Abstract Details

Title STING is silenced by DNA methylation in primary brain tumors and is rescued by methyltransferase inhibition

Topic Neuro-oncology

Presentation(s) P13 - Poster Session 13 (8:00 AM-9:00 AM)

Poster/Presentation
Number 4-004

Background The STING pathway is a critical sensor of cytosolic DNA and initiates inflammatory signaling in the context of viral infection and cancer. STING suppression has recently been described in a variety of solid tumors, but its role in brain tumors remains poorly understood. Here we investigate the mechanisms of STING signaling disruption in gliomas, and extend our analyses to the normal brain, other primary brain tumors, and extracranial tumors.

Objective To determine how STING signaling is disrupted in gliomas, other primary brain tumors, and the normal brain.

Design/Methods We used methylation arrays, RNA sequencing, and protein expression assays to probe STING pathway expression in patient-derived glioblastoma tissues and glioma cell culture systems. We additionally used published methylation array datasets to investigate the STING methylation landscape across cancer and non-cancerous neurologic disease states.

Results STING expression and function are suppressed in glioblastomas and other primary brain tumors. This suppression is mediated by promoter hypermethylation and is rare amongst extracranial cancers. However, neuroectoderm-derived cancers, and normal adult and fetal brain also exhibit methylation-mediated silencing, suggesting a neurodevelopmental origin for STING epigenetic silencing. In gliomas, we demonstrate that STING expression is suppressed specifically in malignant cells but is intact in immune and stromal cells in the tumor microenvironment. We further demonstrate that this epigenetic silencing is reversible via DNA methyltransferase (DNMT) inhibition in a manner that reconstitutes double-stranded DNA sensing and inflammatory signaling.

Conclusions STING silencing via promoter hypermethylation characterizes the normal and cancerous brain, correlates with an immunosuppressive microenvironment, and is therapeutically reversible by DNMT inhibitors.

Authors/Disclosures
Justin T. Low, MD, PhD (Duke University School of Medicine) PRESENTER	Dr. Low has nothing to disclose.
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Kevin Stevenson	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file