Summary
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.
These changes indicate an adaptive shift toward constitutive expression of genes required for growth under the nutritional and microaerobic conditions created by suppurative secretions in the lungs of patients with CF. In addition, these results provide important clues about the persistence strategies used by P. aeruginosa during progressive CF lung disease.
Mutator strains may evolve from the initially infecting PA strain and generate numerous variants with a loss of destructive virulence factors, probably because of selection for improved survival in the deteriorated CF lung but at the expense of the ability to live freely.
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