Epigenetics and immune cells in medulloblastoma

Abstract

Medulloblastoma (MB) is a highly malignant childhood tumor of the cerebellum. Transcriptional and epigenetic signatures have classified MB into four molecular subgroups, further stratified into biologically different subtypes with distinct somatic copy-number aberrations, driver genes, epigenetic alterations, activated pathways, and clinical outcomes. The brain tumor microenvironment (BTME) is of importance to regulate a complex network of cells, including immune cells, involved in cancer progression in brain malignancies. MB was considered with a "cold" immunophenotype due to the low influx of immune cells across the blood brain barrier (BBB). Recently, this assumption has been reconsidered because of the identification of infiltrating immune cells showing immunosuppressive phenotypes in the BTME of MB tumors. Here, we are providing a comprehensive overview of the current status of epigenetics alterations occurring during cancer progression with a description of the genomic landscape of MB by focusing on immune cells within the BTME. We further describe how new immunotherapeutic approaches could influence concurring epigenetic mechanisms of the immunosuppressive cells in BTME. In conclusion, the modulation of these molecular genetic complexes in BTME during cancer progression might enhance the therapeutic benefit, thus firing new weapons to fight MB.

Keywords: brain tumor microenvironment; epigenetics; immune cells; immunotherapeutics; medulloblastoma.

FIGURE 1

Epigenetic regulation of microglia in MB. Microglia polarize into M1 phenotype following the H3K27 histone tri-methyltransferase activity of EZH2. The M1 classical microglia secretes proinflammatory cytokines, with a most prominent action of interleukins IL-23, IL-12, IL-6, IL-1𝛃 and tumor necrosis factor-alpha (TNF-α). In contrast, the demethylase activity of JMJD3 promotes M2 microglia, which is associated with low expression of MHC-II, IL-12, and IL-23 and production of anti-inflammatory cytokines acting like TGF-𝛃 and IL-10.

FIGURE 2

Overview of MB treatment modalities in the last decade. The scheme represents the therapeutic strategy for MB currently used in clinics that generally includes the surgical resection followed by irradiation and cycles of adjuvant chemotherapy mostly based on molecular and histopathological features. Recently, genomics and epigenomics approaches have clarified the molecular risk assessment among the molecular MB subgroups. Furthermore, the presence of immunosuppressive immune cells infiltrating the BTME in MB patients has been also reported. Thus, genetic and epigenetic modulators targeting the immune cells within the BTME could obtain the most efficient and personalized therapy to increase the patient survival timing. The figure was created via Biorender.com.