MicroRNAs and dendritic cell-based vaccination in melanoma patients Francesco de Rosa a , Francesca Fanini b , Massimo Guidoboni a , Ivan Vannini b , Dino Amadori c , Ruggero Ridolfi a , Laura Ridolfi a, * and Muller Fabbri b,d, * MicroRNAs are increasingly being recognized to play an important role in finely tuning gene expression; therefore, their dysregulation in cancer has been investigated extensively. In terms of melanoma, they are involved in the regulation of many genes and pathways impacting invasiveness, dissemination, and disease progression. Many microRNAs also target genes regulating ontogenesis and functions of the immune system. Indeed, fine-tuning of gene expression by microRNAs is necessary for normal differentiation of the various components of the immune system and for mounting an effective innate and cell-mediated response, which has been shown to be able to control tumor growth. Dendritic cells, by presenting antigens to and activating naive T cells, constitute a critical aspect and have been therefore been used in many studies of cancer vaccination with promising results. Many genes regulating functions and plasticity of dendritic cells are indeed targeted by microRNAs, whose expression is also dependent on maturation status. Therefore, microRNAs could provide new potential therapeutic targets both on the tumor and on the immune system, and could also be used to characterize dendritic cells utilized in immunotherapy trials. Melanoma Res 24:181–189 c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. Melanoma Research 2014, 24:181–189 Keywords: anticancer vaccination, dendritic cell, immunotherapy, melanoma, microRNAs a Immunotherapy Unit, b Gene Therapy Unit, c Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy and d Department of Pediatrics and Molecular Microbiology & Immunology, Norris Comprehensive Cancer Center, the Saban Research Institute and Children’s Center for Cancer and Blood Diseases, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California, USA Correspondence to Laura Ridolfi, MD, PhD, Immunotherapy Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, via Piero Maroncelli, 40, 47014 Meldola (FC), Italy Tel: + 39 0543 739100; fax: + 39 0543 739151; e-mail: l.ridolfi@irst.emr.it *Laura Ridolfi and Muller Fabbri contributed equally to the writing of this article. Received 17 October 2013 Accepted 30 January 2014 Introduction Noncoding RNAs are transcripts that are not translated into proteins. As such, they are not mRNAs, but are, nevertheless, involved in many biological processes. Among these, microRNAs (miRNAs) are increasingly being recognized as regulators of gene expression in many physiological and pathological processes [1]. The present review, after presenting a few hints on the physiology of miRNAs, will discuss their role in human melanoma and in ontogenesis and regulation of the innate and adaptive immune response, linked by dendritic cells (DCs). An antitumor immune response can actually achieve disease control in melanoma, as indicated by clinical trials with the immune checkpoint inhibitor ipilimumab [2] and DC anticancer vaccination [3]. Finally, the limited but consistent data linking miRNAs and immunological potency of DCs used for vaccination will be presented. Biogenesis and physiology of microRNAs MiRNAs are 18–24 nucleotide noncoding RNAs that exert regulatory functions of gene expression by control- ling the translation and the degradation of their target mRNAs [1]. About 80% of mammalian miRNA genes have been identified in the intron region of both protein- coding and protein-noncoding genes: the others are exonic or variable depending on the alternative splicing pattern of their host genes [4]. The biogenesis of miRNAs is quite complex and its discussion is beyond the scope of this review. Briefly, they are transcribed as different precursors in the nucleus (pri-miRNAs or mirtrons), which are then processed to generate pre-miRNAs [5,6]. They are then translocated to the cytoplasm and cleaved into a 24–28 nucleotide by the ribonuclease Dicer, generating an imperfectly matched miRNA/miRNA* duplex. The duplex subsequently interacts with a protein complex called RISC, guiding it to specific binding sites located mainly (but not exclusively) at the 3 0 -untranslated regions of the target mRNAs [7,8]. In this way, translational silencing of the target is achieved. The more recent discovery of the ability of some miRNAs to upregulate translation of their target genes has shown that the picture is far more complicated [9]. Role of microRNAs in human melanoma Compared with other solid tumors, relatively few studies have focused on the role of miRNAs in melanoma. A first profiling study, in particular, has identified a six-miRNA signature (miR-145, miR-150, miR-155, miR-342-3p, miR-455-3p, miR-497) able to stratify patients with stage Review article 181 0960-8931 c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI: 10.1097/CMR.0000000000000058 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.