Targeting an RNA Editor to Impede H3K27M+ Pediatric Gliomas
Ramsoomair, C. K.; Alvarez, V.; Sarmiento, F.; Aramburu Berckemeyer, M.; Seetharam, D.; Kalliecharan, K.; Moorkkannur, S. N.; Mitchell, J.; Hudson, A.; Taylor, J.; Ceccarelli, M.; Bayik, D.; Becher, O. J.; Prabahakar, R.; Welford, S.; Gampel, B.; De Carvalho, D. D.; Reinberg, D.; Shah, A. H.
Show abstract
Diffuse midline glioma (DMG) is a lethal pediatric brain tumor with no curative therapies. Immune checkpoint blockade (ICB) has shown limited efficacy in DMG, largely due to poor T cell infiltration, low immune checkpoint (IC) expression, and a low tumor mutational burden. Here, we identify adenosine deaminase acting on RNA (ADAR), an RNA-editing enzyme that suppresses endogenous dsRNA sensing, as a key mediator of immune evasion in H3K27M-mutant DMG. ADAR is significantly overexpressed in H3K27M tumors relative to wild-type high-grade gliomas, and its depletion selectively suppresses proliferation in patient-derived DMG cells. The H3K27M mutation was found to synergize with ADAR loss to increase retroelement expression, activate type I interferon signaling, and induce immune checkpoint expression. We further identify all-trans retinoic acid (ATRA) as a pharmacologic inducer of ADAR degradation. At clinically relevant doses, ATRA phenocopies ADAR depletion, enhancing antiviral and interferon responses while increasing tumor immunogenicity. In orthotopic immunocompetent DMG models, ATRA enhances CD8+ T cell infiltration and synergizes with ICB and irradiation to improve survival.
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