更新于：2024-11-01

PDL1 x HBX

更新于：2024-11-01

基本信息

关联

项与 PDL1 x HBX 相关的药物

SA-1211

靶点

HBX x PDL1

作用机制

HBX抑制剂 [+1]

在研机构

Suzhou Siran Biotech Co., Ltd.

原研机构

Suzhou Siran Biotech Co., Ltd.

在研适应症

乙型肝炎

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 PDL1 x HBX 相关的临床结果

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100 项与 PDL1 x HBX 相关的转化医学

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0 项与 PDL1 x HBX 相关的专利（医药）

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项与 PDL1 x HBX 相关的文献（医药）

2020-10-01·Journal for ImmunoTherapy of Cancer2区 · 医学

2,5-dimethylcelecoxib improves immune microenvironment of hepatocellular carcinoma by promoting ubiquitination of HBx-induced PD-L1

2区 · 医学

ArticleOA

作者: Chen, Zhanfei ; Peng, Lirong ; Chen, Yiyin ; Tang, Nanhong ; Wang, Xiaoqian

Background2,5-dimethylcelecoxib (DMC) is a targeted inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1), a key enzyme in the PGE2 synthesis pathway of inflammatory mediators. Previous studies have confirmed that DMC can inhibit the growth of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). However, it is not known whether DMC is involved in the changes of tumor immune microenvironment.MethodsIn this study, we explored the effects of DMC on HBV-related HCC immune microenvironment, and deeply analyzed its unique effect and mechanism on programmed death receptor 1 (PD-1)/and its ligand 1 (PD-L1) pathway.ResultsClinical hepatoma tissues detection showed that compared with non-virus-related HCC, the level of CD8 of HBV-related HCC was significantly lower, while the levels of PD-L1 and CD163 were higher. In vivo experiments indicated that DMC could increase the level of tumor infiltrating CD8+ T cells in hepatitis B virus X (HBx) (+) hepatoma cells implanted mouse models, and inhibit the expression of PD-L1 and CD163 in tumor tissues. DMC combined with atezolizumab had more significant antitumor effect and stronger blocking effect on PD-1/PD-L1 pathway. Mechanism studies have shown that DMC can promote ubiquitin degradation of HBx-induced PD-L1 protein in HCC cells by activating adenosine 5′-monophosphate-activated protein kinase pathway. Further experiments confirmed that this process was mainly mediated by E3 ligase RBX1.ConclusionsOur results uncover a role for DMC in promoting HBV-related HCC immune microenvironment, which not only enrich the relationship between inflammatory factors (mPGES-1/PGE2 pathway) and immunosuppression (PD-L1), but also provide an important strategic reference for multitarget or combined immunotherapy of HBV-related HCC.

2020-07-01·Gene

Up-regulation of S100A4 expression by HBx protein promotes proliferation of hepatocellular carcinoma cells and its correlation with clinical survival

Article

作者: Li, Ruhong ; Gao, Hui ; Tan, Jing ; Li, Lin ; Wang, Wenju ; Liang, Luxin ; Xu, Jingyi ; Liao, Liwei ; Zhu, Kai ; Meng, Mingyao ; Li, Shuo ; Huang, Wenwen ; Xie, Yanhua ; Zhou, Haodong ; Yang, Songlin ; He, Shan ; Hou, Zongliu ; Tang, Weiwei ; Zhao, Yiyi

BACKGROUNDHepatocellular carcinoma is one of the most common cancers worldwide. HBV-related HCC has characteristics of faster progression and worse prognosis. Previous studies have confirmed that HBx protein plays numbers of important roles in development of HBV-HCC. However, the molecular mechanism of carcinogenicity of HBx is still not well documented.METHODSFirstly, a HCC cell line over-expressing HBx was established and its function was verified. Subsequently, the differentially expressed genes were detected by transcriptome sequencing technology and use the Western Blot technology to detect the up-regulated genes in HBx overexpressed cells, and the functional correlation of the genes was analyzed. Finally, tissue microarray was used to correlate up-regulated gene with clinical follow-up data to verify correlation with clinical prognosis.RESULTSOver-expression of HBx could promote cell proliferation, and over-expression of HBx could up-regulate the expression of S100A4 protein. ShRNA experiments showed that HBx promoted cell proliferation by upregulating the expression of S100A4. IFN-α2b can down-regulate the expression of S100A4 and inhibit the proliferation of HCC cells. The expression of S100A4 in cancer was significantly up-regulated compared with adjacent tissues, and was also significantly associated with tumors volume, the expression of PD-L1 and the survival time of patients with HCC.CONCLUSIONIn general, S100A4 may be an effective therapeutic target for HBV-HCC. And the connection between S100A4 and HBV are not clear yet. This study may play a guiding role in the future clinical treatment of HCC.

2020-01-01·American Journal of Physiology-Gastrointestinal and Liver Physiology3区 · 医学

Hepatitis B virus-triggered PTEN/β-catenin/c-Myc signaling enhances PD-L1 expression to promote immune evasion

3区 · 医学

Article

作者: Guo, Deyin ; Yu, Mengxue ; Li, Guorui ; Zheng, Dandan ; Sun, Yishuang ; Qu, Mengmeng ; Zheng, Weishuai ; Li, Changyong ; Guo, Shuting ; Yue, Yanan ; Wang, Min ; Tang, Li ; Ma, Yuhong

Hepatitis B virus (HBV) exploits multiple strategies to evade host immune surveillance. Programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) signaling plays a critical role in regulating T cell homeostasis. However, it remains largely unknown as to how HBV infection elevates PD-L1 expression in hepatocytes. A mouse model of HBV infection was established by hydrodynamic injection with a vector containing 1.3-fold overlength HBV genome (pHBV1.3) via the tail vein. Coculture experiments with HBV-expressing hepatoma cells and Jurkat T cells were established in vitro. We observed significant decrease in the expression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and increase in β-catenin/PD-L1 expression in liver tissues from patients with chronic hepatitis B and mice subjected to pHBV1.3 hydrodynamic injection. Mechanistically, decrease in PTEN enhanced β-catenin/c-Myc signaling and PD-L1 expression in HBV-expressing hepatoma cells, which in turn augmented PD-1 expression, lowered IL-2 secretion, and induced T cell apoptosis. However, β-catenin disruption inhibited PTEN-mediated PD-L1 expression, which was accompanied by decreased PD-1 expression, and increased IL-2 production in T cells. Luciferase reporter assays revealed that c-Myc stimulated transcriptional activity of PD-L1. In addition, HBV X protein (HBx) and HBV polymerase (HBp) contributed to PTEN downregulation and β-catenin/PD-L1 upregulation. Strikingly, PTEN overexpression in hepatocytes inhibited β-catenin/PD-L1 signaling and promoted HBV clearance in vivo. Our findings suggest that HBV-triggered PTEN/β-catenin/c-Myc signaling via HBx and HBp enhances PD-L1 expression, leading to inhibition of T cell response, and promotes HBV immune evasion. NEW & NOTEWORTHY This study demonstrates that during HBV infection, HBV can increase PD-L1 expression via PTEN/β-catenin/c-Myc signaling pathway, which in turn inhibits T cell response and ultimately promotes HBV immune evasion. Targeting this signaling pathway is a potential strategy for immunotherapy of chronic hepatitis B.