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Downregulation of NKG2DLs by TGF-β in human lung cancer cells
Young Shin Lee1, Hojung Choi1, Hae-Ryung Cho1,2
1Department of Biochemistry, Pusan National University School of Medicine, Yangsan, 50162, South Korea.
Background:
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).
Results:
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.
Conclusions:
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.
Insights
Transforming growth factor beta (TGF-β) reduces natural killer group 2 (NKG2) cell-activating ligands on lung cancer cells. Inhibiting TGF-β may restore anti-cancer immunity by increasing these ligands.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Transforming growth factor beta (TGF-β) is an immunosuppressive cytokine secreted by lung cancer cells.
- TGF-β's immunosuppressive effects on natural killer (NK) cells may involve altered expression of immune-related molecules.
Purpose of the Study:
- To investigate the effect of TGF-β on the expression of NKG2DLs, PD-L1, and PD-L2 in lung cancer cells.
- To evaluate the potential of TGF-β inhibition using Galunisertib to reverse these effects.
Main Methods:
- Lung cancer cells were treated with TGF-β and the TGF-β inhibitor Galunisertib (LY2157299).
- Expression levels of NKG2DLs, PD-L1, and PD-L2 were analyzed.
- The role of matrix metalloproteinases (MMPs) was investigated using MMP inhibitors.
Main Results:
- TGF-β reduced surface protein levels of five NKG2DLs without altering transcription.
- Galunisertib reversed TGF-β-induced NKG2DL downregulation.
- MMP inhibitors restored NKG2DL expression, suggesting TGF-β induces MMP2-mediated shedding.
- PD-L1 and PD-L2 expression remained unchanged.
Conclusions:
- Inhibiting TGF-β may reverse immunosuppression in the tumor microenvironment.
- Upregulation of NKG2DLs by TGF-β inhibition could restore NK cell-mediated anti-cancer immunity.
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