Inhibiting DNA Methylation Causes an Interferon Response in Cancer Via DsRNA Including Endogenous Retroviruses

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2015 Aug 29

PMID 26317466

Citations 929

Authors

Katherine B Chiappinelli

Pamela L Strissel

Alexis Desrichard

Huili Li

Christine Henke

Benjamin Akman

Alexander Hein

Neal S Rote

Leslie M Cope

Alexandra Snyder

Vladimir Makarov

Sadna Budhu

Sadna Buhu

Dennis J Slamon

Jedd D Wolchok

Drew M Pardoll

Matthias W Beckmann

Cynthia A Zahnow

Taha Merghoub

Taha Mergoub

Timothy A Chan

Stephen B Baylin

Reiner Strick

Affiliations

Soon will be listed here.

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.

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