GSK3 Inhibition Drives Maturation of NK Cells and Enhances Their Antitumor Activity.
GSK3 Inhibition Drives Maturation of NK Cells and Enhances Their Antitumor Activity.
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DOI：
10.1158/0008-5472.can-17-0799
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发表时间：
2017-10-15
期刊：
影响因子：
11.2
通讯作者：
Miller JS
中科院分区：
文献类型：
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作者：
Cichocki F;Valamehr B;Bjordahl R;Zhang B;Rezner B;Rogers P;Gaidarova S;Moreno S;Tuininga K;Dougherty P;McCullar V;Howard P;Sarhan D;Taras E;Schlums H;Abbot S;Shoemaker D;Bryceson YT;Blazar BR;Wolchko S;Cooley S;Miller JS
如通过CD 57的细胞表面表达的积累所定义的人自然杀伤细胞（NK细胞）的成熟与靶细胞识别后增加的细胞毒性特征以及TNF和IFN-γ产生相关。值得注意的是，多项研究指出了CD 57 + NK细胞在癌症免疫监视中的独特作用，但关于它们如何成熟的信息很少。在这项研究中，我们表明，药理学抑制GSK 3激酶在外周血NK细胞扩增离体与IL-15大大提高了CD 57上调和后期成熟。GSK 3抑制提高了与晚期NK细胞成熟相关的几种转录因子的表达，包括T-BET、ZEB 2和BLIMP-1，而不影响活力或增殖。当暴露于人癌细胞时，在GSK 3抑制剂存在下离体扩增的NK细胞表现出显著更高的TNF和IFN-γ产生、升高的天然细胞毒性和增加的抗体依赖性细胞毒性（ADCC）。在建立的卵巢癌小鼠异种移植模型中，以相同方式调节的NK细胞的过继转移也显示出更稳健和持久的肿瘤控制。我们的研究结果显示了GSK 3激酶抑制如何极大地增强NK细胞的成熟特性，这是有效的癌症免疫治疗最需要的。
Maturation of human natural killer cells (NK cells) as defined by accumulation of cell surface expression of CD57 is associated with increased cytotoxic character and TNF and IFN-γ production upon target cell recognition. Notably, multiple studies point to a unique role for CD57+ NK cells in cancer immunosurveillance, yet there is scant information about how they mature. In this study, we show that pharmacological inhibition of GSK3 kinase in peripheral blood NK cells expanded ex vivo with IL-15 greatly enhances CD57 upregulation and late-stage maturation. GSK3 inhibition elevated the expression of several transcription factors associated with late-stage NK cell maturation including T-BET, ZEB2 and BLIMP-1 without affecting viability or proliferation. When exposed to human cancer cells, NK cell expanded ex vivo in the presence of a GSK3 inhibitor exhibited significantly higher production of TNF and IFN-γ, elevated natural cytotoxicity, and increased antibody-dependent cellular cytotoxicity (ADCC). In an established mouse xenograft model of ovarian cancer, adoptive transfer of NK cells conditioned in the same way also displayed more robust and durable tumor control. Our findings show how GSK3 kinase inhibition can greatly enhance the mature character of NK cells most desired for effective cancer immunotherapy.