PD-L1 tumor-intrinsic signaling and its therapeutic implication in triple-negative breast cancer.

Abstract

Although the immune checkpoint role of programmed death ligand 1 (PD-L1) has been established and targeted in cancer immunotherapy, the tumor-intrinsic role of PD-L1 is less appreciated in tumor biology and therapeutics development, partly because of the incomplete mechanistic understanding. Here we demonstrate a potentially novel mechanism by which PD-L1 promotes the epithelial-mesenchymal transition (EMT) in triple-negative breast cancer (TNBC) cells by suppressing the destruction of the EMT transcription factor Snail. PD-L1 directly binds to and inhibits the tyrosine phosphatase PTP1B, thus preserving p38-MAPK activity that phosphorylates and inhibits glycogen synthase kinase 3β (GSK3β). Via this mechanism, PD-L1 prevents the GSK3β-mediated phosphorylation, ubiquitination, and degradation of Snail and consequently promotes the EMT and metastatic potential of TNBC. Significantly, PD-L1 antibodies that confine the tumor-intrinsic PD-L1/Snail pathway restricted TNBC progression in immunodeficient mice. More importantly, targeting both tumor-intrinsic and tumor-extrinsic functions of PD-L1 showed strong synergistic tumor suppression effect in an immunocompetent TNBC mouse model. Our findings support that PD-L1 intrinsically facilitates TNBC progression by promoting the EMT, and this potentially novel PD-L1 signaling pathway could be targeted for better clinical management of PD-L1-overexpressing TNBCs.

• Authors: Chunhua Chen, Shiheng Li, Junli Xue, Manlong Qi, Xin Liu, Yan Huang, Jinghua Hu, Haidong Dong, Kun Ling
• Journal: JCI insight (JCI Insight) Vol. 6 Issue 8 (04 22 2021) ISSN: 2379-3708 [Electronic] United States
• PMID: 33884962 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• B7-H1 Antigen
• SNAI1 protein, human
• Snail Family Transcription Factors
• Glycogen Synthase Kinase 3 beta
• PTPN1 protein, human
• Protein Tyrosine Phosphatase, Non-Receptor Type 1

Topics

• Animals
• B7-H1 Antigen (immunology, metabolism)
• Cell Line, Tumor
• Epithelial-Mesenchymal Transition (immunology, physiology)
• Glycogen Synthase Kinase 3 beta (metabolism)
• Humans
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Phosphorylation
• Protein Tyrosine Phosphatase, Non-Receptor Type 1 (metabolism)
• Snail Family Transcription Factors (metabolism)
• Triple Negative Breast Neoplasms (immunology, metabolism)