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.
Highlights
Cancer cells often upregulate programmed death ligand 1 (PD-L1) to exhaust activated T cells by stimulating PD-1 on T cells [1, 2]
Results from further investigation showed that protein levels of epithelial markers E-cadherin and Claudin-1 were notably increased in PD-L1–null clones compared with their WT counterparts (Figure 1A)
PD-L1–null cells exhibited a substantial decrease of Snail (Figure 1A), an epithelial-mesenchymal transition (EMT)-promoting transcription factor (EMT-TF) that suppresses the expression of E-cadherin and Claudin-1 [20]
Summary
Cancer cells often upregulate programmed death ligand 1 (PD-L1) to exhaust activated T cells by stimulating PD-1 on T cells [1, 2]. We demonstrate that PD-L1 facilitates the EMT in TNBC cells by protecting the EMT-promoting transcription factor Snail from being destructed by the proteosome This tumor-intrinsic function of PD-L1, which is achieved via the protein tyrosine phosphatase1B (PTP1B)/p38-MAPK/glycogen synthase kinase 3β (GSK3β) axis and can be activated by PD-1 binding, regulates the aggressiveness of TNBC cells. Blockade of both tumor-extrinsic and -intrinsic functions of PD-L1 synergistically suppressed cancer progression in a syngeneic, immunocompetent TNBC mouse model These results broaden the current paradigm regarding the role of PD-L1 in cancer progression and emphasize an underestimated concept that the tumor-intrinsic PD-L1 pathway needs to be considered when applying the anti–PD-L1 therapy
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
