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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Vydané v:	Cancer research (Chicago, Ill.) Ročník 73; číslo 24; s. 7265
Hlavní autori:	West, Alison C, Mattarollo, Stephen R, Shortt, Jake, Cluse, Leonie A, Christiansen, Ailsa J, Smyth, Mark J, Johnstone, Ricky W
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 15.12.2013
Predmet:	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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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. 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.
AbstractList	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. 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.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.
Author	Shortt, Jake Christiansen, Ailsa J West, Alison C Mattarollo, Stephen R Smyth, Mark J Cluse, Leonie A Johnstone, Ricky W
Author_xml	– sequence: 1 givenname: Alison C surname: West fullname: West, Alison C organization: Authors' Affiliations: Cancer Therapeutics Program, and Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria; The University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba; Queensland Institute of Medical Research; and School of Medicine, University of Queensland, Herston, Queensland, Australia – sequence: 2 givenname: Stephen R surname: Mattarollo fullname: Mattarollo, Stephen R – sequence: 3 givenname: Jake surname: Shortt fullname: Shortt, Jake – sequence: 4 givenname: Leonie A surname: Cluse fullname: Cluse, Leonie A – sequence: 5 givenname: Ailsa J surname: Christiansen fullname: Christiansen, Ailsa J – sequence: 6 givenname: Mark J surname: Smyth fullname: Smyth, Mark J – sequence: 7 givenname: Ricky W surname: Johnstone fullname: Johnstone, Ricky W
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SubjectTerms	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
Title	An intact immune system is required for the anticancer activities of histone deacetylase inhibitors
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