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Updated: Nov 26, 2025
Isolation and Flow Cytometric Analysis of Glioma-infiltrating Peripheral Blood Mononuclear Cells
Published on: November 28, 2015
Platelet-derived growth factor beta is a potent inflammatory driver in paediatric high-grade glioma
James L Ross1,2, Zhihong Chen1,3, Cameron J Herting1,4
1Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA.
Insights
Pediatric high-grade gliomas (HGGs) have distinct tumor-associated macrophages (TAMs). PDGFB drives inflammation and TAM infiltration, suggesting CCL3 as a therapeutic target to improve survival in pediatric HGG.
Area of Science:
- Neuro-oncology
- Immunology
- Cancer Biology
Background:
- Pediatric high-grade gliomas (HGGs) are aggressive brain tumors with poor prognosis.
- Tumor-associated macrophages (TAMs) play complex roles in gliomagenesis, differing between adult and pediatric settings.
- The unique genetic landscape of pediatric HGGs may influence TAM populations and function.
Purpose of the Study:
- To investigate the characteristics and role of TAMs in pediatric HGG.
- To explore the influence of genetic drivers (PDGF A/B) on the tumor microenvironment and TAM infiltration.
- To identify potential therapeutic targets for pediatric HGG.
Main Methods:
- Analysis of human pediatric HGG tissue samples.
- Development of genetically engineered mouse models (RCAS/tv-a system) of pediatric HGG.
- In vitro studies using bone marrow-derived monocytes and microglial cultures.
- Gene expression analysis (NanoString, qPCR) and chemokine knockout studies.
Main Results:
- Diffuse midline gliomas show a higher inflammatory gene expression profile than hemispheric pediatric HGGs.
- PDGFB-driven tumors exhibit increased TAM infiltration, reduced survival, and a highly inflammatory microenvironment compared to PDGFA-driven tumors.
- Bone marrow-derived monocytes are key producers of inflammatory signals in response to PDGFB.
- CCL3 is identified as a critical chemokine involved in TAM infiltration and tumor progression.
Conclusions:
- PDGFB significantly drives inflammation and TAM infiltration in pediatric HGG, contributing to reduced survival.
- Targeting specific chemokines, such as CCL3, may represent a viable therapeutic strategy to reduce TAM infiltration and improve outcomes.
- These findings highlight the importance of understanding the tumor microenvironment in developing novel pediatric HGG therapies.
Abstract:
Paediatric high-grade gliomas (HGGs) account for the most brain tumour-related deaths in children and have a median survival of 12-15 months. One promising avenue of research is the development of novel therapies targeting the properties of non-neoplastic cell-types within the tumour such as tumour associated macrophages (TAMs). TAMs are immunosuppressive and promote tumour malignancy in adult HGG; however, in paediatric medulloblastoma, TAMs exhibit anti-tumour properties. Much is known about TAMs in adult HGG, yet little is known about them in the paediatric setting. This raises the question of whether paediatric HGGs possess a distinct constituency of TAMs because of their unique genetic landscapes. Using human paediatric HGG tissue samples and murine models of paediatric HGG, we demonstrate diffuse midline gliomas possess a greater inflammatory gene expression profile compared to hemispheric paediatric HGGs. We also show despite possessing sparse T-cell infiltration, human paediatric HGGs possess high infiltration of IBA1+ TAMs. CD31, PDGFRβ, and PDGFB all strongly correlate with IBA1+ TAM infiltration. To investigate the TAM population, we used the RCAS/tv-a system to recapitulate paediatric HGG in newborn immunocompetent mice. Tumours are induced in Nestin-positive brain cells by PDGFA or PDGFB overexpression with Cdkn2a or Tp53 co-mutations. Tumours driven by PDGFB have a significantly lower median survival compared to PDGFA-driven tumours and have increased TAM infiltration. NanoString and quantitative PCR analysis indicates PDGFB-driven tumours have a highly inflammatory microenvironment characterized by high chemokine expression. In vitro bone marrow-derived monocyte and microglial cultures demonstrate bone marrow-derived monocytes are most responsible for the production of inflammatory signals in the tumour microenvironment in response to PDGFB stimulation. Lastly, using knockout mice deficient for individual chemokines, we demonstrate the feasibility of reducing TAM infiltration and prolonging survival in both PDGFA and PDGFB-driven tumours. We identify CCL3 as a potential key chemokine in these processes in both humans and mice. Together, these studies provide evidence for the potent inflammatory effects PDGFB has in paediatric HGGs.
