Interleukin-15 Dendritic Cells Harness NK Cell Cytotoxic Effector Function in a Contact- and IL-15-Dependent Manner

Abstract

The contribution of natural killer (NK) cells to the treatment efficacy of dendritic cell (DC)-based cancer vaccines is being increasingly recognized. Much current efforts to optimize this form of immunotherapy are therefore geared towards harnessing the NK cell-stimulatory ability of DCs. In this study, we investigated whether generation of human monocyte-derived DCs with interleukin (IL)-15 followed by activation with a Toll-like receptor stimulus endows these DCs, commonly referred to as “IL-15 DCs”, with the capacity to stimulate NK cells. In a head-to-head comparison with “IL-4 DCs” used routinely for clinical studies, IL-15 DCs were found to induce a more activated, cytotoxic effector phenotype in NK cells, in particular in the CD56bright NK cell subset. With the exception of GM-CSF, no significant enhancement of cytokine/chemokine secretion was observed following co-culture of NK cells with IL-15 DCs. IL-15 DCs, but not IL-4 DCs, promoted NK cell tumoricidal activity towards both NK-sensitive and NK-resistant targets. This effect was found to require cell-to-cell contact and to be mediated by DC surface-bound IL-15. This study shows that DCs can express a membrane-bound form of IL-15 through which they enhance NK cell cytotoxic function. The observed lack of membrane-bound IL-15 on “gold-standard” IL-4 DCs and their consequent inability to effectively promote NK cell cytotoxicity may have important implications for the future design of DC-based cancer vaccine studies.

CD56bright NK cells exhibit potent antitumor responses following IL-15 priming

“…In addition, we confirmed no change in KIR (CD158a, CD158b1/2, CD158d, CD158e1/2, and CD158i) or CD57 expression on CD56 bright NK cells following IL-15 priming. However, we did observe significantly increased expression of NKG2D, NKp30, NKp44, CD69, CD2, and CD11a ( Figure 5A and Supplemental Figure 7) on IL-15-primed, compared with control, CD56 bright NK cells, in agreement with prior reports (37,38). Because of their role in promoting antitumor responses by NK cells, NKG2D, NKp44, NKp30, CD2, and CD11a were thus evaluated for their contribution to IL-15-primed CD56 bright NK cell responses to tumor targets.…”

Toll-Like Receptors in Natural Killer Cells and Their Application for Immunotherapy

“…DC-derived IL-12, IL-15, IL-18, and type I IFN are crucial for the production of IFN-γ in NK cells, and NK cell-derived IFN-γ then facilitates the activation of DCs. They have a positive feedback loop that amplifies TLRinduced activation of NK cells and DCs [95,[98][99][100]. Macrophages secrete IL-12, IL-18, and type I IFN to activate NK cells during microbial infection through TLR signaling pathways.…”

Independent control of natural killer cell responsiveness and homeostasis at steady-state by CD11c+ dendritic cells

“…In addition to this role, DC have been shown to provide homeostatic support to naïve T cells, securing their sensitivity to subsequent challenges with cognate antigens234. A role for DC in NK cell activation and priming has also been suggested56789. A question that has so far not been extensively studied, however, is if DC provide basic support for NK cells also at steady-state.…”