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

被引：1449

作者：

Chiappinelli, Katherine B. ^{[1
]}

Strissel, Pamela L. ^{[2
]}

Desrichard, Alexis ^{[3
]}

Li, Huili ^{[1
]}

Henke, Christine ^{[2
]}

Akman, Benjamin ^{[1
]}

Hein, Alexander ^{[2
]}

Rote, Neal S. ^{[4
]}

Cope, Leslie M. ^{[1
]}

Snyder, Alexandra ^{[3
,5
]}

Makarov, Vladimir ^{[3
]}

Buhu, Sadna ^{[5
]}

Slamon, Dennis J. ^{[6
]}

Wolchok, Jedd D. ^{[5
]}

Pardoll, Drew M.

Beckmann, Matthias W. ^{[2
]}

Zahnow, Cynthia A. ^{[1
]}

Mergoub, Taha ^{[5
]}

Chan, Timothy A. ^{[3
,5
]}

Baylin, Stephen B. ^{[1
]}

Strick, Reiner ^{[2
]}

机构：

[1] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Dept Oncol, Baltimore, MD 21287 USA

[2] Univ Clin Erlangen, Dept Obstet & Gynaecol, Mol Med Lab, D-91054 Erlangen, Germany

[3] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[4] Case Western Reserve Univ, Dept Reprod Biol, Cleveland, OH 44106 USA

[5] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA

[6] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA

来源：

CELL | 2015年 / 162卷 / 05期

关键词：

CODING ENVELOPE GENES; HUMAN BREAST-CANCER; CELL LUNG-CANCER; HERV-K; CPG METHYLATION; OVARIAN-CANCER; NONCODING RNA; PD-1; BLOCKADE; HUMAN GENOME; TUMOR-CELLS;

D O I：

10.1016/j.cell.2015.07.011

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：974 / 986

页数：13

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