Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML-Reference-Cited by-同舟云学术

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

Published:2022-03-21 Issue:6 Volume:12 Page:1560-1579
ISSN:2159-8274
Container-title:Cancer Discovery
language:en
Short-container-title:

Author:

Salmon Jessica M.¹²^ORCID,Todorovski Izabela¹³^ORCID,Stanley Kym L.¹,Bruedigam Claudia⁴⁵^ORCID,Kearney Conor J.¹³,Martelotto Luciano G.⁶,Rossello Fernando⁶⁷^ORCID,Semple Timothy⁸,Arnau Gisela Mir³⁸^ORCID,Zethoven Magnus¹^ORCID,Bots Michael⁹,Bjelosevic Stefan¹³^ORCID,Cluse Leonie A.¹,Fraser Peter J.¹,Litalien Veronique²,Vidacs Eva¹,McArthur Kate¹⁰^ORCID,Matthews Antony Y.¹¹^ORCID,Gressier Elise¹²^ORCID,de Weerd Nicole A.¹¹^ORCID,Lichte Jens¹³,Kelly Madison J.¹^ORCID,Hogg Simon J.¹³^ORCID,Hertzog Paul J.¹¹,Kats Lev M.¹³^ORCID,Vervoort Stephin J.¹³,De Carvalho Daniel D.¹⁴^ORCID,Scheu Stefanie¹³^ORCID,Bedoui Sammy¹²,Kile Benjamin T.¹⁰¹⁵^ORCID,Lane Steven W.⁴⁵,Perkins Andrew C.²^ORCID,Wei Andrew H.²^ORCID,Dominguez Pilar M.¹³^ORCID,Johnstone Ricky W.¹³^ORCID

Affiliation:

1. 1Translational Haematology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

2. 2Australian Centre for Blood Diseases, Monash University and The Alfred Hospital, Melbourne, Australia.

3. 3The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.

4. 4Cancer Program, Queensland Institute of Medical Research (QIMR) Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

5. 5School of Medicine, University of Queensland, Brisbane, Queensland, Australia.

6. 6Single Cell Innovation Lab, Department of Clinical Pathology, University of Melbourne, Parkville, Victoria, Australia.

7. 7University of Melbourne Centre for Cancer Research, The University of Melbourne, Melbourne, Victoria, Australia.

8. 8Molecular Genomics Core, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

9. 9Laboratory of Clinical Chemistry, Academic Medical Center, University of Amsterdam, the Netherlands.

10. 10Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia.

11. 11Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular and Translational Sciences, Monash University Clayton Victoria, Australia.

12. 12Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria, Australia.

13. 13Institute of Medical Microbiology and Hospital Hygiene, University of Düsseldorf, Düsseldorf, Germany.

14. 14Princess Margaret Cancer Centre, University Health Network, Toronto, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Canada.

15. 15Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia.

Abstract

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. Significance: We demonstrate that HDACis induce terminal differentiation of AML through epigenetic remodeling of pDCs, resulting in production of type I IFN that is important for the therapeutic effects of HDACis. The study demonstrates the important functional interplay between the immune system and leukemias in response to HDAC inhibition. This article is highlighted in the In This Issue feature, p. 1397

Funder

Cure Cancer Australia

Netherlands Organization for Scientific Research

NHMRC EL1 Fellowship

Victorian Cancer Agency Fellowship

German Research Foundation

Canadian Institute of Health Research

Canada Research Chairs NHMRC

NHMRC Principal Research Fellowship

Cancer Council Victoria

Publisher

American Association for Cancer Research (AACR)