Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses

Katherine B. Chiappinelli; Pamela L. Strissel; Alexis Desrichard; Huili Li; Christine Henke; Benjamin Akman; Alexander Hein; Neal S. Rote; Leslie M. Cope; Alexandra Snyder; Vladimir Makarov; Sadna Buhu; Dennis J. Slamon; Jedd D. Wolchok; Drew M. Pardoll; Matthias W. Beckmann; Cynthia A. Zahnow; Taha Mergoub; Timothy A. Chan; Stephen B. Baylin; Reiner Strick

doi:10.1016/j.cell.2015.07.011

Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses

Katherine B. Chiappinelli, Pamela L. Strissel, Alexis Desrichard, Huili Li, Christine Henke, Benjamin Akman, Alexander Hein, Neal S. Rote, Leslie M. Cope, Alexandra Snyder, Vladimir Makarov, Sadna Buhu, Dennis J. Slamon, Jedd D. Wolchok, Drew M. Pardoll, Matthias W. Beckmann, Cynthia A. Zahnow, Taha Mergoub, Timothy A. Chan, Stephen B. BaylinReiner Strick

School of Medicine

Research output: Contribution to journal › Article › peer-review

657 Scopus citations

Abstract

Summary We show that DNA methyltransferase inhibitors (DNMTis) upregulate immune signaling in cancer through the viral defense pathway. In ovarian cancer (OC), DNMTis trigger cytosolic sensing of double-stranded RNA (dsRNA) causing a type I interferon response and apoptosis. Knocking down dsRNA sensors TLR3 and MAVS reduces this response 2-fold and blocking interferon beta or its receptor abrogates it. Upregulation of hypermethylated endogenous retrovirus (ERV) genes accompanies the response and ERV overexpression activates the response. Basal levels of ERV and viral defense gene expression significantly correlate in primary OC and the latter signature separates primary samples for multiple tumor types from The Cancer Genome Atlas into low versus high expression groups. In melanoma patients treated with an immune checkpoint therapy, high viral defense signature expression in tumors significantly associates with durable clinical response and DNMTi treatment sensitizes to anti-CTLA4 therapy in a pre-clinical melanoma model.

Original language	English (US)
Pages (from-to)	974-986
Number of pages	13
Journal	Cell
Volume	162
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2015.07.011
State	Published - Aug 27 2015

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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Chiappinelli, K. B., Strissel, P. L., Desrichard, A., Li, H., Henke, C., Akman, B., Hein, A., Rote, N. S., Cope, L. M., Snyder, A., Makarov, V., Buhu, S., Slamon, D. J., Wolchok, J. D., Pardoll, D. M., Beckmann, M. W., Zahnow, C. A., Mergoub, T., Chan, T. A., ... Strick, R. (2015). Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses. Cell, 162(5), 974-986. https://doi.org/10.1016/j.cell.2015.07.011

Chiappinelli, KB, Strissel, PL, Desrichard, A, Li, H, Henke, C, Akman, B, Hein, A, Rote, NS, Cope, LM, Snyder, A, Makarov, V, Buhu, S, Slamon, DJ, Wolchok, JD, Pardoll, DM, Beckmann, MW, Zahnow, CA, Mergoub, T, Chan, TA, Baylin, SB & Strick, R 2015, 'Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses', Cell, vol. 162, no. 5, pp. 974-986. https://doi.org/10.1016/j.cell.2015.07.011

