A novel immune resistance mechanism of melanoma cells controlled by the ADAR1 enzyme

Oncotarget. 2015 Oct 6;6(30):28999-9015. doi: 10.18632/oncotarget.4905.


The blossom of immunotherapy in melanoma highlights the need to delineate mechanisms of immune resistance. Recently, we have demonstrated that the RNA editing protein, adenosine deaminase acting on RNA-1 (ADAR1) is down-regulated during metastatic transition of melanoma, which enhances melanoma cell proliferation and tumorigenicity. Here we investigate the role of ADAR1 in melanoma immune resistance.Importantly, knockdown of ADAR1 in human melanoma cells induces resistance to tumor infiltrating lymphocytes in a cell contact-dependent mechanism. We show that ADAR1, in an editing-independent manner, regulates the biogenesis of miR-222 at the transcription level and thereby Intercellular Adhesion Molecule 1 (ICAM1) expression, which consequently affects melanoma immune resistance. ADAR1 thus has a novel, pivotal, role in cancer immune resistance. Corroborating with these results, the expression of miR-222 in melanoma tissue specimens was significantly higher in patients who had no clinical benefit from treatment with ipilimumab as compared to patients that responded clinically, suggesting that miR-222 could function as a biomarker for the prediction of response to ipilimumab.These results provide not only novel insights on melanoma immune resistance, but also pave the way to the development of innovative personalized tools to enable optimal drug selection and treatment.

Keywords: ADAR1; ICAM1; immune resistance; melanoma; microRNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Deaminase / genetics
  • Adenosine Deaminase / metabolism*
  • Antibodies, Monoclonal / therapeutic use
  • Cell Communication
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Intercellular Adhesion Molecule-1 / genetics
  • Intercellular Adhesion Molecule-1 / metabolism
  • Ipilimumab
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Melanoma / drug therapy
  • Melanoma / enzymology*
  • Melanoma / genetics
  • Melanoma / immunology
  • Melanoma / pathology
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • RNA Interference
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Signal Transduction
  • Skin Neoplasms / drug therapy
  • Skin Neoplasms / enzymology*
  • Skin Neoplasms / genetics
  • Skin Neoplasms / immunology
  • Skin Neoplasms / pathology
  • Transcription, Genetic
  • Transfection
  • Tumor Escape


  • Antibodies, Monoclonal
  • ICAM1 protein, human
  • Ipilimumab
  • MIRN222 microRNA, human
  • MicroRNAs
  • RNA-Binding Proteins
  • Intercellular Adhesion Molecule-1
  • ADAR protein, human
  • Adenosine Deaminase