ITOC2 – 009. Role of signal transduction and microRNAs on the immunogenicity of melanoma cells

Abstract

Melanoma is a heterogeneous malignancy with a distinct clinical outcome of patients due to different genetic features and various strategies of melanoma cells leading to immune evasion. For a better understanding of the aggressive melanoma phenotype the molecular mechanisms of aberrant expression of the classical HLA class I antigen processing and presentation machinery (APM) and of the non-classical HLA-G antigen is analysed. A reduced mRNA and/or protein expression of various APM components was identified in a large series of melanoma cell lines and lesions, which correlated with an increased tumour grading and lack of immune therapy response. In addition, microRNAs (miRs) targeting HLA class I APM components as well as HLA-G thereby affecting the immune response have been identified suggesting an important role for posttranscriptional control in this process. These miRs might be used as novel targets for the treatment of melanoma or for selection of melanoma patients undergoing the most effective (immuno)therapy. Furthermore, a direct link between the interferon (IFN) signalling pathway and the constitutive HLA class I expression was found. Altered expression or loss of single components of the IFN-<i>γ</i> signal cascade was detected, which was accompanied by deficient IFN-<i>γ</i> response due to structural alterations, epigenetic control or transcriptional/post-transcriptional deregulation. These were directly associated with a downregulation of basal HLA class I APM component expression in melanoma lesions and melanoma cell lines and confirmed by silencing of STAT1, JAK1 and JAK2. Thus these data provide novel insights into the complex regulation of HLA class I expression and the rational for selecting patients for specific immunotherapies.