Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses

By Katherine B. Chiappinelli, P. Strissel, A. Desrichard, Huili Li, C. Henke, Benjamin Akman, A. Hein, N. Rote, Leslie M. Cope, A. Snyder and 11 more. Cell, 2015

917 citations recorded by the source corpus.

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.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/0507057dfdd78684d0ea144a7829ccd272ec31c6

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

  1. S. Valsesia-Wittmann
  2. J. Valladeau-Guilemond
  3. V. Alcazer
  4. C. Caux
  5. Paola Bonaventura
  6. S. Depil
  7. S. Amigorena
  8. T. Shekarian

Citations in the corpus