期刊
JOURNAL OF IMMUNOTHERAPY
卷 34, 期 3, 页码 270-278出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/CJI.0b013e31820b370b
关键词
NK cells; dendritic cells; vaccination; CTL; tumor immunity; humans
资金
- NIH grants CA095128, CA101944, and CA114931, and [CA095128, CA101944, CA114931]
- Clinical and Translational Science Institute [5TL1RR024155-04]
Natural killer (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 dendritic cell (DC) exhaustion, inducing the development of type-1 polarized mature DCs (DC1) with an enhanced ability to produce interleukin (IL)-12p70, a factor essential for type-1 immunity and effective anticancer 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 tumor-specific cytotoxic T lymphocytes. NK cells isolated from patients with late-stage (stage III and IV) melanoma responded with high interferon-g production and the induction of type-1-polarized DCs on exposure to defined combinations of stimulatory agents, including interferon-alpha and IL-18. The resulting DCs showed strongly-enhanced IL-12p70 production on subsequent T-cell interaction compared with immature DCs (average of 19-fold enhancement) and nonpolarized IL-1b/TNF-alpha/IL-6/PGE2-matured standard DCs (average of 215-fold enhancement). Additional inclusion of polyinosinic: polycytidylic acid during NK-DC cocultures optimized the expression of CD80, CD86, CD40, and HLA-DR on the resulting (NK)DC1, increased their CCR7-mediated migratory responsiveness to the lymph node-associated chemokine CCL21, and further enhanced their IL-12-producing capacity. When compared in vitro with immature DCs and nonpolarized standard DCs, NKDC1 were superior in inducing functional melanoma-specific cytotoxic T lymphocytes capable of recognizing multiple melanoma-associated antigens and killing melanoma cells. These results indicate that the helper function of NK cells can be used in clinical settings to improve the effectiveness of DC-based cancer vaccines.
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