Current perspectives on diffuse midline glioma and a different role for the immune microenvironment compared to glioblastoma

Abstract

Diffuse midline glioma (DMG), formerly called diffuse intrinsic pontine glioma (DIPG), is a high-grade malignant pediatric brain tumor with a near-zero survival rate. To date, only radiation therapy provides marginal survival benefit; however, the median survival time remains less than a year. Historically, the infiltrative nature and sensitive location of the tumor rendered surgical removal and biopsies difficult and subsequently resulted in limited knowledge of the disease, as only post-mortem tissue was available. Therefore, clinical decision-making was based upon experience with the more frequent and histologically similar adult glioblastoma (GBM). Recent advances in tissue acquisition and molecular profiling revealed that DMG and GBM are distinct disease entities, with separate tissue characteristics and genetic profiles. DMG is characterized by heterogeneous tumor tissue often paired with an intact blood-brain barrier, possibly explaining its resistance to chemotherapy. Additional profiling shed a light on the origin of the disease and the influence of several mutations such as a highly recurring K27M mutation in histone H3 on its tumorigenesis. Furthermore, early evidence suggests that DMG has a unique immune microenvironment, characterized by low levels of immune cell infiltration, inflammation, and immunosuppression that may impact disease development and outcome. Within the tumor microenvironment of GBM, tumor-associated microglia/macrophages (TAMs) play a large role in tumor development. Interestingly, TAMs in DMG display distinct features and have low immune activation in comparison to other pediatric gliomas. Although TAMs have been investigated substantially in GBM over the last years, this has not been the case for DMG due to the lack of tissue for research. Bit by bit, studies are exploring the TAM-glioma crosstalk to identify what factors within the DMG microenvironment play a role in the recruitment and polarization of TAMs. Although more research into the immune microenvironment is warranted, there is evidence that targeting or stimulating TAMs and their factors provide a potential treatment option for DMG. In this review, we provide insight into the current status of DMG research, assess the knowledge of the immune microenvironment in DMG and GBM, and present recent findings and therapeutic opportunities surrounding the TAM-glioma crosstalk.

Keywords: Diffuse intrinsic pontine glioma; Diffuse midline glioma; Glioblastoma; H3K27M; Immune microenvironment; Tumor-associated microglia/macrophages.

Fig. 1

Overview of brain areas affected by the tumor in DMG patients. Most tumors are centered around the pons but can extend to the thalamus and cerebellum. Created with BioRender.com

Fig. 2

The H3K27M variant interferes with the EZH2 subunit within the PRC2 complex. A The EZH2 subunit within the PRC2 complex is involved in histone methylation and subsequent transcriptional repression. H3K27M variant proteins interfere with histone methylation through an inhibitory interaction with the EZH2 subunit, while wild-type proteins do not. B In the H3K27 wild type, trimethylation of lysine residues preserves transcriptional repression. In the H3K27M variant, methylation is reduced, resulting in chromatin unwinding and increased gene expression of genes repressed in the H3K27 wild type. Additionally, a focal gain of methylation at other loci results in decreased gene expression elsewhere. Created with BioRender.com

Fig. 3

Comparison of the immune microenvironment in DMG and GBM. A DMG is found in the midline of the brain and consists of heterogeneous tumor tissue with a high spatial and temporal homogeneity in driver mutations. The microenvironment shows low levels of immune infiltration, inflammation, and immunosuppression. There is no increase in T cell infiltration compared to other pediatric gliomas, while there is a decrease in natural killer (NK) cells compared to healthy children. The TAM population (consisting of microglia and macrophages) is unpolarized, expressing low levels of pro-inflammatory markers. Only selected cytokine/chemokine factors have been confirmed in DMG. The standard-of-care for DMG is radiation therapy. B GBM is found throughout the brain, consists of heterogeneous tumor tissue with low spatial and temporal homogeneity of driver mutations, and often coincides with a disrupted blood–brain barrier (BBB). The microenvironment shows high levels of immunosuppression, characterized by infiltration of Treg T cells. In addition, the ratio of CD8 + to CD4 + T cells and the number of NK cells in the tumor are increased. The TAM population in GBM shows some pro-inflammatory markers and is associated with an M0 phenotype. TAMs show an increase in the CD163/CD68 ratio, with increased PD-L1 expression. Many cytokines and chemokines have been found in GBM samples, of which a selection is shown in the figure. The standard-of-care for GBM is surgery, radiation therapy, and chemotherapy. Created with BioRender.com