title: Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses.
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.
authors: Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
authors: Katherine B
authors: KB
authors: Chiappinelli
authors: Department of Gynaecology and Obstetrics, Laboratory for Molecular Medicine, University-Clinic Erlangen, 91054 Erlangen, Germany.
authors: Pamela L
authors: PL
authors: Strissel
authors: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Alexis
authors: A
authors: Desrichard
authors: Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
authors: Huili
authors: H
authors: Li
authors: Department of Gynaecology and Obstetrics, Laboratory for Molecular Medicine, University-Clinic Erlangen, 91054 Erlangen, Germany.
authors: Christine
authors: C
authors: Henke
authors: Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
authors: Benjamin
authors: B
authors: Akman
authors: Department of Gynaecology and Obstetrics, Laboratory for Molecular Medicine, University-Clinic Erlangen, 91054 Erlangen, Germany.
authors: Alexander
authors: A
authors: Hein
authors: Department of Reproductive Biology, Case Western Reserve University, Cleveland, OH 44106, USA.
authors: Neal S
authors: NS
authors: Rote
authors: Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
authors: Leslie M
authors: LM
authors: Cope
authors: 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.
authors: Alexandra
authors: A
authors: Snyder
authors: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Vladimir
authors: V
authors: Makarov
authors: Sadna
authors: S
authors: Budhu
authors: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Sadna
authors: S
authors: Buhu
authors: The Jonsson Comprehensive Cancer Center, University of California-Los Angeles, Los Angeles, CA 90095, USA.
authors: Dennis J
authors: DJ
authors: Slamon
authors: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Jedd D
authors: JD
authors: Wolchok
authors: Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
authors: Drew M
authors: DM
authors: Pardoll
authors: Department of Gynaecology and Obstetrics, Laboratory for Molecular Medicine, University-Clinic Erlangen, 91054 Erlangen, Germany.
authors: Matthias W
authors: MW
authors: Beckmann
authors: Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
authors: Cynthia A
authors: CA
authors: Zahnow
authors: Taha
authors: T
authors: Merghoub
authors: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Taha
authors: T
authors: Mergoub
authors: 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.
authors: Timothy A
authors: TA
authors: Chan
authors: Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA. Electronic address: sbaylin@jhmi.edu.
authors: Stephen B
authors: SB
authors: Baylin
authors: Department of Gynaecology and Obstetrics, Laboratory for Molecular Medicine, University-Clinic Erlangen, 91054 Erlangen, Germany. Electronic address: reiner.strick@uk-erlangen.de.
authors: Reiner
authors: R
authors: Strick
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000494:pharmacology; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects*; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D020077:Endogenous Retroviruses / Q000235:genetics; D005260:Female; D006801:Humans; D007167:Immunotherapy; D007370:Interferon Type I / Q000276:immunology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000276:immunology; D008545:Melanoma / Q000276:immunology* / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D010051:Ovarian Neoplasms / Q000276:immunology / Q000628:therapy; D012330:RNA, Double-Stranded / Q000378:metabolism
chemical_list: D007370:Interferon Type I; D012330:RNA, Double-Stranded; D015254:DNA Modification Methylases; D001374:Azacitidine