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PMID: 26317466 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

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

Cell ·Vol. 162 ·No. 5 ·2015-08-27 ·Pages 974-86

Chiappinelli KB, Strissel PL, Desrichard A, Li H, Henke C, Akman B, Hein A, Rote NS, Cope LM, Snyder A, Makarov V, Budhu S, Buhu S, Slamon DJ, Wolchok JD, Pardoll DM, Beckmann MW, Zahnow CA, Merghoub T, Mergoub T, Chan TA, Baylin SB, Strick R

Abstract

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.

MeSH Terms
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,immunology Melanoma/immunology,therapy Mice Mice, Inbred C57BL Ovarian Neoplasms/immunology,therapy RNA, Double-Stranded/metabolism
Chemicals
Interferon Type I RNA, Double-Stranded DNA Modification Methylases Azacitidine
Authors & Affiliations
23 authors, click to expand affiliations / ORCID
Chiappinelli Katherine B
Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
Strissel Pamela L
Department of Gynaecology and Obstetrics, Laboratory for Molecular Medicine, University-Clinic Erlangen, 91054 Erlangen, Germany.
Desrichard Alexis
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Li Huili
Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
Henke Christine
Department of Gynaecology and Obstetrics, Laboratory for Molecular Medicine, University-Clinic Erlangen, 91054 Erlangen, Germany.
Akman Benjamin
Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
Hein Alexander
Department of Gynaecology and Obstetrics, Laboratory for Molecular Medicine, University-Clinic Erlangen, 91054 Erlangen, Germany.
Rote Neal S
Department of Reproductive Biology, Case Western Reserve University, Cleveland, OH 44106, USA.
Cope Leslie M
Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
Snyder Alexandra
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Makarov Vladimir
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Budhu Sadna
Buhu Sadna
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Slamon Dennis J
The Jonsson Comprehensive Cancer Center, University of California-Los Angeles, Los Angeles, CA 90095, USA.
Wolchok Jedd D
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Pardoll Drew M
Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
Beckmann Matthias W
Department of Gynaecology and Obstetrics, Laboratory for Molecular Medicine, University-Clinic Erlangen, 91054 Erlangen, Germany.
Zahnow Cynthia A
Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
Merghoub Taha
Mergoub Taha
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Chan Timothy A
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Baylin Stephen B
Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA. Electronic address: sbaylin@jhmi.edu.
Strick Reiner
Department of Gynaecology and Obstetrics, Laboratory for Molecular Medicine, University-Clinic Erlangen, 91054 Erlangen, Germany. Electronic address: reiner.strick@uk-erlangen.de.
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2015.07.011
Email
sbaylin@jhmi.edu
reiner.strick@uk-erlangen.de
Published
2015-08-27
Pages
974-86
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC4556003
Subset
IM
Grants
NCI NIH HHS · F32CA183214 · United States
NCI NIH HHS · CA058184 · United States
NCI NIH HHS · F32 CA183214 · United States
NCI NIH HHS · P50 CA058184 · United States
NCI NIH HHS · P30 CA008748 · United States
Corrections
CommentIn
PMID: 26317460
ErratumIn
PMID: 27064190
ErratumIn
PMID: 28388418
External Links
PubMed source DOI: 10.1016/j.cell.2015.07.011 PMC Full Text View journal details
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