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.
Highlights
Malignant melanoma, arising from pigment pro ducing melanocytes, is among the most aggressive and treatment-resistant human cancers
We have recently shown that adenosine deaminase acting on RNA-1 (ADAR1) is commonly down-regulated in metastatic melanoma [21]
We show that down-regulation of ADAR1 renders melanoma cells more resistant to tumor infiltrating lymphocytes (TILs)-mediated killing, in all E:T ratios tested, which may partially explain why metastatic melanoma tends to evade the immune system
Summary
Malignant melanoma, arising from pigment pro ducing melanocytes, is among the most aggressive and treatment-resistant human cancers. The incidence of melanoma in Caucasian populations has been increasing at a higher rate than any other malignancy [1]. Metastatic melanoma responds poorly to conventional chemotherapies and predicts poor survival rates. In 2011 the FDA approved anti- cytotoxic T lymphocyte-associated protein 4. (CTLA4) mAb (ipilimumab) for the indication of metastatic melanoma, based on significant improved overall survival in Phase III trials [4, 5]. Recent clinical trials with PD1 [6,7,8] or PD-L1 blocking antibodies [9] showed impressive effects, leading to FDA approval of anti-PD1 drugs pembrolizumab and nivolumab in 2014. Combination of ipilimumab and PD1 blockade yield dramatic effects with ~80% 2-year survival, but with very high toxicity [10]. Since metastatic melanoma uses many mechanisms to escape the immune system [2], www.impactjournals.com/oncotarget delineation of mechanisms involved in melanoma immuneresistance is of cardinal importance
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