Institute of Natural Medicine, University of Toyama, Toyama, Japan.
Project Division of Cancer Biomolecular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Cancer Sci. 2020 Aug;111(8):2770-2778. doi: 10.1111/cas.14538. Epub 2020 Jul 14.
Thalidomide and its analogues are known as immunomodulatory drugs (IMiDs) that possess direct antimyeloma effects, in addition to other secondary effects, including antiangiogenic, antiinflammatory, and immunomodulatory effects. Although the involvement of natural killer (NK) cells in the antitumor effects of IMiDs has been reported, it is unclear whether IMiDs inhibit cancer cell metastasis by regulating the antitumor function of NK cells. In this study, we examined the protective effects of thalidomide against cancer metastasis by focusing on its immunomodulatory effects through NK cells. Using experimental lung metastasis models, we found that pharmacological effects of thalidomide on host cells, but not its direct anticancer tumor effects, are responsible for the inhibition of lung metastases. To exert the antimetastatic effects of thalidomide, both γ-interferon (IFN-γ) production and direct cytotoxicity of NK cells were essential, without notable contribution from T cells. In thalidomide-treated mice, there was a significant increase in the terminally differentiated mature CD27 NK cells in the peripheral tissues and NK cells in thalidomide-treated mice showed significantly higher cytotoxicity and IFN-γ production. The NK cell expression of T-bet was upregulated by thalidomide treatment and the downregulation of glycogen synthase kinase-3β expression was observed in thalidomide-treated NK cells. Collectively, our study suggests that thalidomide induces the functional maturation of peripheral NK cells through alteration of T-bet expression to inhibit lung metastasis of cancer cells.
沙利度胺及其类似物被称为免疫调节药物（IMiDs），除了具有抗血管生成、抗炎和免疫调节等其他次要作用外，还具有直接的抗骨髓瘤作用。尽管已经报道了自然杀伤（NK）细胞参与 IMiD 的抗肿瘤作用，但尚不清楚 IMiD 是否通过调节 NK 细胞的抗肿瘤功能来抑制癌细胞转移。在这项研究中，我们通过关注 NK 细胞的免疫调节作用，研究了沙利度胺对癌症转移的保护作用。通过实验性肺转移模型，我们发现沙利度胺对宿主细胞的药理作用，而不是其直接的抗癌肿瘤作用，是抑制肺转移的原因。为了发挥沙利度胺的抗转移作用，NK 细胞的γ-干扰素（IFN-γ）产生和直接细胞毒性都是必需的，而 T 细胞的贡献不大。在沙利度胺处理的小鼠中，外周组织中终末分化的成熟 CD27 NK 细胞和沙利度胺处理的小鼠中的 NK 细胞数量显著增加，且 NK 细胞的细胞毒性和 IFN-γ产生显著增强。沙利度胺处理上调了 NK 细胞中 T 细胞特异性转录因子（T-bet）的表达，并且观察到沙利度胺处理的 NK 细胞中糖原合成酶激酶-3β（glycogen synthase kinase-3β，GSK-3β）的表达下调。综上所述，我们的研究表明，沙利度胺通过改变 T-bet 的表达诱导外周 NK 细胞的功能成熟，从而抑制癌细胞的肺转移。
