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Epigenetic activation of plasmacytoid DC drives IFNAR-dependent therapeutic differentiation of AML.

Pharmacological inhibition of epigenetic enzymes can have therapeutic benefit against hematological malignancies. In addition to affecting tumor cell growth and proliferation, these epigenetic agents may induce anti-tumor immunity. Here we discovered a novel immuno-regulatory mechanism through inhibition of histone deacetylases (HDACs). In models of AML, leukemia cell differentiation and therapeutic benefit mediated by the HDAC inhibitor panobinostat required activation of the type I interferon (IFN) pathway. Plasmacytoid dendritic cells (pDCs) produced type I IFN after panobinostat treatment, through transcriptional activation of IFN genes concomitant with increased H3K27 acetylation at these loci. Depletion of pDCs abrogated panobinostat-mediated induction of type I IFN signaling in leukemia cells and impaired therapeutic efficacy, while combined treatment of panobinostat and IFN improved outcomes in pre-clinical models. These discoveries offer a new therapeutic approach for AML and demonstrate that epigenetic rewiring of pDCs enhances anti-tumor immunity, opening the possibility of exploiting this approach for immunotherapies.