EPCO-43. STING EPIGENETIC SILENCING IN GBM: IMPLICATIONS FOR INFLAMING THE IMMUNE MICROENVIRONMENT AND DESIGNING COMBINATION THERAPIES

Abstract

Abstract Primary brain tumors including glioblastoma (GBM) are notoriously resistant to immunotherapy due in part to disrupted innate immunity. The stimulator of interferon genes (STING) pathway is a key component of innate immunity and senses pathogenic cytosolic DNA, stimulating the production of type I interferons (IFN) and pro-inflammatory cytokines. We have recently shown that STING signaling is silenced in the neoplastic compartment of the GBM tumor microenvironment, but remains intact in vascular and immune cells. Methylation analysis of bulk GBM tumor samples revealed a STING promoter region that is highly methylated and strongly correlates inversely with STING RNA expression, suggesting epigenetic control of STING expression. Methylation array analysis of patient specimens demonstrates that such promoter hypermethylation is unique amongst innate immune genes, and STING RNA expression correlates strongly with markers of immune inflammation. STING epigenetic silencing is also present in normal fetal and adult brains, suggesting that STING silencing occurs early in neural development and may provide an immunosuppressive environment conducive to tumorigenesis. Treatment with the blood brain barrier-penetrant DNA methyltransferase inhibitor Decitabine demethylates the STING promoter and activates interferon stimulated genes (ISG). STING knockout experiments and treatment with the DNMT1-selective inhibitor GSK-3685032 suggest that STING expression is necessary but not sufficient for ISG activation. These results suggest that innate immune silencing is a fundamental characteristic of GBM that underlies its intrinsic therapy resistance, yet may also represent a vulnerability that can be exploited by epigenetic therapies to inflame the GBM tumor microenvironment. However, epigenetic therapies that de-represses STING may need to be coupled with DNA damaging agents, immunotherapy, or STING agonists for optimal immune inflammation.