title: Effective induction of melanoma-antigen-specific CD8+ T cells via Vγ9γδT cell expansion by CD56(high+) Interferon-α-induced dendritic cells.
abstract: 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, 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-α (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+ Vγ9γδT cells highly producing IFNγ 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+ Vγ9γδT 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.
authors.affiliation: Biotherapy Institute of Japan, Koutou-ku, Tokyo, Japan.
authors.forename: Mie
authors.initials: M
authors.lastname: Nieda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Terunuma
authors.forename: Yuuta
authors.initials: Y
authors.lastname: Eiraku
authors.forename: Xuewen
authors.initials: X
authors.lastname: Deng
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Nicol
mesh_terms: D019002:CD56 Antigen / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology*; D003713:Dendritic Cells / Q000378:metabolism*; D004164:Diphosphonates / Q000737:chemistry; D005434:Flow Cytometry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D015789:HLA-A2 Antigen / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D007167:Immunotherapy; D016898:Interferon-alpha / Q000378:metabolism*; D007376:Interleukin-2 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology; D008545:Melanoma / Q000276:immunology / Q000378:metabolism* / Q000628:therapy; D009000:Monocytes / Q000166:cytology; D010455:Peptides / Q000378:metabolism; D010641:Phenotype; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D012878:Skin Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D000077211:Zoledronic Acid
chemical_list: D019002:CD56 Antigen; D004164:Diphosphonates; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D007093:Imidazoles; D016898:Interferon-alpha; D007376:Interleukin-2; D018950:Lipopolysaccharide Receptors; D010455:Peptides; D016692:Receptors, Antigen, T-Cell, gamma-delta; C521522:T-cell receptor Vgamma9, human; D000077211:Zoledronic Acid; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: IFN
  α; Vγ9γδT; immunotherapy; melanoma-antigen-specific CD8+ T; zoledronate