PD-L1 positively regulates MET phosphorylation through inhibiting PTP1B.

Abstract

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.

• Authors: Shangyun Lu, Zhenou Sun, Wenli Hu, Shutao Yin, Chong Zhao, Hongbo Hu
• Journal: Cancer science (Cancer Sci) Vol. 112 Issue 5 Pg. 1878-1887 (May 2021) ISSN: 1349-7006 [Electronic] England
• PMID: 33583114 (Publication Type: Journal Article)
• Copyright: © 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• B7-H1 Antigen
• CD274 protein, human
• Interferon-gamma
• Proto-Oncogene Proteins c-met
• PTPN1 protein, human
• Protein Tyrosine Phosphatase, Non-Receptor Type 1

Topics

• Animals
• B7-H1 Antigen (antagonists & inhibitors, drug effects, metabolism)
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Disease Progression
• Heterografts
• Humans
• Interferon-gamma (pharmacology)
• Lung Neoplasms (metabolism, therapy)
• MAP Kinase Signaling System
• Male
• Melanoma (metabolism, therapy)
• Mice
• Mice, Inbred C57BL
• Phosphorylation
• Protein Tyrosine Phosphatase, Non-Receptor Type 1 (metabolism)
• Proto-Oncogene Proteins c-met (metabolism)
• RNA Interference