Deubiquitination and stabilization of programmed cell death ligand 1 by ubiquitin‐specific peptidase 9, X‐linked in oral squamous cell carcinoma

Wu, Jingjing; Guo, Wenzheng; Di, Wen; Hou, Guangyu; Zhou, Aiping; Wu, Wenjuan

doi:10.1002/cam4.1675

Cited by 60 publications

(41 citation statements)

References 25 publications

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“…To overcome the clinical response problem, it is crucial to find the upstream regulator that may modulate the amount of PD-L1 in GC 31 , 32 . Hence, deubiquitinase attracted our eyes as there have been three deubiquitinases reported to stabilize PD-L1, including COP9 signalosome 5 (CSN5), ubiquitin specific peptidase 9 X-linked (USP9X) and ubiquitin specific peptidase 22 (USP22) 33 , 34 , 35 . Nevertheless, correlation analysis using GEPIA ( http://gepia.cancer-pku.cn ) 36 indicated that PD-L1 is not correlated with CSN5, USP9X and USP22 in GC ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Abrogation of USP7 is an alternative strategy to downregulate PD-L1 and sensitize gastric cancer cells to T cells killing

Wang

Kang

et al. 2021

Acta Pharmaceutica Sinica B

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Targeting immune checkpoints such as programmed cell death protein 1 (PD-1) and programmed death ligand-1 (PD-L1) have been approved for treating melanoma, gastric cancer (GC) and bladder cancer with clinical benefit. Nevertheless, many patients failed to respond to anti-PD-1/PD-L1 treatment, so it is necessary to seek an alternative strategy for traditional PD-1/PD-L1 targeting immunotherapy. Here with the data from The Cancer Genome Atlas (TCGA) and our in-house tissue library, PD-L1 expression was found to be positively correlated with the expression of ubiquitin-specific processing protease 7 (USP7) in GC. Furthermore, USP7 directly interacted with PD-L1 in order to stabilize it, while abrogation of USP7 attenuated PD-L1/PD-1 interaction and sensitized cancer cells to T cell killing in vitro and in vivo . Besides, USP7 inhibitor suppressed GC cells proliferation by stabilizing P53 in vitro and in vivo . Collectively, our findings indicate that in addition to inhibiting cancer cells proliferation, USP7 inhibitor can also downregulate PD-L1 expression to enhance anti-tumor immune response simultaneously. Hence, these data posit USP7 inhibitor as an anti-proliferation agent as well as a novel therapeutic agent in PD-L1/PD-1 blockade strategy that can promote the immune response of the tumor.

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Section: Resultsmentioning

confidence: 99%

Abrogation of USP7 is an alternative strategy to downregulate PD-L1 and sensitize gastric cancer cells to T cells killing

Wang

Kang

et al. 2021

Acta Pharmaceutica Sinica B

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“…The Casitas B-lineage lymphoma (Cbl) family has three major isoforms, c-Cbl, Cbl-b, and Cbl-c, among which c-Cbl and Cbl-b with a ubiquitin-associated (UBA) domain suppressed PD-L1 expression after inhibiting PI3K/Akt, JAK-STAT, and MEK/Erk signaling pathways in NSCLC [ 140 ]. Additionally, ubiquitin-specific peptidase 22 (USP22) in HCC [ 141 ], ubiquitin-specific peptidase 9, X-linked (USP9X) in OSCC [ 142 ], and ubiquitin C-terminal hydrolase L1 (UCHL1) in NSCLC [ 143 ] deubiquitinate and upregulate the PD-L1 expression.…”

Section: Regulation Of Pd-l1 At Protein Levelmentioning

confidence: 99%

Regulatory mechanisms of immune checkpoints PD-L1 and CTLA-4 in cancer

Zhang

Dai

et al. 2021

J Exp Clin Cancer Res

295

168

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The cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4)/B7 and programmed death 1 (PD-1)/ programmed cell death-ligand 1 (PD-L1) are two most representative immune checkpoint pathways, which negatively regulate T cell immune function during different phases of T-cell activation. Inhibitors targeting CTLA-4/B7 and PD1/PD-L1 pathways have revolutionized immunotherapies for numerous cancer types. Although the combined anti-CTLA-4/B7 and anti-PD1/PD-L1 therapy has demonstrated promising clinical efficacy, only a small percentage of patients receiving anti-CTLA-4/B7 or anti-PD1/PD-L1 therapy experienced prolonged survival. Regulation of the expression of PD-L1 and CTLA-4 significantly impacts the treatment effect. Understanding the in-depth mechanisms and interplays of PD-L1 and CTLA-4 could help identify patients with better immunotherapy responses and promote their clinical care. In this review, regulation of PD-L1 and CTLA-4 is discussed at the levels of DNA, RNA, and proteins, as well as indirect regulation of biomarkers, localization within the cell, and drugs. Specifically, some potential drugs have been developed to regulate PD-L1 and CTLA-4 expressions with high efficiency.

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“…ese studies suggest that targeting PD-L1 ubiquitination may be an alternative way to improve immune checkpoint therapy. In oral squamous cell cancer (OSCC), ubiquitin-specific peptidase 9, X-linked (USP9X) was found to be upregulated and protected PD-L1 from ubiquitination and degradation, leading to high protein level of PD-L1, resulting in the failure of checkpoint blockade [33]. Abnormal ubiquitination is usually catalyzed by the mutation or ectopic expression of genes that encode E3 ubiquitin ligases or deubiquitinases [34].…”

Section: Ubiquitinationmentioning

confidence: 99%

Recent Findings in the Posttranslational Modifications of PD-L1

Zhou

Wang

et al. 2020

Journal of Oncology

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Immune checkpoint therapy, such as the reactivation of T-cell activity by targeting programmed cell death 1 (PD-1) and its ligand PD-L1 (also called B7-H1 and CD274) has been found pivotal in changing the historically dim prognoses of malignant tumors by causing durable objective responses. However, the response rate of immune checkpoint therapy required huge improvements. It has been shown that the expression of PD-L1 on cancer cells and immune cell membranes is correlated with a more durable objective response rate to PD-L1 antibodies, which highlights the importance of deeply understanding how this protein is regulated. Posttranslational modifications such as phosphorylation, N-glycosylation, and ubiquitination of PD-L1 have emerged as important regulatory mechanisms that modulate immunosuppression in patients with cancer. In this review, we summarized the latest findings of PD-L1 protein modification and their clinical applications.

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Deubiquitination and stabilization of programmed cell death ligand 1 by ubiquitin‐specific peptidase 9, X‐linked in oral squamous cell carcinoma

Cited by 60 publications

References 25 publications

Abrogation of USP7 is an alternative strategy to downregulate PD-L1 and sensitize gastric cancer cells to T cells killing

Abrogation of USP7 is an alternative strategy to downregulate PD-L1 and sensitize gastric cancer cells to T cells killing

Regulatory mechanisms of immune checkpoints PD-L1 and CTLA-4 in cancer

Recent Findings in the Posttranslational Modifications of PD-L1

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