IMMU-15. INTERPLAY BETWEEN ATRXAND IDH1 MUTATIONS GOVERNS INNATE IMMUNE RESPONSES IN DIFFUSE GLIOMAS

Abstract

Abstract Stimulating the innate immune system has been explored as a therapeutic option for the treatment of gliomas. Inactivating mutations in alpha-thalassemia retardation X-linked (ATRX) are defining molecular alterations in IDH-mutant astrocytomas and have been implicated in dysfunctional immune signaling. However, little is known about the interplay between ATRX loss and IDH mutation on innate immunity. To explore this interaction, we used both CRISPR and the RCAS/tva system to generate murine models of ATRX-deficient glioma, in the presence and absence of the IDH1 R132H mutation. We found that ATRX-deficient glioma cells were exquisitely sensitive to dsRNA-based innate immune agonism, displaying increases in inflammatory gene expression and profound cytokine release in vitro, while mice bearing ATRX KO tumors displayed increased T-cell infiltration and improved survival. The presence of IDH1 R132H dampened baseline expression of key innate immune genes and cytokines, with genetic and pharmacological inhibition of IDH1 R132H partially rescuing this suppression. Despite the suppression observed at baseline, IDH1 R132H expression did not interfere with the ATRX KO-mediated sensitivity to dsRNA agonism. These results demonstrate that ATRX loss primes cells for recognition of and activation against dsRNA, while IDH1 R132H reversibly masks this priming. Thus, this study suggests that innate immunity is a potential therapeutic vulnerability of astrocytoma. Further studies are in progress to validate the influence of ATRX loss on immune signaling and tumor-immune coevolution within human tumors.