Abstract
Extracellular interaction between programmed death ligand-1 (PD-L1) and programmed cell death protein-1 (PD-1) leads to tumour-associated immune escape. Here we show that the immunosuppression activity of PD-L1 is stringently modulated by ubiquitination and N-glycosylation. We show that glycogen synthase kinase 3β (GSK3β) interacts with PD-L1 and induces phosphorylation-dependent proteasome degradation of PD-L1 by β-TrCP. In-depth analysis of PD-L1 N192, N200 and N219 glycosylation suggests that glycosylation antagonizes GSK3β binding. In this regard, only non-glycosylated PD-L1 forms a complex with GSK3β and β-TrCP. We also demonstrate that epidermal growth factor (EGF) stabilizes PD-L1 via GSK3β inactivation in basal-like breast cancer. Inhibition of EGF signalling by gefitinib destabilizes PD-L1, enhances antitumour T-cell immunity and therapeutic efficacy of PD-1 blockade in syngeneic mouse models. Together, our results link ubiquitination and glycosylation pathways to the stringent regulation of PD-L1, which could lead to potential therapeutic strategies to enhance cancer immune therapy efficacy.
Highlights
Extracellular interaction between programmed death ligand-1 (PD-L1) and programmed cell death protein-1 (PD-1) leads to tumour-associated immune escape
Programmed death ligand-1 (PD-L1), known as B7 homologue 1 or B7-H1, is a 33 kDa type 1 transmembrane protein that binds to its receptor, programmed cell death protein-1 (PD-1), which leads to the inhibition of T lymphocyte proliferation, cytokine production, and cytolytic activity and suppression of the body’s immune response[1,2]
CRISPR/Cas9-mediated PD-L1 knockout depleted the 45-kDa form (Fig. 1c, right panel). These results suggest that both bands represent PD-L1 and that the higher band may be attributed to post-translational modifications
Summary
Extracellular interaction between programmed death ligand-1 (PD-L1) and programmed cell death protein-1 (PD-1) leads to tumour-associated immune escape. Our results link ubiquitination and glycosylation pathways to the stringent regulation of PD-L1, which could lead to potential therapeutic strategies to enhance cancer immune therapy efficacy. Programmed death ligand-1 (PD-L1), known as B7 homologue 1 or B7-H1, is a 33 kDa type 1 transmembrane protein that binds to its receptor, programmed cell death protein-1 (PD-1), which leads to the inhibition of T lymphocyte proliferation, cytokine production, and cytolytic activity and suppression of the body’s immune response[1,2]. Ligation of PD-L1 and PD-1 receptor complex hijacks the activation state of CD28/MHC with a higher affinity to inhibit T lymphocyte proliferation, cytokine production and cytolytic activity[2] Monoclonal antibodies blocking this inhibitory pathwayreactivate T-cell activity against cancer cells[3]. Inhibition of GSK3b allows b-catenin to translocate to the nucleus, form complexes with T-cell factor/lymphoid enhancer factor and thereby activates target gene expression[21]
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