EPCO-50. THE TRANSCRIPTIONAL LANDSCAPE OF KEY INNATE DNA SENSORS WITHIN PRIMARY BRAIN TUMORS

Abstract

Abstract Primary brain tumors are notoriously resistant to immunotherapy. The efficacy of these treatments potentially requires normal expression of DNA innate sensors within both the immune and tumor compartments. Recently, we found that STING1, involved in the CGAS/STING pathway, is epigenetically silenced in the neoplastic cells of primary brain tumors. This silencing can be traced back to the normal brain. We and others have shown that rescue of STING1 expression can be modulated with epigenetic treatments. The mechanism by which DNA damage in cancer leads to an inflammatory response sheds light on the significance of other DNA sensors. We hypothesize that innate immune silencing within the tumor contributes to immunotherapy resistance and the addition of epigenetic treatments could increase efficacy. We evaluated the transcriptional landscape of DNA innate sensors within normal adult brain and in patient derived tumors including glioblastoma, pilocytic astrocytoma, and diffuse midline gliomas, H3K27M mutant. We found low expression of additional cytosolic DNA sensors including cGAS, AIM2, ZBP1 in normal neuronal as well as tumor cells. Since epigenetic silencing is modulated during normal development, we compared the transcriptional innate profiles from normal cortex brain development to primary brain cancers. DNA innate immune sensor expression correlates with pre-oligodendrocyte progenitor cells and oligodendrocyte progenitor cells. These results suggest the innate immune suppression of these key cytosolic DNA sensors is established early in fetal brain development and retained in the context of primary brain tumors. We are currently exploring the epigenetic profiles of fetal brain and brain tumors to determine how these innate immune expression patterns affect tumorigenesis and response to immunotherapy treatment.