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Epigenetic therapy activates type I interferon signaling in murine ovarian cancer to reduce immunosuppression and tumor burden.

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Title: Epigenetic therapy activates type I interferon signaling in murine ovarian cancer to reduce immunosuppression and tumor burden.
Authors: Stone, Meredith L.1, Chiappinelli, Katherine B.1, Huili Li1, Murphy, M.1, Travers, Meghan E.1, Topper, Michael J.1, Baylin, Stephen B.1, Zahnow, Cynthia A.1, Mathios, Dimitrios2, Michael Lim2, Ie-Ming Shih3, Tian-Li Wang4, Chien-Fu Hung4, Bhargava, Vipul5, Cowley, Glenn S.5, Wiehagen, Karla R.6, Bachman, Kurtis E.7, Strick, Reiner8, Strissel, Pamela L.8
Source: Proceedings of the National Academy of Sciences of the United States of America. 12/19/2017, Vol. 114 Issue 51, pE10981-E10990. 10p.
Subjects: Ovarian cancer, Immunosuppression, Epigenetics, Type I interferons, Immune system
Abstract: Ovarian cancer is the most lethal of all gynecological cancers and there is an urgent unmet need to develop new therapies. Epithelial ovarian cancer (EOC) is characterized by an immune suppressive microenvironment and response of ovarian cancers to immune therapies has thus far been disappointing. We now find, in a mouse model of EOC, that clinically relevant doses of DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi, respectively) reduce the immune suppressive microenvironment through type I IFN signaling and improve response to immune checkpoint therapy. These data indicate that the type I IFN response is required for effective in vivo antitumorigenic actions of the DNMTi 5-azacytidine (AZA). Through type I IFN signaling, AZA increases the numbers of CD45+ immune cells and the percentage of active CD8+ T and natural killer (NK) cells in the tumor microenvironment, while reducing tumor burden and extending survival. AZA also increases viral defense gene expression in both tumor and immune cells and reduces the percentage of macrophages and myeloid-derived suppressor cells in the tumor microenvironment. The addition of an HDACi to AZA enhances themodulation of the immune microenvironment, specifically increasing T and NK cell activation and reducing macrophages over AZA treatment alone, while further increasing the survival of the mice. Finally, a triple combination of DNMTi/HDACi plus the immune checkpoint inhibitor α-PD-1 provides the best antitumor effect and longest overall survival and may be an attractive candidate for future clinical trials in ovarian cancer. [ABSTRACT FROM AUTHOR]
Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Engineering Source
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DbLabel: Engineering Source
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PubTypeId: academicJournal
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  Data: Epigenetic therapy activates type I interferon signaling in murine ovarian cancer to reduce immunosuppression and tumor burden.
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  Data: <searchLink fieldCode="AR" term="%22Stone%2C+Meredith+L%2E%22">Stone, Meredith L.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Chiappinelli%2C+Katherine+B%2E%22">Chiappinelli, Katherine B.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Huili+Li%22">Huili Li</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Murphy%2C+M%2E%22">Murphy, M.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Travers%2C+Meghan+E%2E%22">Travers, Meghan E.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Topper%2C+Michael+J%2E%22">Topper, Michael J.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Baylin%2C+Stephen+B%2E%22">Baylin, Stephen B.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Zahnow%2C+Cynthia+A%2E%22">Zahnow, Cynthia A.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Mathios%2C+Dimitrios%22">Mathios, Dimitrios</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Michael+Lim%22">Michael Lim</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Ie-Ming+Shih%22">Ie-Ming Shih</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Tian-Li+Wang%22">Tian-Li Wang</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Chien-Fu+Hung%22">Chien-Fu Hung</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Bhargava%2C+Vipul%22">Bhargava, Vipul</searchLink><relatesTo>5</relatesTo><br /><searchLink fieldCode="AR" term="%22Cowley%2C+Glenn+S%2E%22">Cowley, Glenn S.</searchLink><relatesTo>5</relatesTo><br /><searchLink fieldCode="AR" term="%22Wiehagen%2C+Karla+R%2E%22">Wiehagen, Karla R.</searchLink><relatesTo>6</relatesTo><br /><searchLink fieldCode="AR" term="%22Bachman%2C+Kurtis+E%2E%22">Bachman, Kurtis E.</searchLink><relatesTo>7</relatesTo><br /><searchLink fieldCode="AR" term="%22Strick%2C+Reiner%22">Strick, Reiner</searchLink><relatesTo>8</relatesTo><br /><searchLink fieldCode="AR" term="%22Strissel%2C+Pamela+L%2E%22">Strissel, Pamela L.</searchLink><relatesTo>8</relatesTo>
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  Data: <searchLink fieldCode="DE" term="%22Ovarian+cancer%22">Ovarian cancer</searchLink><br /><searchLink fieldCode="DE" term="%22Immunosuppression%22">Immunosuppression</searchLink><br /><searchLink fieldCode="DE" term="%22Epigenetics%22">Epigenetics</searchLink><br /><searchLink fieldCode="DE" term="%22Type+I+interferons%22">Type I interferons</searchLink><br /><searchLink fieldCode="DE" term="%22Immune+system%22">Immune system</searchLink>
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  Label: Abstract
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  Data: Ovarian cancer is the most lethal of all gynecological cancers and there is an urgent unmet need to develop new therapies. Epithelial ovarian cancer (EOC) is characterized by an immune suppressive microenvironment and response of ovarian cancers to immune therapies has thus far been disappointing. We now find, in a mouse model of EOC, that clinically relevant doses of DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi, respectively) reduce the immune suppressive microenvironment through type I IFN signaling and improve response to immune checkpoint therapy. These data indicate that the type I IFN response is required for effective in vivo antitumorigenic actions of the DNMTi 5-azacytidine (AZA). Through type I IFN signaling, AZA increases the numbers of CD45+ immune cells and the percentage of active CD8+ T and natural killer (NK) cells in the tumor microenvironment, while reducing tumor burden and extending survival. AZA also increases viral defense gene expression in both tumor and immune cells and reduces the percentage of macrophages and myeloid-derived suppressor cells in the tumor microenvironment. The addition of an HDACi to AZA enhances themodulation of the immune microenvironment, specifically increasing T and NK cell activation and reducing macrophages over AZA treatment alone, while further increasing the survival of the mice. Finally, a triple combination of DNMTi/HDACi plus the immune checkpoint inhibitor α-PD-1 provides the best antitumor effect and longest overall survival and may be an attractive candidate for future clinical trials in ovarian cancer. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1073/pnas.1712514114
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      – SubjectFull: Epigenetics
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      – SubjectFull: Type I interferons
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