Tumour immune landscape of paediatric high-grade gliomas

Abstract

Over the last decade, remarkable progress has been made towards elucidating the origin and genomic landscape of childhood high-grade brain tumors. It has become evident that pediatric high-grade gliomas (pHGGs) differ from adult HGGs with respect to multiple defining aspects including: DNA copy number, gene expression profiles, tumor locations within the central nervous system, and genetic alterations such as somatic histone mutations. Despite these advances, clinical trials for children with glioma have historically been based on ineffective adult regimens that fail to take into consideration the fundamental biological differences between the two. Additionally, although our knowledge of the intrinsic cellular mechanisms driving tumor progression has considerably expanded, little is known concerning the dynamic tumor immune microenvironment (TIME) in pHGGs. In this review, we explore the genetic and epigenetic landscape of pHGGs and how this drives the creation of specific tumor sub-groups with meaningful survival outcomes. Further, we provide a comprehensive analysis of the pHGG TIME and discuss emerging therapeutic efforts aimed at exploiting the immune functions of these tumors.

Generation of immunocompetent syngeneic allograft mouse models for pediatric diffuse midline glioma

“…Much of our knowledge on the immunophenotype of DMG has been obtained through immunohistochemical analyses of biopsy or autopsy tissues, which has consistently shown that DMG tumors are characterized by substantial infiltration of tolerogenic bone marrow-derived macrophages and tissue-resident microglia but very limited T- or NK cells. 10 , 11 Furthermore, these tumors do not appear to express the chemokines or cytokines required to recruit these cells, nor do they express significant amounts of immunosuppressive factors, resulting in an immunologically inert microenvironment that may considerably limit the efficacy of various immunotherapeutic compounds. 10 , 11 This is in contrast with pediatric low-grade gliomas, cortical gliomas, and adult glioblastomas, which demonstrate more extensive lymphoid cell infiltration compared to adjacent brain tissues, and express high levels of both pro- and anti-inflammatory factors, emphasizing the significance of using the appropriate disease models for DMG research.…”

“… 10 , 11 Furthermore, these tumors do not appear to express the chemokines or cytokines required to recruit these cells, nor do they express significant amounts of immunosuppressive factors, resulting in an immunologically inert microenvironment that may considerably limit the efficacy of various immunotherapeutic compounds. 10 , 11 This is in contrast with pediatric low-grade gliomas, cortical gliomas, and adult glioblastomas, which demonstrate more extensive lymphoid cell infiltration compared to adjacent brain tissues, and express high levels of both pro- and anti-inflammatory factors, emphasizing the significance of using the appropriate disease models for DMG research. 11 While these initial studies comprehensively highlight the unique TIME of DMG, advanced knowledge about immune cell subpopulations that modulate DMG progression is urgently needed.…”

“… 10 , 11 This is in contrast with pediatric low-grade gliomas, cortical gliomas, and adult glioblastomas, which demonstrate more extensive lymphoid cell infiltration compared to adjacent brain tissues, and express high levels of both pro- and anti-inflammatory factors, emphasizing the significance of using the appropriate disease models for DMG research. 11 While these initial studies comprehensively highlight the unique TIME of DMG, advanced knowledge about immune cell subpopulations that modulate DMG progression is urgently needed. In our syngeneic implant model, we observed a high number of myeloid cells and minimal presence of T-lymphocytes and NK cells, corresponding to previous reports and validating our model as being representative of the human disease.…”

“… 9 It is now increasingly accepted that the composition of the tumor immune microenvironment (TIME) impacts responsiveness to immunotherapy and therefore acts as a pivotal factor for effective immunotherapeutic strategies. 10 , 11 Research on the DMG immune landscape is limited, but initial reports show that these tumors are characterized by a non-inflammatory TIME that consists largely of tolerogenic myeloid cells and very few lymphoid cells. 12 , 13 Case reports from preliminary clinical studies show that immunotherapy can be applied safely to pediatric glioma patients.…”

Current knowledge on the immune microenvironment and emerging immunotherapies in diffuse midline glioma

“…Despite our knowledge on cell intrinsic mechanisms driving tumor growth, there is a paucity of information on the immune landscape of pHGGs, let alone DMG [110] . To date, there is insufficient research on the tumor immune microenvironment of DMG, yet this scope of research is imperative to developing effective therapeutic strategies.…”