MET regulates expression of co-stimulatory and co-inhibitory molecules in tumor cells and contributes to suppression of immune cell function

MET-altered human cancer cell lines including Hs746T (MET-mutated/amplified), H596 (MET-mutated) and H1993 (MET-amplified) cells were used. In microarray analysis, MET suppression using MET inhibitor or siRNAs up-regulated variable co-stimulatory molecules, including 4-1BBL, OX40L and CD70, and down-regulated variable co-inhibitory molecules. Among co-inhibitory molecules, PD-L1 was one of the most markedly down-regulated genes by MET suppression, which was validated at the mRNA and total/surface protein levels in Hs746T and H1993 cells. Consistently, MET activation by HGF treatment increased PD-L1 expression in H596 cells. Co-culture of human peripheral blood mononuclear cells (PBMC) with Hs746T cells suppressed IFNg production from PBMC, which was restored by an MET inhibitor or PD-L1 blockade. A significant positive correlation between MET and PD-L1 expression was observed in The Cancer Genome Atlas (TCGA) analysis for variable cancer types and immunohistochemistry for lung cancer. MET overexpression in PD-L1-high tumor exhibited decreased expressions of T-cell effector molecules in TCGA analysis for lung cancer. In summary, MET overexpression/activation is related to immunosuppressive phenotype and is involved in immune escape of tumor by PD-L1 up-regulation. MET-targeted therapy combined with immunotherapy could be a potential therapeutic strategy in MET-dependent cancer. Gene expression of Hs746T cell line: DMSO (control) versus PHA665752 (MET inhibitor), scramble siRNA (control) versus MET siRNA (MET knockdown), total 4 samples