Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses.
Cell
; 162(5): 974-86, 2015 Aug 27.
Article
in En
| MEDLINE
| ID: mdl-26317466
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Interferon Type I
/
DNA Methylation
/
Melanoma
Type of study:
Etiology_studies
Limits:
Animals
/
Female
/
Humans
Language:
En
Journal:
Cell
Year:
2015
Type:
Article
Affiliation country:
United States