An intact immune system is required for the anticancer activities of histone deacetylase inhibitors

West, Alison C., Mattarollo, Stephen R., Shortt, Jake, Cluse, Leonie A., Christiansen, Ailsa J., Smyth, Mark J. and Johnstone, Ricky W. (2013) An intact immune system is required for the anticancer activities of histone deacetylase inhibitors. Cancer Research, 73 24: 7265-7276. doi:10.1158/0008-5472.CAN-13-0890

Author West, Alison C.
Mattarollo, Stephen R.
Shortt, Jake
Cluse, Leonie A.
Christiansen, Ailsa J.
Smyth, Mark J.
Johnstone, Ricky W.
Title An intact immune system is required for the anticancer activities of histone deacetylase inhibitors
Journal name Cancer Research   Check publisher's open access policy
ISSN 0008-5472
Publication date 2013-12-15
Year available 2013
Sub-type Article (original research)
DOI 10.1158/0008-5472.CAN-13-0890
Volume 73
Issue 24
Start page 7265
End page 7276
Total pages 12
Place of publication Philadelphia, PA, United States
Publisher American Association for Cancer Research
Collection year 2014
Language eng
Subject 1306 Cancer Research
2730 Oncology
Formatted abstract
Cell-intrinsic effects such as induction of apoptosis and/or inhibition of cell proliferation have been proposed as the major antitumor responses to histone deacetylase inhibitors (HDACi). These compounds can also mediate immune-modulatory effects that may contribute to their anticancer effects. However, HDACi can also induce anti-inflammatory, and potentially immunosuppressive, outcomes. We therefore sought to clarify the role of the immune system in mediating the efficacy of HDACi in a physiologic setting, using preclinical, syngeneic murine models of hematologic malignancies and solid tumors.Weshowed an intact immune system was required for the robust anticancer effects of the HDACi vorinostat and panobinostat against a colon adenocarcinoma and two aggressive models of leukemia/lymphoma. Importantly, although HDACi-treated immunocompromised mice bearing established lymphoma succumbed to disease significantly earlier than tumor bearing, HDACitreated wild-type (WT) mice, treatment with the conventional chemotherapeutic etoposide equivalently enhanced the survival of both strains. IFN-γ and tumor cell signaling through IFN-γR were particularly important for the anticancer effects of HDACi, and vorinostat and IFN-γ acted in concert to enhance the immunogenicity of tumor cells. Furthermore, we show that a combination of vorinostat with α-galactosylceramide (α-GalCer), an IFN-γ-inducing agent, was significantly more potent against established lymphoma than vorinostat treatment alone. Intriguingly, B cells, but not natural killer cells or CD8+ T cells, were implicated as effectors of the vorinostat antitumor immune response. Together, our data suggest HDACi are immunostimulatory during cancer treatment and that combinatorial therapeutic regimes with immunotherapies should be considered in the clinic.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Medicine Publications
UQ Diamantina Institute Publications
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Citation counts: TR Web of Science Citation Count  Cited 34 times in Thomson Reuters Web of Science Article | Citations
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