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

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...

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Published in:Cell Vol. 162; no. 5; p. 974
Main Authors: Chiappinelli, Katherine B, Strissel, Pamela L, Desrichard, Alexis, Li, Huili, Henke, Christine, Akman, Benjamin, Hein, Alexander, Rote, Neal S, Cope, Leslie M, Snyder, Alexandra, Makarov, Vladimir, Budhu, Sadna, Buhu, Sadna, Slamon, Dennis J, Wolchok, Jedd D, Pardoll, Drew M, Beckmann, Matthias W, Zahnow, Cynthia A, Merghoub, Taha, Mergoub, Taha, Chan, Timothy A, Baylin, Stephen B, Strick, Reiner
Format: Journal Article
Language:English
Published: United States 27.08.2015
Subjects:
Animals
Azacitidine - pharmacology
Cell Line, Tumor
DNA Methylation - drug effects
DNA Modification Methylases - antagonists & inhibitors
Endogenous Retroviruses - genetics
Female
Humans
Immunotherapy
Interferon Type I - immunology
Lung Neoplasms - drug therapy
Lung Neoplasms - immunology
Melanoma - immunology
Melanoma - therapy
Mice
Mice, Inbred C57BL
Ovarian Neoplasms - immunology
Ovarian Neoplasms - therapy
RNA, Double-Stranded - metabolism
ISSN:1097-4172, 1097-4172
Online Access:Get more information
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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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ISSN:1097-4172
1097-4172
DOI:10.1016/j.cell.2015.07.011