Interleukin-15-induced CD56(+) myeloid dendritic cells combine potent tumor antigen presentation with direct tumoricidal potential

• Published in: PloS one Vol. 7; no. 12; p. e51851
• Main Authors: Anguille, Sébastien, Lion, Eva, Tel, Jurjen, de Vries, I Jolanda M, Couderé, Karen, Fromm, Phillip D, Van Tendeloo, Viggo F, Smits, Evelien L, Berneman, Zwi N
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 28.12.2012; Public Library of Science (PLoS)
• Subjects: Adaptive immunity; Adaptive systems; Antigen presentation; Antigen-presenting cells; Antigen-Presenting Cells - immunology; Apoptosis; Biology; Breast cancer; Cancer; Cancer immunotherapy; CD56 antigen; CD56 Antigen - immunology; CD95 antigen; Cell culture; Cell death; Cell Differentiation; Cytokines; Cytotoxicity; Cytotoxicity, Immunologic - immunology; Data processing; Dendritic cells; Dendritic Cells - cytology; Dendritic Cells - immunology; Fas antigen; FasL protein; Flow Cytometry; Genotype & phenotype; Granzyme B; Granzymes - immunology; Granzymes - metabolism; Health sciences; Hematology; Hospitals; Humans; Immune response; Immune system; Immunogenicity; Immunology; Immunostimulation; Immunotherapy; Infectious diseases; Interleukin 15; Interleukin-15 - immunology; Killer Cells, Natural - immunology; Laboratories; Life sciences; Ligands; Lymphocytes; Lymphocytes T; Medicine; Monocytes; Monocytes - cytology; Monocytes - immunology; Myeloid Cells - immunology; Natural killer cells; Neoplasms - immunology; Neoplasms - metabolism; Neoplasms - pathology; Perforin; Toxicity; TRAIL protein; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Belgium
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0051851

Dendritic cells (DCs) are the quintessential antigen-presenting cells of the human immune system and play a prime role in coordinating innate and adaptive immune responses, explaining the strong and still growing interest in their application for cancer immunotherapy. Much current research in the field of DC-based immunotherapy focuses on optimizing the culture conditions for in vitro DC generation in order to assure that DCs with the best possible immunogenic qualities are being used for immunotherapy. In this context, monocyte-derived DCs that are alternatively induced by interleukin-15 (IL-15 DCs) have attracted recent attention due to their superior immunostimulatory characteristics. In this study, we show that IL-15 DCs, in addition to potent tumor antigen-presenting function, possess tumoricidal potential and thus qualify for the designation of killer DCs. Notwithstanding marked expression of the natural killer (NK) cell marker CD56 on a subset of IL-15 DCs, we found no evidence of a further phenotypic overlap between IL-15 DCs and NK cells. Allostimulation and antigen presentation assays confirmed that IL-15 DCs should be regarded as bona fide myeloid DCs not only from the phenotypic but also from the functional point of view. Concerning their cytotoxic activity, we demonstrate that IL-15 DCs are able to induce apoptotic cell death of the human K562 tumor cell line, while sparing tumor antigen-specific T cells. The cytotoxicity of IL-15 DCs is predominantly mediated by granzyme B and, to a small extent, by tumor necrosis factor-α (TNF-α)-related apoptosis-inducing ligand (TRAIL) but is independent of perforin, Fas ligand and TNF-α. In conclusion, our data provide evidence of a previously unappreciated role for IL-15 in the differentiation of human monocytes towards killer DCs. The observation that IL-15 DCs have killer DC capacity lends further support to their implementation in DC-based immunotherapy protocols.