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| Home > Institute Collections > W500 > N-glycosylation of PD-L1 modulates the efficacy of immune checkpoint blockades targeting PD-L1 and PD-1. |
| Home > Institute Collections > W500 > N-glycosylation of PD-L1 modulates the efficacy of immune checkpoint blockades targeting PD-L1 and PD-1. |
| Journal Article | DKFZ-2025-02494 |
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2025
Biomed Central
London
Abstract: The PD-L1/PD-1 pathway is crucial for immune regulation and has become a target in cancer immunotherapy. However, in order to improve patient selection for immune checkpoint blockade (ICB) therapies, better selection criteria are needed. This study explores how the N-glycosylation of PD-L1 affects its interaction with PD-1 and ICB efficacy, focusing on its four N-linked glycosylation sites: N35, N192, N200, and N219.Human PD-L1 glycosylation mutants-at each individual site or at all four sites together (Nx4)-were tested for their functional interaction with PD-1 using an artificial immune checkpoint reporter assay (IcAR-PD1). The blocking efficacy of anti-PD-L1 and anti-PD-1 antibodies was evaluated using human breast cancer cell lines (MDA-MB231 and MCF7), as well as A375 melanoma and A549 lung carcinoma cells expressing the glycosylation mutants. Results were validated through ex vivo activation and cytotoxicity assays using human CD8+ T cells.The binding of the PD-L1N35A mutant to PD-1 was not effectively blocked by anti-PD-L1 and anti-PD-1 ICBs. In contrast, high blocking efficacy of PD-L1 binding to PD-1 was obtained at minimal ICB concentrations when PD-L1 did not express any glycosylation site (PD-L1Nx4 mutant). The PD-L1N35A mutant produced elevated levels of PD-L1 as a soluble (sPD-L1) and extracellular vesicles (EV)-bound molecule; in contrast, the PD-L1Nx4 mutant had lower sPD-L1 and EV levels. PD-L1 glycosylation status influenced the ability of PD-L1 interactions with PD-1 to down-regulate T-cell activation and cytotoxicity, with the PD-L1N35A mutant showing the lowest levels of T cell functions and the PD-L1Nx4 mutant the highest.The N-glycosylation of PD-L1 at all four sites interferes with the ability of anti-PD-L1 and anti-PD-1 ICBs to block PD-L1 interactions with PD-1; in contrast, glycosylation at the N35 site enhances ICB blocking efficacy. These effects are connected to the ability of sPD-L1 to compete with ICB binding to PD-L1 or PD-1. Thus, assessing PD-L1 glycosylation, beyond expression levels, could improve patient stratification and outcomes.
Keyword(s): Humans (MeSH) ; Glycosylation (MeSH) ; B7-H1 Antigen: metabolism (MeSH) ; B7-H1 Antigen: genetics (MeSH) ; B7-H1 Antigen: antagonists & inhibitors (MeSH) ; B7-H1 Antigen: chemistry (MeSH) ; Immune Checkpoint Inhibitors: pharmacology (MeSH) ; Programmed Cell Death 1 Receptor: metabolism (MeSH) ; Programmed Cell Death 1 Receptor: antagonists & inhibitors (MeSH) ; Cell Line, Tumor (MeSH) ; CD8-Positive T-Lymphocytes: immunology (MeSH) ; CD8-Positive T-Lymphocytes: metabolism (MeSH) ; CD8-Positive T-Lymphocytes: drug effects (MeSH) ; Neoplasms: metabolism (MeSH) ; Neoplasms: drug therapy (MeSH) ; Neoplasms: immunology (MeSH) ; Protein Binding (MeSH) ; Mutation (MeSH) ; Anti-PD-L1/PD-1 antibodies ; Cancer immunotherapy ; Cytotoxicity ; Degranulation assay ; Glycosylation mutants ; Inhibitory immune checkpoints ; N-glycosylation ; PD-1 ; PD-L1 ; T-cell activation ; B7-H1 Antigen ; Immune Checkpoint Inhibitors ; Programmed Cell Death 1 Receptor ; CD274 protein, human ; PDCD1 protein, human
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