ANXA1-Derived&amp;nbsp;Peptide Inhibits Tumor Immune Evasion by Binding and Destabilizing PD-L1 in Multiple Cancers

Yu, Zheng-Zheng; Liu, Yunya; Wei, Zhu; Ding, Xiaoqing; Huang, Wei; Shen, Lu; Yang, Hong; Zhang, Ting; Xu, Feng; Li, Yuan; Qiu, Jie-Ya; Zhou, Jingnan; Zhuang, Wei; Xiao, Zhi‐Qiang

doi:10.2139/ssrn.4164242

Cited by 4 publications

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“…Deubiquitylases have been implicated with a number of cancers, including HCC, according to recent research. USP7 regulates the function and turnover of a wide range of substrates, including P53, ERK1/2, PD‐L1, PRMT5, ANXA1, STAT3 and ECT2, which are crucial components of numerous oncogenic signalling pathways 46–52 . For example, USP7 is a crucial deubiquitinase needed to stabilise oncogenic versions of DDX3X.…”

Section: Discussionmentioning

confidence: 99%

SP1‐activated USP27X‐AS1 promotes hepatocellular carcinoma progression via USP7‐mediated AKT stabilisation

Su,

Zhang,

et al. 2024

Clinical & Translational Med

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BackgroundHepatocellular carcinoma (HCC) continues to pose a significant threat to patient survival. Emerging evidence underscores the pivotal involvement of long non‐coding RNAs (lncRNAs) in the cancer process. Nevertheless, our understanding of the roles and processes of lncRNAs in HCC remains limited.MethodsThe expression level of USP27X‐AS1 was assessed in an HCC patient cohort through a combination of bioinformatics analysis and qRT‐PCR. Subsequent biological experiments were conducted to delve into the functional aspects of USP27X‐AS1. Additional molecular biology techniques, including RNA pulldown and RNA immunoprecipitation (RIP), were employed to elucidate the potential mechanisms involving USP27X‐AS1 in HCC. Finally, CUT–RUN assay and other investigations were carried out to determine the factors contributing to the heightened expression of USP27X‐AS1 in HCC.ResultsHigh expression of the novel oncogene USP27X‐AS1 predicted poor prognosis in HCC patients. Further investigation confirmed that USP27X‐AS1 promoted the proliferation and metastasis of HCC by enabling USP7 to interact with AKT, which reduced level of AKT poly‐ubiquitylation and enhanced AKT protein stability, which improves protein stabilisation of AKT and promotes the progression of HCC. Moreover, we also revealed that SP1 binds to USP27X‐AS1 promoter to activate its transcription.ConclusionsNovel oncogenic lncRNA USP27X‐AS1 promoted HCC progression via recruiting USP7 to deubiquitinate AKT. SP1 transcriptionally activated USP27X‐AS1 expression. These findings shed light on HCC and pointed to USP27X‐AS1 as a potential predictive biomarker and treatment target for the malignancy.

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Section: Discussionmentioning

confidence: 99%

SP1‐activated USP27X‐AS1 promotes hepatocellular carcinoma progression via USP7‐mediated AKT stabilisation

Su,

Zhang,

et al. 2024

Clinical & Translational Med

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“…We further identified the significant ligandreceptor interactions between CTNND1+ tumor cells and immune subsets using the "CellphoneDB" tool [41] (Figure 4D-4E). Results showed that CTNND1+ tumor cells communicated with myeloid cells via ANXA1-FPR1/3, SIRPA-CD47, and LGALS9-CD44, which have been reported to involve in the inhibition of anti-tumor response [45][46][47]. In addition, the CTNND+ tumor cells mediated the dysfunction of T cells via inhibitory ligand-receptor pairs, such as ANXA1-FPR3 [48,49].…”

Section: Ctnnd1+ Tumor Cells Communicated With Microenvironment Subpo...mentioning

confidence: 96%

Anoikis-related CTNND1 is associated with immuno-suppressive tumor microenvironment and predicts unfavorable immunotherapeutic outcome in non-small cell lung cancer

