Saccharide analog, 2‐deoxy‐<scp>d</scp>‐glucose enhances 4‐1BB‐mediated antitumor immunity via PD‐L1 deglycosylation

Kim, Bareun; Sun, Ruoxuan; Oh, Wonkyung; Kim, Alyssa Min Jung; Schwarz, Johann Richard; Lim, Seung-Oe

doi:10.1002/mc.23170

Cited by 31 publications

(26 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…25,38 Several small molecules, such as 2-deoxyglucose, metformin, and resveratrol, have been shown to cause abnormal PD-L1 glycosylation and induce its ER accumulation or decrease its stability. [39][40][41] Our data that the PD-L1 3NQ glycosylation mutant failed to induce PD-1 degradation in the coculture supported the essentiality of glycosylation for the function of PD-L1 (Figure 4(b)). However, the blockade of PD-L1 ER exporting by BMS1166 was not a consequence of inhibition of PD-L1 glycosylation, because a complete loss of N-glycosylation induced by TM did not affect the ER exporting and membrane localization of PD-L1 ( Figure S5).…”

Section: Discussionsupporting

confidence: 59%

Small-molecule PD-L1 inhibitor BMS1166 abrogates the function of PD-L1 by blocking its ER export

Chen

et al. 2020

OncoImmunology

View full text Add to dashboard Cite

Therapeutic monoclonal antibodies against the PD-L1/PD-1 (programmed death ligand-1/programmed cell death protein-1) axis have achieved great successes in cancer treatments, but the development of smallmolecule immunomodulators of the pathway has lagged far behind. We established a cellular coculture assay with two stable transfectant cell lines, a PD-L1-expressing tumor cell line PC9/PD-L1 and a PD-1-expressing T cell line Jurkat/PD-1. Western blotting analyses were used to monitor the PD-L1/PD-1 interaction and signaling. We analyzed PD-L1 glycosylation by lectin binding assay and glycosidase digestion, and examined subcellular localization of PD-L1 by immunocytochemical staining. Luciferase assay and real-time PCR were used to evaluate T cell activation in the coculture experiments. We found that coculturing of the PC9/PD-L1 cells with the Jurkat/PD-1 cells induced a lysosomal degradation of PD-1. A smallmolecule PD-L1 inhibitor BMS1166 developed by Bristol-Myers Squibb inhibited the coculture-induced PD-1 degradation through a unique mechanism. BMS1166 specifically affected PD-L1 glycosylation and prevented transporting of the under-glycosylated form of PD-L1 from endoplasmic reticulum (ER) to Golgi, leading to accumulation of PD-L1 in ER. In doing so, BMS1166 blocked PD-L1/PD-1 signaling. Coculturing PD-L1-expressing cells with PD-1-expressing cells induced degradation of PD-1, which could be used as a readout to identify inhibitors of PD-L1/PD-1 signaling. The small-molecule PD-L1 inhibitor BMS1166 abolished the glycosylation and maturation of PD-L1 by blocking its exporting from ER to Golgi. Our study discovered a new strategy to identify inhibitors of the PD-L1/PD-1 signaling pathway and to develop new drugs for the treatment of cancer.

show abstract

Section: Discussionsupporting

confidence: 59%

Small-molecule PD-L1 inhibitor BMS1166 abrogates the function of PD-L1 by blocking its ER export

Chen

et al. 2020

OncoImmunology

View full text Add to dashboard Cite

show abstract

“…In a Research Article, Kim B et al found that 2‐deoxy‐ d ‐glucose (2‐DG) could inhibit glycosylation of PD‐L1. Combining 2‐DG and EGFR inhibitor gefitinib could decrease the expression level of PD‐L1 in triple‐negative breast cancer (TNBC) lines 9 . Additionally, the authors showed that combining 2‐DG, gefitinib, and 4‐1BB antibody could induce strong antitumor responses in a TNBC mouse model.…”

Section: The Role Of T Cells In Immunotherapymentioning

confidence: 98%

Harnessing the power of the immune system in cancer immunotherapy and cancer prevention

Wang

2020

Molecular Carcinogenesis

View full text Add to dashboard Cite

After finishing his Ph.D. training in 2009, he became a postdoctoral visiting fellow at Surgery Branch, under Dr. Steven Rosenberg, a pioneer in cancer immunotherapy. He was later promoted to the current staff scientist position in 2016. Dr. Lu's research focuses on the development of effective T cell-based immunotherapies for patients with metastatic cancers. He has played a pivotal role in the successful cancer treatments using the T-cell therapies targeting shared cancer antigens or patientspecific mutated antigens. More recently, he utilizes single-cell sequencing technologies to facilitate the development of new Tcell therapies against cancer.

