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Dendritic cells (DCs) can be differentiated from CD14+ monocytes in the presence of interferon-α (IFNα) and granulocyte/macrophage-colony stimulating factor (GM-CSF) in vitro and are known as IFN-DCs. Circulating blood CD56+ cells expressing high levels of CD14, HLA-DR and CD86 have been shown to spontaneously differentiate into DC-like cells in vitro after their isolation from blood. We show here that IFN-DCs expressing high levels of CD56 (hereafter, CD56high+ IFN-DCs) can be differentiated in vitro from monocytes obtained as adherent cells from healthy donors and patients with metastatic melanoma. These cells expressed high levels of CD14, HLA-DR and CD86 and possessed many pseudopodia. These CD56high+ IFN-DCs may be an in vitro counterpart of the circulating CD56+ CD14+ CD86+ HLA-DR+ cells in blood. Conventional mature DCs differentiated from monocytes as adherent cells in the presence of GM-CSF, IL-4 and TNF-α (hereafter, mIL-4DCs) did not express CD56 or CD14. In contrast to mIL-4DCs, the CD56high+ IFN-DCs exhibited a stronger capacity to stimulate autologous CD56+ Vγ9γδT cells highly producing IFNγ in the presence of zoledronate and IL-2. The CD56high+ IFN-DCs possessing HLA-A*0201 effectively induced Mart-1-modified melanoma peptide (A27L)-specific CD8+ T cells through preferential expansion of CD56+ Vγ9γδT cells in the presence of A27L, zoledronate and IL-2. Vaccination with CD56high+ IFN-DCs copulsed with tumor antigens and zoledronate may orchestrate the induction of various CD56+ immune cells possessing high effector functions, resulting in strong immunological responses against tumor cells. This study may be relevant to the design of future clinical trials of CD56high+ IFN-DCs-based immunotherapies for patients with melanoma.