ABSTRACT
Brain tumors are the leading cause of cancer-related mortality in children. Despite the development of immunotherapeutic strategies for adult brain tumors, progress in pediatric neuro-oncology has been hindered by the complex and poorly understood nature of the brain's immune system during early development, a phase that is critical for the onset of many pediatric brain tumors. A defining characteristic of these tumors is the abundance of microglia, the resident immune cells of the central nervous system. In this review, we explore the concept of microglial diversity across brain regions and throughout development and discuss how their maturation stage may contribute to tumor growth in children. We also summarize the current knowledge on the roles of microglia in common pediatric brain tumor entities and provide examples of myeloid-based immunotherapeutic strategies. Our review underscores the importance of microglial plasticity in pediatric brain tumors and its significance for developing effective immunotherapeutic strategies.
Subject(s)
Brain Neoplasms , Microglia , Child , Humans , Microglia/physiology , Brain Neoplasms/therapy , Central Nervous System , Brain , ImmunotherapyABSTRACT
Diffuse intrinsic pontine glioma (DIPG) is an incurable brain tumor of childhood characterized by histone mutations at lysine 27, which results in epigenomic dysregulation. There has been a failure to develop effective treatment for this tumor. Using a combined RNAi and chemical screen targeting epigenomic regulators, we identify the polycomb repressive complex 1 (PRC1) component BMI1 as a critical factor for DIPG tumor maintenance in vivo. BMI1 chromatin occupancy is enriched at genes associated with differentiation and tumor suppressors in DIPG cells. Inhibition of BMI1 decreases cell self-renewal and attenuates tumor growth due to induction of senescence. Prolonged BMI1 inhibition induces a senescence-associated secretory phenotype, which promotes tumor recurrence. Clearance of senescent cells using BH3 protein mimetics co-operates with BMI1 inhibition to enhance tumor cell killing in vivo.
Subject(s)
Aging/genetics , Diffuse Intrinsic Pontine Glioma/genetics , Polycomb Repressive Complex 1/metabolism , Astrocytoma/genetics , Brain Stem Neoplasms/drug therapy , Brain Stem Neoplasms/genetics , Cell Differentiation/genetics , Cell Line, Tumor , Cell Proliferation/drug effects , Child , Child, Preschool , Chromatin/genetics , Diffuse Intrinsic Pontine Glioma/drug therapy , Diffuse Intrinsic Pontine Glioma/metabolism , Epigenomics , Female , Glioma/drug therapy , Glioma/genetics , Glioma/pathology , Histones/metabolism , Humans , Lysine/metabolism , Male , Mutation , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/genetics , Polycomb Repressive Complex 1/antagonists & inhibitors , Polycomb Repressive Complex 1/geneticsABSTRACT
Diffuse midline gliomas (DMG) are rapidly fatal tumors of the midbrain in children, characterized by a diffuse growing pattern and high levels of intrinsic resistance to therapy. The location of these tumors, residing behind the blood-brain barrier (BBB), and the limited knowledge about the biology of these tumors, has hindered the development of effective treatment strategies. However, the introduction of diagnostic biopsies and the implementation of autopsy protocols in several large centers world-wide has allowed for a detailed characterization of these rare tumors. This has resulted in the identification of novel therapeutic targets, as well as major advances in understanding the biology of DMG in relation to therapy resistance. We here provide an overview of the cellular pathways and tumor-specific aberrations that have been targeted in preclinical DMG research, and discuss the advantages and limitations of these therapeutic strategies in relation to therapy resistance and BBB-penetration. Therewith, we aim to provide researchers with a framework for successful preclinical therapy development.
