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. 2020 Feb 1;10(2):564-571.
eCollection 2020.

Inhibition of c-MET Upregulates PD-L1 Expression in Lung Adenocarcinoma

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Free PMC article

Inhibition of c-MET Upregulates PD-L1 Expression in Lung Adenocarcinoma

Xian Sun et al. Am J Cancer Res. .
Free PMC article

Abstract

Non-small cell lung cancer (NSCLC) patients with c-MET dysregulation may benefit from c-MET inhibitors therapy as inhibition of c-MET activity has emerged as a therapeutic approach against this disease. Although several c-MET inhibitors have been evaluated in multiple clinical trials in lung cancer, their benefits so far have been modest. Thus, furthering our understanding of the mechanisms contributing to the lack of success of c-MET inhibitors in clinical trials is essential toward the development of rational and effective combination strategies. Here we show that exposure of NCSLC cell lines to c-MET inhibitor tivantinib increases their expression of PD-L1, which in turn causes cells to become more resistant to T-cell killing. Mechanistically, inhibition of c-MET suppresses p-GSK3β, leading to the stabilization of PD-L1 similar to that observed in liver cancer cells. Collectively, our findings suggest a potential crosstalk between c-MET inhibition and immune escape and provide a rationale for the combination therapy of c-MET inhibitors and immune checkpoint blockade in NSCLC.

Keywords: GSK3β; NSCLC; PD-L1; c-MET; combination therapy.

Conflict of interest statement

None.

Figures

Figure 1
Figure 1
c-MET inhibitor upregulates PD-L1 expression in NSCLC cells. A and B. Western blot analysis of PD-L1 levels in NSCLC cell lines H1975 and H1993 treated with c-MET inhibitor tivantinib (1 μM). C and D. Western blot analysis of PD-L1 levels in H1975 and H1993 shc-MET cells. E and F. Flow cytometric analysis of cell-surface PD-L1 in H1975 and H1993 shc-MET cells.
Figure 2
Figure 2
c-MET inhibitor induces PD-L1 expression in NSCLC cells in dose and time-dependent manner. A and B. Western blot analysis of whole cell lysates from H1993 and H1975 treated with the indicated concentrations of c-MET inhibitor tivantinib for 24 hours. C and D. Western blot analysis of whole cell lysates from H1993 and H1975 treated with c-MET inhibitor tivantinib (1 μM) for the indicated time. E. H1975 cells were treated with the indicated concentration of tivantinib for 24 hours followed by flow cytometric analysis of cell surface PD-L1 levels. F. H1975 cells were treated with tivantinib (1 μM) for the indicated time followed by flow cytometric analysis of cell surface PD-L1 levels.
Figure 3
Figure 3
c-MET inhibition enhances PD-L1 expression by suppressing GSK3β. A and B. H1975 and H1993 cells were treated with tivantinib (1 μM) for 24 hours followed by RT-PCR to measure PD-L1 mRNA levels. Relative fold ratio of PD-L1 mRNA levels is shown. C and D. H1975 and H1993 shc-MET cells were treated with 20 mM cycloheximide (CHX) at the indicated intervals and subjected to Western blot analysis to evaluate PD-L1 expression levels. E and F. Quantification of PD-L1 half-life in the indicated groups. G and H. H1975 and H1993 cells were treated with tivantinib followed by Western blot analysis with the indicated antibodies. Tubulin served as loading control.
Figure 4
Figure 4
c-MET inhibitor blocks T-cell-mediated cell killing by stabilizing PD-L1. (A and B) H1975 and H1993 shc-MET cells were co-cultured with or without activated T cells for 4 days followed by crystal violet staining to evaluate the cancer cell survival. Relative fold change in survival cell intensity is shown. *P < 0.05. (C and D) Quantitation of panel (A and B). (E and F) H1975 and H1993 cells were treated with or without tivantinib (1 μM) for 24 hours and then subjected to immunofluorescence assay to evaluate PD-L1 expression and localization.

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