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DIPG is a universally fatal pediatric brainstem tumor with no effective therapy. Recent work has shown that over 80% of DIPG cases harbor the H3K27M mutation leading to global loss of the repressive H3K27 trimethylation mark, global DNA hypomethylation, and a distinct gene expression signature. We sought to exploit epigenetic vulnerabilities in DIPG through the use of DNA methyltransferase inhibitors and histone deacetylase (HDAC) inhibitors. We find that treatment with low-dose 5-aza-2’-deoxycytidine (decitabine), alone and in combination with HDAC inhibitors, elicits profound genome-wide demethylation in DIPG patient-derived neurosphere cell lines, impairs proliferation, and induces apoptosis. We show that this treatment induces immune activation, with induction of type I interferon signaling, increased expression of major histocompatibility complexes, and expression of tumor antigens. These results suggest that the immunogenicity of DIPG may be modulated by epigenetic therapies, suggesting the possibility of novel combination approaches to immunotherapy of DIPG in the future.

DIPG-12. TARGETING EPIGENETIC MODIFIERS TO INDUCE IMMUNE SIGNALING IN DIPG