Department of Biochemistry, Pusan National University School of Medicine, Yangsan, 50162, South Korea.
PNU BK21 Plus Biomedical Science Education Center, Pusan National University School of Medicine, Yangsan, 50612, South Korea.
BMC Immunol. 2021 Jul 12;22(1):44. doi: 10.1186/s12865-021-00434-8.
Transforming growth factor beta (TGF-β) is a typical immuno-inhibitory cytokine and highly secreted by lung cancer cells. It was supposed that its immunosuppressive effects to NK cell might be related with the altered expression of activating and inhibitory molecules in lung cancer cells. In this study, we examined the expression of NKG2DLs, PD-L1 and PD-L2 in lung cancer cells after treatment of TGF-β and a TGF-β inhibitor, Galunisertib (LY2157299).
TGF-β reduced the level of surface proteins of five NKG2DLs without altered transcription levels in lung cancer cells. Galunisertib reversed the effect of TGF-β on the expression of NKG2DLs. Since MMP inhibitors, MMPi III and MMP2 inhibitor I, restored the reduced expression of NKG2DLs after treatment of TGF-β, it was thought that TGF-β induced the expression of MMP2 which facilitated the shedding of the NKG2DLs in cancer cells. However, the expression of PD-L1, L2 were not changed by treatment with TGF-β or Galunisertib.
Therefore, inhibition of TGF-β might reverse the immunosuppressive status on immune cells and restore NK cell mediated anticancer immune responses by upregulation of NKG2DLs in cancer cells.
转化生长因子-β（TGF-β）是一种典型的免疫抑制细胞因子，高度分泌于肺癌细胞中。据推测，其对 NK 细胞的免疫抑制作用可能与肺癌细胞中激活和抑制分子的改变表达有关。在这项研究中，我们在 TGF-β和 TGF-β抑制剂 Galunisertib（LY2157299）处理后，检测了肺癌细胞中 NKG2DLs、PD-L1 和 PD-L2 的表达。
TGF-β降低了肺癌细胞表面五种 NKG2DLs 的蛋白水平，而转录水平没有改变。Galunisertib 逆转了 TGF-β对 NKG2DLs 表达的影响。由于 MMP 抑制剂 MMPi III 和 MMP2 抑制剂 I 在 TGF-β 处理后恢复了 NKG2DLs 的表达降低，因此认为 TGF-β诱导了 MMP2 的表达，促进了癌细胞中 NKG2DLs 的脱落。然而，PD-L1、L2 的表达不受 TGF-β 或 Galunisertib 处理的影响。
因此，抑制 TGF-β可能通过上调癌细胞中 NKG2DLs，逆转免疫细胞的免疫抑制状态，并恢复 NK 细胞介导的抗癌免疫反应。
