Epigenetic reprogramming of plasmacytoid dendritic cells drives type I interferon-dependent differentiation of acute myeloid leukemias for therapeutic benefit

Abstract

Pharmacological inhibition of epigenetic enzymes can have therapeutic benefit, particularly against hematological malignancies. While these agents can affect tumor cell growth and proliferation, recent studies have demonstrated that pharmacological de-regulation of epigenetic modifiers may additionally mediate anti-tumor immune responses. Here we discovered a novel mechanism of immune regulation through the inhibition of histone deacetylases (HDACs). In a genetically engineered model of t(8;21) AML, leukemia cell differentiation and therapeutic benefit mediated by the HDAC inhibitor panobinostat required activation of the type I interferon (IFN) signaling pathway. Plasmacytoid dendritic cells (pDCs) were identified as the cells producing type I IFN in response to panobinostat, through transcriptional activation of IFN genes concomitant with increased H3K27 acetylation at these loci. Depletion of pDCs abrogated panobinostat-mediated activation of type I IFN signaling in leukemia cells and impaired therapeutic efficacy, while combined treatment of panobinostat and recombinant IFN improved therapeutic outcomes. These discoveries offer a new therapeutic approach for t(8;21) AML and demonstrate that epigenetic rewiring of pDCs enhances anti-tumor immunity, opening the possibility of exploiting this cell type as a new target for immunotherapy.