@article{a77af8f0c7bf4526949f739186b09e28,
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",
note = "Funding Information: Research was supported by grants from The National Cancer Institute (NCI) CA058184 (S.B.B.), Stand Up To Cancer (SU2C) Epigenetic Dream Team (S.B.B.), the Hodson Trust (S.B.B.), the Samuel Waxman Cancer Research Foundation (S.B.B.), The Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (S.B.B., D.J.S.), Department of Defense (DOD) Teal Award BC031272 (S.B.B.), the Pershing Square Sohn Cancer Research Alliance (T.A.C.), the STARR Cancer Consortium (T.A.C.), the Ludwig Foundation (J.D.W.), and NIH award F32CA183214 (K.B.C.), and German Cancer Aid (Deutsche Krebshilfe 108215) (R.S.). We acknowledge Mrs. Elizabeth Stiegler and Florentine Koppitz for their expert technical help and Kathy Bender for manuscript preparation. ABI TLDA qRT-PCR was conducted at the Genetic Resources Core Facility, Johns Hopkins Institute of Genetic Medicine, Baltimore, MD. We thank Ms. Jennifer Meyers and the Next Generation Sequencing Center at the Sidney Kimmel Comprehensive Cancer Center for Agilent Bioanalyzer analysis. D.M.P. is a consultant for Pfizer and Amplimmune. J.D.W. is a consultant for Bristol-Myers Squibb and receives research funding. S.B.B. consults for MDxHealth. Methylation-specific PCR (MSP) is licensed to MDxHealth in agreement with Johns Hopkins University (JHU), and S.B.B. and JHU are entitled to royalty shares received from sales. Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",
year = "2015",
month = aug,
day = "27",
doi = "10.1016/j.cell.2015.07.011",
language = "English (US)",
volume = "162",
pages = "974--986",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "5",
}