Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses Journal Article

   

Authors:	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.; Budhu, S.; Slamon, D. J.; Wolchok, J. D.; Pardoll, D. M.; Beckmann, M. W.; Zahnow, C. A.; Merghoub, T.; Chan, T. A.; Baylin, S. B.; Strick, R.
Article 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. © 2015 Elsevier Inc.
Keywords:	signal transduction; controlled study; treatment response; unclassified drug; human cell; interferon; drug efficacy; drug potentiation; nonhuman; mouse; animal tissue; gene overexpression; cytotoxic t lymphocyte antigen 4 antibody; cancer immunotherapy; low drug dose; melanoma; apoptosis; multiple cycle treatment; ovary cancer; animal experiment; animal model; immunoreactivity; dna methylation; rna binding protein; genome analysis; epigenetics; oncolytic virotherapy; upregulation; gene silencing; host resistance; cytotoxic t lymphocyte antigen 4; dna methyltransferase; mitochondrial protein; multiple cancer; beta interferon; azacitidine; double stranded rna; virus immunity; genetic correlation; virus gene; endogenous retrovirus; beta interferon receptor; toll like receptor 3; cytokine response; human; female; priority journal; article; mavs protein
Journal Title:	Cell
Volume:	162
Issue:	5
ISSN:	0092-8674
Publisher:	Cell Press
Date Published:	2015-08-27
Start Page:	974
End Page:	986
Language:	English
DOI:	10.1016/j.cell.2015.07.011
PROVIDER:	scopus
PMCID:	PMC4556003
PUBMED:	26317466
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84940381273&partnerID=40&md5=d154a71e4b0010e15e5768f7ae62c125
Notes:	Errata issued, see DOI: 10.1016/j.cell.2015.10.020 and DOI:10.1016/j.cell.2017.03.036 -- Export Date: 2 October 2015 -- Source: Scopus

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