Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML.
Journal
Cancer discovery
ISSN: 2159-8290
Titre abrégé: Cancer Discov
Pays: United States
ID NLM: 101561693
Informations de publication
Date de publication:
02 06 2022
02 06 2022
Historique:
received:
10
08
2020
revised:
28
10
2021
accepted:
16
03
2022
pubmed:
22
3
2022
medline:
7
6
2022
entrez:
21
3
2022
Statut:
ppublish
Résumé
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. 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.
Identifiants
pubmed: 35311997
pii: 682300
doi: 10.1158/2159-8290.CD-20-1145
pmc: PMC9355625
doi:
Substances chimiques
Histone Deacetylase Inhibitors
0
Panobinostat
9647FM7Y3Z
Histone Deacetylases
EC 3.5.1.98
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1560-1579Subventions
Organisme : CIHR
ID : 201512MSH360794-228629
Pays : Canada
Organisme : CIHR
ID : FDN 148430
Pays : Canada
Organisme : CIHR
ID : PJT 165986
Pays : Canada
Informations de copyright
©2022 The Authors; Published by the American Association for Cancer Research.
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