Abstract
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.
Highlights
Over the past years, the phenotypic and functional boundaries distinguishing the main cell subsets of the human immune system have become increasingly blurred
Numbers of IFN-c spot-forming cells (SFCs)/well in non-antigen-stimulated cultures (i.e. cytotoxic T lymphocyte (CTL) clone cultured with nonantigen-loaded dendritic cells (DCs)) did not differ significantly between CD56+ and CD562 IL-15 DCs and were found to be consistently lower than those in corresponding cultures stimulated with Wilms’ tumor 1 protein (WT1) RNA
We reveal for the first time that IL-15 DCs, in addition to a robust capacity for tumor antigen presentation, possess tumor cell killing potential
Summary
The phenotypic and functional boundaries distinguishing the main cell subsets of the human immune system have become increasingly blurred. In mice, specialized NK cell subsets, collectively designated as ‘natural killer dendritic cells’ (NKDCs), have been identified that display a hybrid NK cell/DC phenotype and combine functional properties of NK cells (cytotoxicity) and DCs (antigen presentation) [4,5,6,7,8,9] Evidence from both rodent and human studies is emerging that DCs may exhibit NK-like activity and play a direct role in innate immunity as killer cells; in the literature, these cells are designated as ‘killer DCs’ [10,11,12,13]. Such killer DCs that can combine both tumor antigen presentation function with direct tumoricidal activity are garnering increasing attention as potential new, multifunctional tools for cancer immunotherapy [10,11,12,14]
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