Ni,

Jiang,

et al. 2024

J. Cancer

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Background: Immunotherapy has greatly changed the treatment of advanced non-small cell lung cancer (NSCLC). Anoikis is a programmed cell death process associated with cancer. However, the correlation between anoikis-related genes and the tumor microenvironment (TME) features and immunotherapeutic outcome in NSCLC has not been fully explored. Methods: The bulk and single-cell transcriptome data of NSCLC were downloaded from TCGA and GEO databases. The distribution of anoikis-related genes on different cell types at the single-cell level was analyzed, and these genes specifically expressed by tumor cells and immunotherapy-related were further extracted. Next, the candidate gene CTNND1 was identified and its correlations with the TME features and immunotherapeutic outcome in NSCLC were explored in multiple public cohorts. Finally, an in-house cohort was used to determine the CTNND1 expression and immuno-correlation in NSCLC. Results: At single-cell atlas, we found that anoikis-related genes expressed specifically in tumor cells of NSCLC. By intersecting anoikis-related genes, immunotherapy-associated genes, and the genes expressed in tumor cells, we obtained a special biomarker CTNND1. In addition, cell-cell communication analysis revealed that CTNND1+ tumor cells communicated with immune subpopulations frequently. Moreover, we found that high expression of CTNND1 was related to immuno-suppressive status of NSCLC. The expression of CTNND1 and its immuno-correlation were also validated, and the results showed that CTNND1 was highly expressed in NSCLC tissues and tumors with high CTNND1 expression accompanied with low CD8+ T cells infiltration. Conclusions: Overall, our study reported that CTNND1 can be considered as a novel biomarker for the predication of immunotherapeutic responses and a potential target for NSCLC therapy.

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“…The deubiquitination of PD-L1 involves a family of ubiquitin-specific proteases (USPs), namely, USP2, USP5, USP7, USP8, USP9X, USP20, USP22, USP28, and USP51, along with CSN5, UCHL1, OTUB1, and microRNAs (miR-199a-5p and miR-328-3p). Positive regulatory interactions are denoted by black arrows USP7 mediates the ubiquitination of PD-L1 and inhibits its degradation [82]. Additionally, UCHL1 promotes PD-L1 deubiquitination and upregulates its expression in NSCLC [83].…”

Section: Deubiquitination Of Pd-l1 Upregulates Its Expression By Enha...mentioning

confidence: 99%

“…Similarly, a study on a USP8 inhibitor demonstrated its effectiveness in suppressing pancreatic tumor growth by activating killer T cells, especially when combined with anti-PD-L1 therapy [81]. Additionally, A11, an inhibitor of USP7, showed promising antitumor effects by blocking PD-L1's ability to help tumors evade immune detection, and when combined with PD-1 antibody therapy, it showed enhanced antitumor activity [82]. Additionally, the application of the CSN5 inhibitor curcumin inhibited the ubiquitination of PD-L1, reduced PD-L1 expression, and increased the sensitivity of tumor cells to CTLA4 immunotherapy [73].…”

Section: Prospects and Clinical Translation Of Targeting The Deubiqui...mentioning

confidence: 99%

Emerging therapeutic frontiers in cancer: insights into posttranslational modifications of PD-1/PD-L1 and regulatory pathways

Wang,

He,

Long

et al. 2024

Exp Hematol Oncol

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The interaction between programmed cell death ligand 1 (PD-L1), which is expressed on the surface of tumor cells, and programmed cell death 1 (PD-1), which is expressed on T cells, impedes the effective activation of tumor antigen-specific T cells, resulting in the evasion of tumor cells from immune-mediated killing. Blocking the PD-1/PD-L1 signaling pathway has been shown to be effective in preventing tumor immune evasion. PD-1/PD-L1 blocking antibodies have garnered significant attention in recent years within the field of tumor treatments, given the aforementioned mechanism. Furthermore, clinical research has substantiated the efficacy and safety of this immunotherapy across various tumors, offering renewed optimism for patients. However, challenges persist in anti-PD-1/PD-L1 therapies, marked by limited indications and the emergence of drug resistance. Consequently, identifying additional regulatory pathways and molecules associated with PD-1/PD-L1 and implementing judicious combined treatments are imperative for addressing the intricacies of tumor immune mechanisms. This review briefly outlines the structure of the PD-1/PD-L1 molecule, emphasizing the posttranslational modification regulatory mechanisms and related targets. Additionally, a comprehensive overview on the clinical research landscape concerning PD-1/PD-L1 post-translational modifications combined with PD-1/PD-L1 blocking antibodies to enhance outcomes for a broader spectrum of patients is presented based on foundational research.

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ANXA1-Derived Peptide Inhibits Tumor Immune Evasion by Binding and Destabilizing PD-L1 in Multiple Cancers

Cited by 4 publications

References 0 publications

SP1‐activated USP27X‐AS1 promotes hepatocellular carcinoma progression via USP7‐mediated AKT stabilisation

SP1‐activated USP27X‐AS1 promotes hepatocellular carcinoma progression via USP7‐mediated AKT stabilisation

Anoikis-related CTNND1 is associated with immuno-suppressive tumor microenvironment and predicts unfavorable immunotherapeutic outcome in non-small cell lung cancer

Emerging therapeutic frontiers in cancer: insights into posttranslational modifications of PD-1/PD-L1 and regulatory pathways

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