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Cell. 2015 Aug 27;162(5):974-86. doi: 10.1016/j.cell.2015.07.011.

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

Author information

1
Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
2
Department of Gynaecology and Obstetrics, Laboratory for Molecular Medicine, University-Clinic Erlangen, 91054 Erlangen, Germany.
3
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
4
Department of Reproductive Biology, Case Western Reserve University, Cleveland, OH 44106, USA.
5
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.
6
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
7
The Jonsson Comprehensive Cancer Center, University of California-Los Angeles, Los Angeles, CA 90095, USA.
8
Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA. Electronic address: sbaylin@jhmi.edu.
9
Department of Gynaecology and Obstetrics, Laboratory for Molecular Medicine, University-Clinic Erlangen, 91054 Erlangen, Germany. Electronic address: reiner.strick@uk-erlangen.de.

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.

PMID:
26317466
PMCID:
PMC4556003
DOI:
10.1016/j.cell.2015.07.011
[Indexed for MEDLINE]
Free PMC Article

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