Department of Biotechnology and Laboratory Science in Medicine, School of Biomedical Science and Engineering, National Yang-Ming University, Taipei, Taiwan.
School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
Immunobiology. 2019 Sep;224(5):649-658. doi: 10.1016/j.imbio.2019.07.002. Epub 2019 Aug 9.
Transforming growth factor-β (TGF-β) is known to function as a dual role regulatory cytokine for being either a suppresser or promoter during tumor initiation and progression. In solid tumors, TGF-β secreted from tumor microenvironment acts as a suppresser against host immunity, like natural killer (NK) cells, to favor tumor evasion. However, besides solid tumors, the underlying mechanism of how TGF-β regulates leukemogenesis, tumor progression, immunoediting, and NK function is still not clear in detail. In this study, we found that TGF-β induced leukemia MEG-01 and U937 cells to become less sensitive to NK-92MI targeting by down-regulating CD48, a ligand for NK activating receptor 2B4, but not down-regulating other tumor-associated carbohydrate antigens (TACAs). In CD48-knockdown cells, cells responding to NK-92MI targeting displayed a phenotype of less NK susceptibility and cell conjugation. On the other hand, when NK cells were treated with TGF-β, TGF-β suppressed NK recognition, degranulation, and killing activity in time-dependent manner by regulating ICAM-1 binding capacity instead of affecting expressions of activating and inhibitory receptors. Taken together, both leukemia cells and immune NK cells could be regulated by TGF-β through suppressing leukemia cell surface CD48 to escape from host surveillance and down-regulating NK cell surface ICAM-1 binding activity to impair NK functions, respectively. Our results suggested that TGF-β had effect in leukemia similar to that observed in solid tumors but through different regulatory mechanism.
转化生长因子-β（TGF-β）被认为在肿瘤发生和进展过程中具有双重作用的调节细胞因子，既可以作为抑制剂，也可以作为促进剂。在实体瘤中，肿瘤微环境分泌的 TGF-β 作为一种抑制剂，作用于自然杀伤（NK）细胞等宿主免疫细胞，有利于肿瘤逃逸。然而，除了实体瘤之外，TGF-β 如何调节白血病发生、肿瘤进展、免疫编辑和 NK 功能的机制尚不清楚。在这项研究中，我们发现 TGF-β 通过下调 NK 激活受体 2B4 的配体 CD48，使白血病 MEG-01 和 U937 细胞对 NK-92MI 靶向作用的敏感性降低，但不下调其他肿瘤相关碳水化合物抗原（TACA）。在 CD48 敲低细胞中，对 NK-92MI 靶向作用有反应的细胞表现出对 NK 敏感性降低和细胞连接的表型。另一方面，当 NK 细胞受到 TGF-β 处理时，TGF-β 通过调节 ICAM-1 结合能力，而不是影响激活和抑制受体的表达，以时间依赖的方式抑制 NK 识别、脱颗粒和杀伤活性。总之，白血病细胞和免疫 NK 细胞都可以通过抑制白血病细胞表面的 CD48 来逃避宿主监视，下调 NK 细胞表面的 ICAM-1 结合活性来损害 NK 功能，从而被 TGF-β 调节。我们的结果表明，TGF-β 对白血病的作用类似于在实体瘤中观察到的作用，但通过不同的调节机制。
