PD-L1 positively regulates MET phosphorylation through inhibiting PTP1B

Increasing bodies of evidence support the involvement of tumor-intrinsic action in PD-L1-mediated cancer progression. However, the mechanisms underlying the tumor-intrinsic function of PD-L1 are less well understood. In the present study, we found a positive correlation between PD-L1 expression and MET phosphorylation in lung cancer and melanoma cell lines. PD-L1 inhibition led to a decrease in MET phosphorylation, while PD-L1 induction by IFN-γ resulted in a PD-L1-dependent increase of MET phosphorylation both in vitro and in vivo. The results indicated that MET phosphorylation can be positively regulated by PD-L1. Furthermore, we identified PTP1B as a mediator contributing to the regulation of MET phosphorylation by PD-L1. In agreement with the induction of MET phosphorylation by PD-L1, inhibition of PD-L1 caused reduced phosphorylation of ERKs, a known downstream kinase of MET, and inhibited cell proliferation. Collectively, the present study demonstrated for the first time that the MET pathway, as a downstream of PD-L1, contributed to its tumor-intrinsic effect, and provided a novel mechanistic explanation for the tumor-intrinsic function of PD-L1 and a rationale for the combination of immunotherapy and MET-targeted therapy in cancer treatment.