show abstract

“…It has also been demonstrated that 2-deoxy-D-glucose (2-DG), a glucose analogue that interferes with protein N-linked glycosylation, reverses poly (ADP-ribose) polymerase (PARP) inhibitor-induced expression of glycosylated PD-L1 and immunosuppression in triple-negative breast cancer (TNBC) cells [41]. It was later shown that targeting PD-L1 glycosylation by 2-DG combined with EGFR inhibition reduced tumor size and enhanced anti-tumor immunity mediated by 4-1BB, a glycoprotein receptor belonging to the tumor necrosis factor receptor superfamily, in syngeneic mouse models of TNBC [42]. In addition, a dietary polyphenol compound called resveratrol, a predicted inhibitor of enzymes responsible for PD-L1 glycosylation by computational approaches, enhances anti-tumor immunity in vitro by promoting abnormal glycosylation and dimerization of PD-L1 [43].…”

Section: The Impact Of Pd-l1 N-linked Glycosylation On Cancer Therapymentioning

confidence: 99%

“…Inhibition of protein N-linked glycosylation through the use of 2-DG, which shares structural similarity with mannose and can inhibit protein glycosylation [94], has been shown to enhance anti-tumor T-cell immunity in TNBC in vivo [41,42], suggesting an oncogenic role of glycan moieties in immunosuppression in cancer treatment. Another glycosylation inhibitor, antibiotic tunicamycin, is widely used to block the initial step of Nlinked glycosylation.…”

Section: Future Perspectivementioning

confidence: 99%

The impact of PD-L1 N-linked glycosylation on cancer therapy and clinical diagnosis

et al. 2020

View full text Add to dashboard Cite

N-linked glycosylation is one of the most abundant posttranslational modifications of membrane-bound proteins in eukaryotes and affects a number of biological activities, including protein biosynthesis, protein stability, intracellular trafficking, subcellular localization, and ligand-receptor interaction. Accumulating evidence indicates that cell membrane immune checkpoint proteins, such as programmed death-ligand 1 (PD-L1), are glycosylated with heavy Nlinked glycan moieties in human cancers. N-linked glycosylation of PD-L1 maintains its protein stability and interaction with its cognate receptor, programmed cell death protein 1 (PD-1), and this in turn promotes evasion of T-cell immunity. Studies have suggested targeting PD-L1 glycosylation as a therapeutic option by rational combination of cancer immunotherapies. Interestingly, structural hindrance by N-glycan on PD-L1 in fixed samples impedes its recognition by PD-L1 diagnostic antibodies. Notably, the removal of N-linked glycosylation enhances PD-L1 detection in a variety of bioassays and more accurately predicts the therapeutic efficacy of PD-1/PD-L1 inhibitors, suggesting an important clinical implication of PD-L1 N-linked glycosylation. A detailed understanding of the regulatory mechanisms, cellular functions, and diagnostic limits underlying PD-L1 N-linked glycosylation could shed new light on the clinical development of immune checkpoint inhibitors for cancer treatment and deepen our knowledge of biomarkers to identify patients who would benefit the most from immunotherapy. In this review, we highlight the effects of protein glycosylation on cancer immunotherapy using N-linked glycosylation of PD-L1 as an example. In addition, we consider the potential impacts of PD-L1 N-linked glycosylation on clinical diagnosis. The notion of utilizing the deglycosylated form of PD-L1 as a predictive biomarker to guide anti-PD-1/PD-L1 immunotherapy is also discussed.

show abstract

Saccharide analog, 2‐deoxy‐d‐glucose enhances 4‐1BB‐mediated antitumor immunity via PD‐L1 deglycosylation

Cited by 31 publications

References 34 publications

Small-molecule PD-L1 inhibitor BMS1166 abrogates the function of PD-L1 by blocking its ER export

Small-molecule PD-L1 inhibitor BMS1166 abrogates the function of PD-L1 by blocking its ER export

Harnessing the power of the immune system in cancer immunotherapy and cancer prevention

The impact of PD-L1 N-linked glycosylation on cancer therapy and clinical diagnosis

Contact Info

Product

Resources

About