Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses.
Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses.
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DOI：
10.1016/j.cell.2015.07.011
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发表时间：
2015-08-27
期刊：
影响因子：
64.5
通讯作者：
Strick R
中科院分区：
文献类型：
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作者：
Chiappinelli KB;Strissel PL;Desrichard A;Li H;Henke C;Akman B;Hein A;Rote NS;Cope LM;Snyder A;Makarov V;Budhu S;Slamon DJ;Wolchok JD;Pardoll DM;Beckmann MW;Zahnow CA;Merghoub T;Chan TA;Baylin SB;Strick R
我们发现DNA甲基转移酶抑制剂（DNMTis）通过病毒防御途径上调癌症中的免疫信号传导。在卵巢癌（OC）中，DNMTis触发双链RNA（dsRNA）的胞质传感，引起I型干扰素应答和细胞凋亡。敲除dsRNA传感器TLR3和MAVS可使这种反应降低两倍，阻断干扰素β或其受体可消除这种反应。高甲基化内源性逆转录病毒（ERV）基因的上调伴随着这种反应，ERV过表达激活了这种反应。ERV和病毒防御基因表达的基础水平在原发性OC中显著相关，并且后者特征将来自癌症基因组图谱的多种肿瘤类型的原发性样品分为低表达组与高表达组。在用免疫检查点疗法治疗的黑色素瘤患者中，肿瘤中的高病毒防御特征表达与持久的临床应答显著相关，并且在临床前黑色素瘤模型中DNMTi治疗对抗CTLA4疗法敏感。
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 twofold, 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.