Department of Surgery, University of Pittsburgh, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213-1863, USA.
J Immunother. 2011 Apr;34(3):270-8. doi: 10.1097/CJI.0b013e31820b370b.
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-γ production and the induction of type-1-polarized DCs on exposure to defined combinations of stimulatory agents, including interferon-α 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-1β/TNF-α/IL-6/PGE(2)-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, (NK)DC1 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.
自然杀伤 (NK) 细胞除了具有细胞毒性作用外，还具有介导重要免疫调节“辅助”功能。特别是，NK 细胞能够防止成熟相关树突状细胞 (DC) 的“衰竭”，诱导具有增强产生白细胞介素 (IL)-12p70 能力的“1 型极化”成熟 DC（DC1）的发育，IL-12p70 是 1 型免疫和有效抗癌反应所必需的因素。在这里，我们表明 NK 细胞介导的 DC1 型极化可应用于晚期癌症患者，以增强 DC 诱导肿瘤特异性细胞毒性 T 淋巴细胞的功效。从晚期（III 期和 IV 期）黑色素瘤患者中分离的 NK 细胞在暴露于包括干扰素-α和 IL-18 在内的特定刺激剂组合时，会产生高水平的干扰素-γ产生和 1 型极化的 DC 诱导。与未成熟的 DC 相比，产生的 DC 在随后与 T 细胞相互作用时表现出强烈增强的 IL-12p70 产生（平均增强 19 倍），并且与非极化的 IL-1β/TNF-α/IL-6/PGE2-成熟的“标准”DC（平均增强 215 倍）。在 NK-DC 共培养物中额外添加聚肌苷酸：聚胞苷酸可优化产生的 (NK)DC1 上 CD80、CD86、CD40 和 HLA-DR 的表达，增加其对淋巴结相关趋化因子 CCL21 的 CCR7 介导的迁移反应性，并进一步增强其 IL-12 产生能力。与未成熟的 DC 和非极化的标准 DC 相比，(NK)DC1 在体外诱导具有识别多种黑色素瘤相关抗原和杀伤黑色素瘤细胞的功能的黑素瘤特异性细胞毒性 T 淋巴细胞方面更为优越。这些结果表明，NK 细胞的辅助功能可用于临床环境中，以提高基于 DC 的癌症疫苗的有效性。
