In a relatively short period of time, treatment strategies for metastatic melanoma have radically changed leading to an unprecedented improvement in patient survival.,In this period, immunotherapy options have evolved from cytokine-based approaches to antibody-mediated inhibition of immune checkpoints, cancer vaccines and pharmacological modulation of the melanoma microenvironment.,Combination of immunotherapy strategies and the association of immune checkpoint inhibitors (ICIs) with BRAF V600 targeted therapy show encouraging results.,The future of drug development in this field is promising.,The comprehension of primary and acquired resistance mechanisms to ICIs and the dissection of melanoma immunobiology will be instrumental for the development of new treatment strategies and to improve clinical trial design.,Moreover, biomarker discovery will help patient stratification and management during immunotherapy treatment.,In this review, we summarize landmark clinical trials of immune checkpoint inhibitors in advanced melanoma and discuss the rational for immunotherapy combinations.,Immunotherapy approaches at early stage of clinical development and recent advances in melanoma immunotherapy biomarker development are also discussed.
CD70 is a costimulatory molecule of the tumour necrosis factor family expressed in activated immune cells and some solid tumours.,In lymphocytes CD70 triggers T cell-mediated cytotoxicity and mitogen-activated protein kinase phosphorylation.,We evaluated the expression of CD70 in biopsies and melanoma cell lines.,Using melanoma cell lines positive or not for CD70, we analysed CD70 function on melanoma progression.,We report CD70 expression in human melanoma cell lines and tumour cells from melanoma biopsies.,This expression was observed in 95% of primary melanomas but only 37% of metastases.,Both monomeric and trimeric forms of CD70 were detected in tumour cell membrane fractions, whereas cytoplasmic fractions contained almost exclusively monomeric CD70.,In vitro and in vivo experiments demonstrated that CD70 expression inhibited melanoma cell migration, invasion and pulmonary metastasis implantation independently of the tumour immune microenvironment.,Increasing the levels of the trimeric form of CD70 through monoclonal antibody binding led to an increase in CD70+ melanoma cell invasiveness through MAPK pathway activation, RhoE overexpression, ROCK1 and MYPT1 phosphorylation decrease, and stress fibres and focal adhesions disappearance.,Our results describe a new non-immunological function of melanoma-expressed CD70, which involves melanoma invasiveness through MAPK pathway, RhoE and cytoskeletal modulation.