NF-κB activation triggers NK-cell stimulation by monocyte-derived dendritic cells

Abstract

Background: In therapeutic cancer vaccination, monocyte-derived dendritic cells (moDCs) efficiently activate specific T-cell responses; however, optimizing the activation of innate immune cells could support and improve the antitumor effects. A major disadvantage of moDCs matured with the standard cytokine cocktail (consisting of IL-1β, IL-6, TNFα, and PGE2) is their inability to secrete IL-12p70. IL-12 prominently activates natural killer (NK) cells, which are crucial in innate antitumor immunity, as they act as helper cells for the induction of a cytotoxic T lymphocyte (CTL) response and are also able to directly kill the tumor. Methods: Previously we have shown that triggering the NF-κB pathway in moDCs by transfection of mRNA encoding constitutively active IKKβ (caIKKβ) led to IL-12p70 secretion and improved the dendritic cells’ capability to activate and expand CTLs with a memory-like phenotype. In this study, we examined whether such dendritic cells could activate autologous NK cells. Results: moDCs matured with the standard cytokine cocktail followed by transfection with the caIKKβ-RNA were able to activate autologous NK cells, detected by the upregulation of CD54, CD69, and CD25 on the NK cells, their ability to secrete IFNγ, and their high lytic activity. Moreover, the ability of NK-cell activation was not diminished by simultaneous T-cell activation. Conclusion: The capacity of caIKKβ-DCs to activate both the adaptive and innate immune response indicates an enhanced potential for clinical efficacy.