The TAM population is composed of brain-resident microglia and infiltrating bone-marrow derived monocytes (BMDMs) that differentiate into macrophages upon extravasation into the brain parenchyma ( Gutmann and Kettenmann, 2019). However, therapies designed to target non-neoplastic infiltrating cell types including tumour associated macrophages (TAMs) are lacking, and may be worth investigating as these cell types constitute a large majority of cells within the tumour mass. As our understanding of the molecular alterations driving paediatric HGGs increases, targeted therapies against molecular alterations and immune processes are being increasingly investigated ( Lasky et al., 2013 Souweidane et al., 2018 Tejada et al., 2018 Chi et al., 2019 Hall et al., 2019). Paediatric HGGs are characterized by PDGFRA amplification, TP53 deletion/mutation, CDKN2A deletion/mutation, and histone mutations such as H3F3A and HIST1H3B ( Mackay et al., 2017). Lastly, the dynamic tumour microenvironment, which has been shown to be critical for tumour progression in adult HGGs, remains highly understudied and unaccounted for in paediatric HGGs. Additionally, until recently, therapeutics for the treatment of paediatric HGG were adapted from their adult counterparts and failed to consider the innate biological and molecular differences between the two ( Jones and Baker, 2014 Vinci et al., 2018). Paediatric HGGs have a high frequency (∼50%) of arising in infra-tentorial regions of the brain such as the brainstem, rendering these tumours surgically inaccessible and limited to therapeutic intervention ( Mackay et al., 2017). Brain tumours account for the most cancer-related deaths in the paediatric population, and paediatric HGGs account for the most deaths among this category which can be attributed to multiple defining features ( Ostrom et al., 2014, 2015). Together, these studies provide evidence for the potent inflammatory effects PDGFB has in paediatric HGGs.ĭespite our continued understanding of high-grade gliomas (HGGs) and the molecular mechanisms driving their malignancy, paediatric HGGs remain one of the most difficult malignancies to treat. We identify CC元 as a potential key chemokine in these processes in both humans and mice. 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. 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. NanoString and quantitative PCR analysis indicates PDGFB-driven tumours have a highly inflammatory microenvironment characterized by high chemokine expression. Tumours driven by PDGFB have a significantly lower median survival compared to PDGFA-driven tumours and have increased TAM infiltration. Tumours are induced in Nestin-positive brain cells by PDGFA or PDGFB overexpression with Cdkn2a or Tp53 co-mutations. To investigate the TAM population, we used the RCAS/tv-a system to recapitulate paediatric HGG in newborn immunocompetent mice. CD31, PDGFRβ, and PDGFB all strongly correlate with IBA1+ TAM infiltration. We also show despite possessing sparse T-cell infiltration, human paediatric HGGs possess high infiltration of IBA1+ TAMs. 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. This raises the question of whether paediatric HGGs possess a distinct constituency of TAMs because of their unique genetic landscapes. Much is known about TAMs in adult HGG, yet little is known about them in the paediatric setting. TAMs are immunosuppressive and promote tumour malignancy in adult HGG however, in paediatric medulloblastoma, TAMs exhibit anti-tumour properties. 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). Paediatric high-grade gliomas (HGGs) account for the most brain tumour-related deaths in children and have a median survival of 12–15 months.
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