Effective induction of melanoma-antigen-specific CD8+ T cells via Vγ9γδT cell expansion by CD56high+ Interferon-α-induced dendritic cells

Dendritic cells (DCs) can be differentiated from CD14(+) monocytes in the presence of interferon- (IFN) and granulocyte/macrophage-colony stimulating factor (GM-CSF) invitro 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, CD56(high+) 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 CD56(high+) 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- (hereafter, mIL-4DCs) did not express CD56 or CD14. In contrast to mIL-4DCs, the CD56(high+) IFN-DCs exhibited a stronger capacity to stimulate autologous CD56(+) V9T cells highly producing IFN in the presence of zoledronate and IL-2. The CD56(high+) IFN-DCs possessing HLA-A*0201 effectively induced Mart-1-modified melanoma peptide (A27L)-specific CD8(+) T cells through preferential expansion of CD56(+) V9T cells in the presence of A27L, zoledronate and IL-2. Vaccination with CD56(high+) 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 CD56(high+) IFN-DCs-based immunotherapies for patients with melanoma.