期刊
CELL
卷 162, 期 5, 页码 974-986出版社
CELL PRESS
DOI: 10.1016/j.cell.2015.07.011
关键词
-
资金
- National Cancer Institute (NCI) [CA058184]
- Stand Up To Cancer (SU2C) Epigenetic Dream Team
- Hodson Trust
- Samuel Waxman Cancer Research Foundation
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Department of Defense (DOD) Teal Award [BC031272]
- Pershing Square Sohn Cancer Research Alliance
- STARR Cancer Consortium
- Ludwig Foundation
- NIH [F32CA183214]
- German Cancer Aid [Deutsche Krebshilfe 108215]
- Bristol-Myers Squibb
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 preclinical melanoma model.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据