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.