Abstract B32: Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses

Abstract

Abstract DNA methyltransferase inhibitors (DNMTis) upregulate immune attraction, including the interferon response, in solid tumors. We now define viral defense signaling as one mechanism for this. In epithelial ovarian cancer cells DNMTis upregulate viral defense by cytosolic sensing of double-stranded RNA (dsRNA), triggering a Type I Interferon response, upregulation of downstream interferon response genes, and increased apoptosis. Knockdown of the dsRNA sensors TLR3 and MAVS and inhibition of the interferon alpha/beta receptor blunt the DNMTi induced dsRNA response. DNMTis cause apoptosis of cancer cells, which is partially rescued by inhibiting the interferon alpha/beta receptor. We observe upregulation and demethylation of hypermethylated endogenous retroviruses (ERVs) and overexpression of individual ERVs whose sense and anti-sense transcripts may be key candidates for triggering the above signaling. Overexpression of ERVs alone is sufficient to trigger an interferon response in the absence of DNMTis. Basal levels of ERV and viral defense gene expression significantly correlate in primary OC and basal expression of the viral defense signature separates primary TCGA samples for multiple tumor types 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. We thus define a major mechanism for how DNMTis may induce cancer cells to increase immune attraction and possibly sensitize patients to immunotherapy. Experiments determining which Aza-upregulated molecules on tumor cells are necessary for attraction and activation of host immune cells are ongoing. Citation Format: 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, Jedd Wolchok, Cynthia A. Zahnow, Taha Mergoub, Timothy A. Chan, Reiner Strick, Stephen B. Baylin. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr B32.