting this skull-specific immune pathway offers a promising avenue for developing localized immunotherapies to improve treatment outcomes.

2025-12-01 | PXD058239 | Pride

Childhood brain tumors instructs cranial haematopoiesis and immunotolerance

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Cerebrospinal fluid regulates skull bone marrow niches via direct access through dural channels

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Childhood brain tumours instruct cranial haematopoiesis and immunotolerance [scRNAseqTCR postTx]

Project description: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 site. 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 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 in the cerebrospinal fluid (CSF) by HSPCs to CD4+ T cells, biased HSPCs 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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Embryonic myeloid cells orchestrate niche cell homeostasis critical for the establishment of the definitive HSC pool

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Embryonic myeloid cells orchestrate niche cell homeostasis critical for the establishment of the definitive HSC pool

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Childhood brain tumors instruct cranial haematopoiesis and immunotolerance [endpoint Fus1 GEX]

Project description: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 HSPCs 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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