Helper Activity of Natural Killer Cells During the Dendritic Cell-mediated Induction of Melanoma-specific Cytotoxic T Cells (original) (raw)

2011, Journal of Immunotherapy

NK cells have been shown to mediate important immunoregulatory "helper" functions in addition to their cytolytic activity. In particular, NK cells are capable of preventing maturation-related DC "exhaustion", inducing the development of "type-1 polarized" mature DCs with an enhanced ability to produce IL-12p70, a factor essential for type-1 immunity and effective anti-cancer responses. Here we show that the NK cell-mediated type-1 polarization of DCs can be applied in the context of patients with advanced cancer to enhance the efficacy of DCs in inducing tumorspecific CTLs. NK cells isolated from late-stage (stage III and IV) melanoma patients responded with high IFNγ production and the induction of type-1-polarized DCs upon exposure to defined combinations of stimulatory agents, including IFNα plus IL-18. The resulting DCs showed strongly-enhanced IL-12p70 production upon subsequent T cell interaction, compared to immature (i)DCs (average of 19-fold enhancement) and non-polarized IL-1β/TNF-α/IL-6/PGE 2 -matured "standard" (s)DCs (average of 215-fold enhancement). Additional inclusion of poly-I:C during NK-DC co-cultures optimized the expression of CD80, CD86, CD40, and HLA-DR on the resulting NK DC1s, increased their CCR7-mediated migratory responsiveness to the lymph nodeassociated chemokine CCL21, and further enhanced their IL-12-producing capacity. When compared in vitro to iDCs and non-polarized sDCs, NK DC1s were superior in inducing functional melanoma-specific CTLs capable of recognizing multiple melanoma-associated antigens and killing melanoma cells. These results indicate that the helper function of NK cells can be utilized in clinical settings to improve the effectiveness of DC-based cancer vaccines.