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

Chiappinelli KB, Strissel P, Desrichard A, Li H, Henke C, Akman B, Hein A, Rote NS, Cope LM, Snyder A, Makarov V, Buhu S, Slamon DJ, Wolchok JD, Pardoll DM, Beckmann M, Zahnow CA, Mergoub T, Chan TA, Baylin SB, Strick R (2015)

Publication Type: Journal article

Publication year: 2015

Journal

Cell Elsevier

Book Volume: 162

Pages Range: 974-86

Journal Issue: 5

DOI: 10.1016/j.cell.2015.07.011

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 with CRIS profile

Pamela Strissel Medizinische Fakultät Christine Henke Department of Obstetrics and Gynaecology Alexander Hein Department of Obstetrics and Gynaecology Matthias Beckmann Lehrstuhl für Geburtshilfe und Frauenheilkunde Reiner Strick Medizinische Fakultät

Involved external institutions

Johns Hopkins Hospital US United States (USA) (US) Memorial Sloan Kettering Cancer Center US United States (USA) (US) Case Western Reserve University US United States (USA) (US) University of California Los Angeles (UCLA) US United States (USA) (US)

How to cite

APA:

Chiappinelli, K.B., Strissel, P., Desrichard, A., Li, H., Henke, C., Akman, B.,... Strick, R. (2015). Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses. Cell, 162(5), 974-86. https://dx.doi.org/10.1016/j.cell.2015.07.011

MLA:

Chiappinelli, Katherine B., et al. "Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses." Cell 162.5 (2015): 974-86.

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