The tumor micro-environment in pediatric glioma: friend or foe?

Abstract

Brain tumors are the leading cause of morbidity and mortality related to cancer in children, where high-grade glioma harbor the worst prognosis. It has become obvious that pediatric glioma differs significantly from their adult counterparts, rendering extrapolations difficult. Curative options for several types of glioma are lacking, albeit ongoing research efforts and clinical trials. As already proven in the past, inter- and intratumoral heterogeneity plays an important role in the resistance to therapy and thus implicates morbidity and mortality for these patients. However, while less studied, the tumor micro-environment (TME) adds another level of heterogeneity. Knowledge gaps exist on how the TME interacts with the tumor cells and how the location of the various cell types in the TME influences tumor growth and the response to treatment. Some studies identified the presence of several (immune) cell types as prognostic factors, but often lack a deeper understanding of the underlying mechanisms, possibly leading to contradictory findings. Although the TME in pediatric glioma is regarded as “cold”, several treatment options are emerging, with the TME being the primary target of treatment. Therefore, it is crucial to study the TME of pediatric glioma, so that the interactions between TME, tumoral cells and therapeutics can be better understood before, during and after treatment. In this review, we provide an overview of the available insights into the composition and role of the TME across different types of pediatric glioma. Moreover, where possible, we provide a framework on how a particular TME may influence responses to conventional- and/or immunotherapy.

Myeloid cells as potential targets for immunotherapy in pediatric gliomas

“…In this review we highlighted the different types of myeloid cells that comprise the pHGG and pGBM microenvironment, as well as other myeloid cell types that we postulate to be relevant to the pediatric glioma TME, due to their established presence in adult gliomas. These include the presence of tumor-associated macrophages and microglia, MDSCs, and dendritic cells (see Figure 1) (79,(94)(95)(96)(97)(98). The role of TAMs, including macrophages and microglia, in brain tumor progression is still an emerging area of research in neuro-oncology and efforts aimed at blocking macrophage polarization to an M2 phenotype have shown promise in mouse studies.…”

Systemic and local immunosuppression in glioblastoma and its prognostic significance

“…It is worth noting that adult glioblastoma/gliomas in general differ significantly from pediatric gliomas. An overview of the composition of the tumor immune infiltrate across different types of pediatric glioma is given elsewhere ( 177 ).…”