Overcoming immunotherapy barriers in pediatric brain tumors: epigenetic strategies

The advent of cancer immunotherapy has led to dramatically improved outcomes in several immunogenic adult cancers. Similar successes have been seen in some pediatric cancers, but only in specific settings. A particular challenge has been the application of immunotherapy approaches to pediatric brain tumors, with early clinical experience showing promise but few durable responses. Key barriers to immunotherapy arise from distinctive features of pediatric brain tumors, including low tumor immunogenicity, an immunosuppressive tumor microenvironment, and impaired effector cell function. Additionally, the application of immunotherapies to the confined space of the CNS must be carefully calibrated to avoid neurological toxicity. Unlike immunogenic adult cancers, many pediatric brain tumors have a paucity of genetic mutations and are driven by epigenetic alterations. Tumor subtypes with the same genetic driver can have markedly different tumor immune microenvironments, illustrating that non-genetic factors contribute to immune dysregulation. Here, we review key features of the tumor immune microenvironments of malignant pediatric brain tumors and consider how these features serve as barriers to successful application of immunotherapy. We evaluate evidence that pharmacologic manipulation of the epigenome can be leveraged to shape the tumor immune microenvironment and consider combinatorial approaches using epigenetic-targeted therapies and immunotherapies to inform future clinical studies of pediatric brain tumors.