A novel immune resistance mechanism of melanoma cells controlled by the ADAR1 enzyme.
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.
Ella Lemelbaum Institute of Melanoma, Sheba Medical Center, Israel.|Department of Clinical Microbiology and Immunology, Tel Aviv University, Tel Aviv, Israel.
Gilli
G
Galore-Haskel
Ella Lemelbaum Institute of Melanoma, Sheba Medical Center, Israel.
Yael
Y
Nemlich
Ella Lemelbaum Institute of Melanoma, Sheba Medical Center, Israel.|Department of Clinical Microbiology and Immunology, Tel Aviv University, Tel Aviv, Israel.
Eyal
E
Greenberg
Ella Lemelbaum Institute of Melanoma, Sheba Medical Center, Israel.|Department of Clinical Microbiology and Immunology, Tel Aviv University, Tel Aviv, Israel.
Shira
S
Ashkenazi
cCAM Biotherapeutics, Misgav Industrial Park, Misgav, Israel.
Motti
M
Hakim
Ella Lemelbaum Institute of Melanoma, Sheba Medical Center, Israel.
Orit
O
Itzhaki
Ella Lemelbaum Institute of Melanoma, Sheba Medical Center, Israel.
Noa
N
Shoshani
Ella Lemelbaum Institute of Melanoma, Sheba Medical Center, Israel.
Ronnie
R
Shapira-Fromer
Ella Lemelbaum Institute of Melanoma, Sheba Medical Center, Israel.
Eytan
E
Ben-Ami
Institute of Pathology, Sheba Medical Center, Israel.
Efrat
E
Ofek
Institute of Pathology, Sheba Medical Center, Israel.
Liat
L
Anafi
Ella Lemelbaum Institute of Melanoma, Sheba Medical Center, Israel.|Department of Clinical Microbiology and Immunology, Tel Aviv University, Tel Aviv, Israel.
Michal J
MJ
Besser
Ella Lemelbaum Institute of Melanoma, Sheba Medical Center, Israel.
Jacob
J
Schachter
Ella Lemelbaum Institute of Melanoma, Sheba Medical Center, Israel.|Talpiot Medical Leadership Program, Sheba Medical Center, Israel.|Department of Clinical Microbiology and Immunology, Tel Aviv University, Tel Aviv, Israel.
Gal
G
Markel
D000243:Adenosine Deaminase / Q000235:genetics / Q000378:metabolism*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D002450:Cell Communication; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D000074324:Ipilimumab; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008545:Melanoma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D014158:Transcription, Genetic; D014162:Transfection; D019139:Tumor Escape
D000243:Adenosine Deaminase; D000911:Antibodies, Monoclonal; D018799:Intercellular Adhesion Molecule-1; D000074324:Ipilimumab; D035683:MicroRNAs; D016601:RNA-Binding Proteins; C573420:ICAM1 protein, human; C525710:MIR222, human; C000595356:ADAR protein, human
ADAR1; ICAM1; immune resistance; melanoma; microRNA