The high risk of metastasis accounts for the need of adjuvant therapy in early tumor stages. To date, IFN-a therapy represents the only effective adjuvant therapeutic approach against malignant melanoma as demonstrated in several studies. In malignant diseases, induction of tolerance by tumor-derived factors is one critical mechanism involved in tumor progression. The production of the immunosuppressive cytokine IL-10 by tumor cells themselves or by tumor-infiltrating immune cells is well known for malignant melanoma and other tumor entities. IL-10 modulates the biologic function of antigen presenting cells and of T cells. In previous studies, we and others demonstrated that IL-10 induces a tolerogenic phenotype of DC with impaired T cell stimulatory properties. Furthermore, IL-10 DC have been shown to induce anergic regulatory CD4+ and CD8+ T cells, which inhibit activated cytotoxic and helper T cells, INCB18424 JAK inhibitor resulting in a failure to kill melanoma cells. Human DC comprise a heterogeneous cell population and their functional potential depends on their origin, the cytokine microenvironment and cell/cell interactions. They are central in inducing immunity and in mediating immune tolerance in their role as professional antigen-presenting cells. Tolerogenic DC control the immune homeostasis and prevent the development of autoimmune diseases but are also involved in tumor development and progression. We hypothesized that IFN-a may interfere with tumorassociated tolerance mechanisms. In the present study, we demonstrate that IFN-a abrogates the tolerogenic function of human IL-10 DC and thereby prevents the induction of T cell anergy and, subsequently the differentiation into suppressive iTregs. The efficacy of IFN-a treatment in cancer and infectious diseases may therefore be related to its capacity to break tumorassociated tolerance induction. In our study, we demonstrate that IFN-a abolishes the tolerogenic phenotype of human IL-10 DC and, thereby, prevents the induction of T cell anergy and regulatory T cells. Tolerogenic DC can be induced by tumor- or immune cellderived factors like IL-10 and are critically involved in tumor progression. Previously, we have shown that addition of IL-10 during the generation of human DC induced a tolerogenic phenotype of DC which provoked antigen-specific tolerance in CD4+ and CD8+ T cells. The induced anergic iTregs inhibited activated effector T cell responses in an antigenspecific fashion and induced a melanoma antigen-specific anergy in CD8+ cytotoxic T cells resulting in failure of tumor lysis.