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

// Gilli Galore-Haskel 1, 4 , Yael Nemlich 1 , Eyal Greenberg 1, 4 , Shira Ashkenazi 1, 4 , Motti Hakim 5 , Orit Itzhaki 1 , Noa Shoshani 1 , Ronnie Shapira-Fromer 1 , Eytan Ben-Ami 1 , Efrat Ofek 2 , Liat Anafi 2 , Michal J. Besser 1, 4 , Jacob Schachter 1, * , Gal Markel 1, 3, 4, * 1 Ella Lemelbaum Institute of Melanoma, Sheba Medical Center, Israel 2 Institute of Pathology, Sheba Medical Center, Israel 3 Talpiot Medical Leadership Program, Sheba Medical Center, Israel 4 Department of Clinical Microbiology and Immunology, Tel Aviv University, Tel Aviv, Israel 5 cCAM Biotherapeutics, Misgav Industrial Park, Misgav, Israel * These authors have contributed equally to this work Correspondence to: Gal Markel, e-mail: markel@post.tau.ac.il Keywords: melanoma, immune resistance, microRNA, ADAR1, ICAM1 Received: May 19, 2015      Accepted: August 10, 2015      Published: August 21, 2015 ABSTRACT 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.