State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
1] State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China [2] Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA.
Immunol Cell Biol. 2014 Mar;92(3):263-74. doi: 10.1038/icb.2013.87. Epub 2013 Dec 3.
Generation of functional dendritic cells (DCs) with boosted immunity after the withdrawal of initial activation/maturation conditions remains a significant challenge. In this study, we investigated the impact of a newly developed maturation cocktail consisting of OK-432 and interferon-gamma (IFN-γ) on the function of human monocyte-derived DCs (MoDCs). We found that OK-432 plus IFN-γ stimulation could induce significantly stronger expression of surface molecules, production of cytokines, as well as migration of DCs compared with OK-432 stimulation alone. Most importantly, DCs matured with OK-432 plus IFN-γ-induced maintained secretion of interleukin-12 (IL-12)p70 in secondary culture after stimulus withdrawal. Functionally, OK-432 plus IFN-γ-conditioned DCs induce remarkable Th1 and Tc1 responses more effectively than OK-432 alone, even more than the use of α-type-1 cytokine cocktail. As a result, DCs matured with OK-432 plus IFN-γ can prime stronger cytotoxic lymphocyte (CTL) and natural killer (NK) cell response against tumor cells in vitro. Peripheral blood mononuclear cells activated by DCs matured with OK-432 plus IFN-γ also showed greater tumor growth inhibition in vivo in null mice. Molecular mechanistic analysis showed that DC maturation using IFN-γ in concert with OK-432 involves the activation of p38 and nuclear factor-kappa B (NF-κB) pathways. This study provided a novel strategy to generate more potent immune segments in DC vaccine.
在撤去初始激活/成熟条件后，生成具有增强免疫功能的功能性树突状细胞（DC）仍然是一个重大挑战。在这项研究中，我们研究了由 OK-432 和干扰素-γ（IFN-γ）组成的新开发的成熟鸡尾酒对人单核细胞来源的 DC（MoDC）功能的影响。我们发现，与仅接受 OK-432 刺激相比，OK-432 加 IFN-γ刺激可诱导表面分子、细胞因子产生以及 DC 迁移的表达显著增强。最重要的是，在撤去刺激后，经 OK-432 加 IFN-γ诱导成熟的 DC 在二次培养中仍能持续分泌白细胞介素-12（IL-12）p70。在功能上，与仅用 OK-432 相比，OK-432 加 IFN-γ条件成熟的 DC 更有效地诱导显著的 Th1 和 Tc1 反应，甚至比使用 α 型-1 细胞因子鸡尾酒更有效。结果，经 OK-432 加 IFN-γ成熟的 DC 可在体外对肿瘤细胞诱导更强的细胞毒性 T 淋巴细胞（CTL）和自然杀伤（NK）细胞反应。由 OK-432 加 IFN-γ成熟的 DC 激活的外周血单核细胞在无胸腺裸鼠体内也显示出更强的肿瘤生长抑制作用。分子机制分析表明，IFN-γ与 OK-432 协同作用使 DC 成熟涉及 p38 和核因子-κB（NF-κB）途径的激活。本研究为 DC 疫苗中生成更有效的免疫成分提供了一种新策略。
