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

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. How...

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Veröffentlicht in:Cancer research (Chicago, Ill.) Jg. 73; H. 24; S. 7265
Hauptverfasser: West, Alison C, Mattarollo, Stephen R, Shortt, Jake, Cluse, Leonie A, Christiansen, Ailsa J, Smyth, Mark J, Johnstone, Ricky W
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 15.12.2013
Schlagworte:
Adenocarcinoma - drug therapy
Adenocarcinoma - immunology
Animals
Apoptosis - drug effects
Apoptosis - immunology
Cell Growth Processes - drug effects
Cell Growth Processes - immunology
Cell Line, Tumor
Colonic Neoplasms - drug therapy
Colonic Neoplasms - immunology
Histone Deacetylase Inhibitors - pharmacology
Immune System - drug effects
Immune System - physiology
Immunotherapy
Interferon gamma Receptor
Leukemia, Lymphoid - drug therapy
Leukemia, Lymphoid - immunology
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Neoplasms, Experimental - drug therapy
Neoplasms, Experimental - immunology
Receptors, Interferon - metabolism
ISSN:1538-7445, 1538-7445
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Zusammenfassung: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. We showed 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, HDACi-treated 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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1538-7445
1538-7445
DOI:10.1158/0008-5472.CAN-13-0890