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title = "Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses",

abstract = "Summary We show that DNA methyltransferase inhibitors (DNMTis) upregulate immune signaling in cancer through the viral defense pathway. In ovarian cancer (OC), DNMTis trigger cytosolic sensing of double-stranded RNA (dsRNA) causing a type I interferon response and apoptosis. Knocking down dsRNA sensors TLR3 and MAVS reduces this response 2-fold and blocking interferon beta or its receptor abrogates it. Upregulation of hypermethylated endogenous retrovirus (ERV) genes accompanies the response and ERV overexpression activates the response. Basal levels of ERV and viral defense gene expression significantly correlate in primary OC and the latter signature separates primary samples for multiple tumor types from The Cancer Genome Atlas into low versus high expression groups. In melanoma patients treated with an immune checkpoint therapy, high viral defense signature expression in tumors significantly associates with durable clinical response and DNMTi treatment sensitizes to anti-CTLA4 therapy in a pre-clinical melanoma model.",

author = "Chiappinelli, {Katherine B.} and Strissel, {Pamela L.} and Alexis Desrichard and Huili Li and Christine Henke and Benjamin Akman and Alexander Hein and Rote, {Neal S.} and Cope, {Leslie M.} and Alexandra Snyder and Vladimir Makarov and Sadna Buhu and Slamon, {Dennis J.} and Wolchok, {Jedd D.} and Pardoll, {Drew M.} and Beckmann, {Matthias W.} and Zahnow, {Cynthia A.} and Taha Mergoub and Chan, {Timothy A.} and Baylin, {Stephen B.} and Reiner Strick",

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doi = "10.1016/j.cell.2015.07.011",

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T1 - Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses

AU - Chiappinelli, Katherine B.

AU - Strissel, Pamela L.

AU - Desrichard, Alexis

AU - Li, Huili

AU - Henke, Christine

AU - Akman, Benjamin

AU - Hein, Alexander

AU - Rote, Neal S.

AU - Cope, Leslie M.

AU - Snyder, Alexandra

AU - Makarov, Vladimir

AU - Buhu, Sadna

AU - Slamon, Dennis J.

AU - Wolchok, Jedd D.

AU - Pardoll, Drew M.

AU - Beckmann, Matthias W.

AU - Zahnow, Cynthia A.

AU - Mergoub, Taha

AU - Chan, Timothy A.

AU - Baylin, Stephen B.

AU - Strick, Reiner

PY - 2015/8/27

Y1 - 2015/8/27

N2 - Summary We show that DNA methyltransferase inhibitors (DNMTis) upregulate immune signaling in cancer through the viral defense pathway. In ovarian cancer (OC), DNMTis trigger cytosolic sensing of double-stranded RNA (dsRNA) causing a type I interferon response and apoptosis. Knocking down dsRNA sensors TLR3 and MAVS reduces this response 2-fold and blocking interferon beta or its receptor abrogates it. Upregulation of hypermethylated endogenous retrovirus (ERV) genes accompanies the response and ERV overexpression activates the response. Basal levels of ERV and viral defense gene expression significantly correlate in primary OC and the latter signature separates primary samples for multiple tumor types from The Cancer Genome Atlas into low versus high expression groups. In melanoma patients treated with an immune checkpoint therapy, high viral defense signature expression in tumors significantly associates with durable clinical response and DNMTi treatment sensitizes to anti-CTLA4 therapy in a pre-clinical melanoma model.

AB - Summary We show that DNA methyltransferase inhibitors (DNMTis) upregulate immune signaling in cancer through the viral defense pathway. In ovarian cancer (OC), DNMTis trigger cytosolic sensing of double-stranded RNA (dsRNA) causing a type I interferon response and apoptosis. Knocking down dsRNA sensors TLR3 and MAVS reduces this response 2-fold and blocking interferon beta or its receptor abrogates it. Upregulation of hypermethylated endogenous retrovirus (ERV) genes accompanies the response and ERV overexpression activates the response. Basal levels of ERV and viral defense gene expression significantly correlate in primary OC and the latter signature separates primary samples for multiple tumor types from The Cancer Genome Atlas into low versus high expression groups. In melanoma patients treated with an immune checkpoint therapy, high viral defense signature expression in tumors significantly associates with durable clinical response and DNMTi treatment sensitizes to anti-CTLA4 therapy in a pre-clinical melanoma model.

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Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses

Abstract

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