Removal of N-Linked Glycosylation Enhances PD-L1 Detection and Predicts Anti-PD-1/PD-L1 Therapeutic Efficacy

Lee, Heng-Huan; Wang, Ying-Nai; Xia, Weiya; Chen, Chia-Hung; Rau, Kun Ming; Ye, Leiguang; Wei, Yongkun; Chou, Chao-Kai; Wang, Shao‐Chun; Yan, Meisi; Tu, Chih Yen; Hsia, Te Chun; Chiang, Shu‐Fen; Chao, K.S. Clifford; Wistuba, Ignacio I.; Hsu, Jennifer L.; Hortobágyi, Gabriel N.; Hung, Mien Chie

doi:10.1016/j.ccell.2019.06.008

Cited by 269 publications

(302 citation statements)

References 45 publications

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“…4A, Data S1) and were extended by the downstream glycosylation machinery. For instance, biosynthetic considerations allowed the assignment of the disaccharide β-Gal-(1-3)-α-GalNAzMe-(Thr*) on the glycopeptide TTPPT*TATPIR of human fibronectin, along with other glycoforms and even a di-glycosylated peptide TTPPT*T*ATPIR (Data S1). DMSO feeding did not lead to discernible signal.…”

Section: Resultsmentioning

confidence: 99%

“…The many facets of cellular glycosylation in health and disease demand methods of visualizing and characterizing glycoconjugates. These methods are essential for the development of next-generation therapeutics and diagnostics that depend on understanding glycosylation of target biomolecules(1, 2). A number of modern experimental techniques have shaped our understanding of biology, such as advanced microscopy, mass spectrometry (MS)-(glyco)proteomics and genome-wide CRISPR-KO screens.…”

Section: Introductionmentioning

confidence: 99%

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Metabolic precision labeling enables selective probing of O-linkedN-acetylgalactosamine glycosylation

Debets¹,

Tastan

Wisnovsky³

et al. 2020

Preprint

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38Protein glycosylation events that happen early in the secretory pathway are often dysregulated during 39 tumorigenesis. These events can be probed, in principle, by monosaccharides with bioorthogonal tags that 40 would ideally be specific for distinct glycan subtypes. However, metabolic interconversion into other 41 monosaccharides drastically reduces such specificity in the living cell. Here, we use a structure-based 42 design process to develop the monosaccharide probe GalNAzMe that is specific for cancer-relevant 43

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Metabolic precision labeling enables selective probing of O-linkedN-acetylgalactosamine glycosylation

Debets¹,

Tastan

Wisnovsky³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Segovia et al [15] found that TMEM176B inhibitor (BayK8644) can promote CD8+ T cell-mediated tumor suppression and enhance anti-tumor activities of anti-CTLA-4 and anti-PD-1 antibodies. For severe glycosylation of PD-L1, Lee et al [16] proposed to remove glycosylated N-chain, further improved the detection of PD-L1, and predicted the therapeutic effect of anti-PD-1/PD-L1.…”

Section: Introductionmentioning

confidence: 99%

Smokers or non-smokers: who benefits more from immune checkpoint inhibitors in treatment of malignancies? An up-to-date meta-analysis

et al. 2020

World J Surg Onc

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Background: Immune checkpoint inhibitors, which are a milestone in anti-cancer therapy, have been applied in the treatment of multiple malignancies. Real-world data have suggested that smoking status may be associated with the efficacy of anti-PD-1/PD-L1 therapy. Hereby, to evaluate "smoking benefit or not", we included numerous high-quality randomized controlled clinical trials (RCTs) without any restriction on category. Methods: A systematic search of online database was performed from July 2010 to July 2019. Eligible studies included phase II/III RCTs comparing PD-1/PD-L1 inhibitors with chemotherapy in the treatment of multiple carcinomas and contained subgroup analysis of smoking status. Then, related hazard ratios (HRs) with 95% confidence intervals (CIs) of overall survival (OS) were pooled.Results: In the initial meta-analysis, compared with chemotherapy, the OS of non-smokers (HR, 0.81; 95% CI, 0.67-0.98) and smokers (HR, 0.77; 95% CI, 0.71-0.83) were significantly prolonged with PD-1/PD-L1 inhibitors. Outcomes from subgroup analysis showed that in anti-PD-1/PD-L1 monotherapy groups, non-smokers showed no significant improvement in OS (HR, 0.94; 95% CI, 0.83-1.06), while the OS of smokers was significantly prolonged (HR, 0.79; 95% CI, 0.74-0.85); in groups of PD-1/PD-L1 inhibitors combined with chemotherapy, the OS of non-smokers (HR, 0.45; 95% CI, 0.28-0.71) and smokers (HR, 0.72; 95% CI, 0.61-0.85) were significantly prolonged. Combined ipilimumab and chemotherapy showed no significance in both groups. Conclusion:Smokers benefit from either anti-PD-1/PD-L1 monotherapy or the combined regimen compared with chemotherapy. Considering cost-effectiveness, monotherapy was recommended to smokers. For non-smokers, only the combined regimen was feasible in non-small cell lung cancer.

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“…Glycans are also indirectly involved in the protein-protein interactions by contributing to protein conformations and oligomerization. Immune checkpoint molecules PD-1 (Okada et al, 2017) and PD-L1 Lee et al, 2019) are both heavily glycosylated, and the glycans are required for their normal interactions and subsequent suppression of T cell activities. In addition, human glycans are receptors of surface proteins of pathogens, such as bacteria, fungi and viruses that are involved in virtually all types of infectious disease processes (Li et al, 2017;Byrd-Leotis et al, 2019b).…”

Section: Introductionmentioning

confidence: 99%

Glycan Microarrays as Chemical Tools for Identifying Glycan Recognition by Immune Proteins

et al. 2019

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Glycans and glycan binding proteins (GBPs or lectins) are essential components in almost every aspect of immunology. Investigations of the interactions between glycans and GBPs have greatly advanced our understanding of the molecular basis of these fundamental immunological processes. In order to better study the glycan-GBP interactions, microscope glass slide-based glycan microarrays were conceived and proved to be an incredibly useful and successful tool. A variety of methods have been developed to better present the glycans so that they mimic natural presentations. Breakthroughs in chemical biology approaches have also made available glycans with sophisticated structures that were considered practically impossible just a few decade ago. Glycan microarrays provide a wealth of valuable information in immunological studies. They allow for discovery of detailed glycan binding preferences or novel binding epitopes of known endogenous immune receptors, which can potentially lead to the discovery of natural ligands that carry the glycans. Glycan microarrays also serve as a platform to discover new GBPs that are vital to the process of infection and invasion by microorganisms. This review summarizes the construction strategies and the immunological applications of glycan microarrays, particularly focused on those with the most comprehensive sets of glycan structures. We also review new methods and technologies that have evolved. We believe that glycan microarrays will continue to benefit the growing research community with various interests in the field of immunology.

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Removal of N-Linked Glycosylation Enhances PD-L1 Detection and Predicts Anti-PD-1/PD-L1 Therapeutic Efficacy

Cited by 269 publications

References 45 publications

Metabolic precision labeling enables selective probing of O-linkedN-acetylgalactosamine glycosylation

Metabolic precision labeling enables selective probing of O-linkedN-acetylgalactosamine glycosylation

Smokers or non-smokers: who benefits more from immune checkpoint inhibitors in treatment of malignancies? An up-to-date meta-analysis

Glycan Microarrays as Chemical Tools for Identifying Glycan Recognition by Immune Proteins

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