Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML

Jessica M. Salmon, Izabela Todorovski, Kym L. Stanley, Claudia Bruedigam, Conor J. Kearney, Luciano G. Martelotto, Fernando Rossello, Timothy Semple, Gisela Mir Arnau, Magnus Zethoven, Michael Bots, Stefan Bjelosevic, Leonie A. Cluse, Peter J. Fraser, Veronique Litalien, Eva Vidacs, Kate McArthur, Antony Y. Matthews, Elise Gressier, Nicole A. De WeerdJens Lichte, Madison J. Kelly, Simon J. Hogg, Paul J. Hertzog, Lev M. Kats, Stephin J. Vervoort, Daniel D. De Carvalho, Stefanie Scheu, Sammy Bedoui, Benjamin T. Kile, Steven W. Lane, Andrew C. Perkins, Andrew H. Wei, Pilar M. Dominguez, Ricky W. Johnstone

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

Abstract

Pharmacologic inhibition of epigenetic enzymes can have therapeutic benefit against hematologic malignancies. In addition to affecting tumor cell growth and proliferation, these epigenetic agents may induce antitumor immunity. Here, we discovered a novel immunoregulatory mechanism through inhibition of histone deacetylases (HDAC). In models of acute myeloid leukemia (AML), leukemia cell differentiation and therapeutic benefit mediated by the HDAC inhibitor (HDACi) panobinostat required activation of the type I interferon (IFN) pathway. Plasmacytoid dendritic cells (pDC) 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, whereas combined treatment with panobinostat and IFNα improved outcomes in preclinical models. These discoveries offer a new therapeutic approach for AML and demonstrate that epigenetic rewiring of pDCs enhances antitumor immunity, opening the possibility of exploiting this approach for immunotherapies.

Original languageEnglish
Pages (from-to)1560-1579
Number of pages20
JournalCancer Discovery
Volume12
Issue number6
DOIs
Publication statusPublished - Jun 2022

Cite this