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Insufficient immunity led to virologic breakthrough in NAs-treated chronic hepatitis B patients switching to Peg-IFN-ɑ. Antiviral Res 2021; 197:105220. [PMID: 34848218 DOI: 10.1016/j.antiviral.2021.105220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 10/16/2021] [Accepted: 11/25/2021] [Indexed: 11/24/2022]
Abstract
BACKGROUND Virologic breakthrough (VBT) may occur in chronic hepatitis B (CHB) patients after switching from nucleos(t)ide analogues (NAs) to pegylated interferon alpha (Peg-IFN-ɑ). This study aimed to characterize the clinical and immunological features of VBT. METHODS In NAs-treated patients switching to Peg-IFN-ɑ, innate and adaptive immune cell proportions were examined in peripheral blood and liver biopsy specimens. In vitro effect of IFN-ɑ on the expressions of toll-like receptors 2 (TLR2) and programmed cell death ligand 1 (PDL1) on monocytes, programmed cell death 1 (PD1) on CD8+T cells was examined. Peripheral blood mononuclear cells (PBMCs) were treated with TLR2 agonist and/or PDL1 blockade to evaluate their effect on HBV replication. RESULTS 33 of 166 patients switching to Peg-IFN-ɑ experienced VBT after NA cessation, with majority being hepatitis B e antigen (HBeAg) positive or having higher hepatitis B core-related antigen (HBcrAg) levels. Patients with VBT exhibited lower proportions of TLR2+monocyte and increased PD1+HBV-specific CD8+T cell during the early phase of Peg-IFN-ɑ therapy after NA cessation in peripheral blood, as well as fewer TLR2+CD68+macrophages but more PDL1+CD68+macrophages and PD1+CD8+T cells in liver tissues. Simultaneous use of TLR2 agonist and PDL1 blockage ex vivo suppressed HBV replication by promoting cytokines production and CD8+T cells cytotoxicity. Upon in vitro IFN-ɑ stimulation, PDL1+monocytes and PD1+CD8+T cells were upregulated, whereas TLR2+monocytes were not increased in PBMC isolated from HBeAg-positive patients, or those with high HBcrAg titers. CONCLUSIONS In NAs-treated patients, lower TLR2+monocyte and increased PD1+HBV-specific CD8+T cell proportions potentially contribute to VBT after switching to Peg-IFN-ɑ therapy. This insufficient immunity may be associated with the HBeAg status and HBcrAg levels.
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Yan L, Xu F, Dai CL. Relationship between epithelial-to-mesenchymal transition and the inflammatory microenvironment of hepatocellular carcinoma. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2018; 37:203. [PMID: 30157906 PMCID: PMC6114477 DOI: 10.1186/s13046-018-0887-z] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Accepted: 08/21/2018] [Indexed: 02/08/2023]
Abstract
Epithelial-to-mesenchymal transition (EMT) is a complex process involving multiple genes, steps and stages. It refers to the disruption of tight intercellular junctions among epithelial cells under specific conditions, resulting in loss of the original polarity, order and consistency of the cells. Following EMT, the cells show interstitial cell characteristics with the capacity for adhesion and migration, while apoptosis is inhibited. This process is critically involved in embryogenesis, wound-healing, tumor invasion and metastasis. The tumor microenvironment is composed of infiltrating inflammatory cells, stromal cells and the active medium secreted by interstitial cells. Most patients with hepatocellular carcinoma (HCC) have a history of hepatitis virus infection. In such cases, major components of the tumor microenvironment include inflammatory cells, inflammatory factors and virus-encoded protein are major components. Here, we review the relationship between EMT and the inflammatory tumor microenvironment in the context of HCC. We also further elaborate the significant influence of infiltrating inflammatory cells and inflammatory mediators as well as the products expressed by the infecting virus in the tumor microenvironment on the EMT process.
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Affiliation(s)
- Long Yan
- Department of Hepatobiliary and Splenic Surgery, Sheng Jing Hospital of China Medical University, No.36 Sanhao Street, Heping District, Shenyang, Liaoning, China
| | - Feng Xu
- Department of Hepatobiliary and Splenic Surgery, Sheng Jing Hospital of China Medical University, No.36 Sanhao Street, Heping District, Shenyang, Liaoning, China
| | - Chao-Liu Dai
- Department of Hepatobiliary and Splenic Surgery, Sheng Jing Hospital of China Medical University, No.36 Sanhao Street, Heping District, Shenyang, Liaoning, China.
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B7-H6 expression is induced by lipopolysaccharide and facilitates cancer invasion and metastasis in human gliomas. Int Immunopharmacol 2018; 59:318-327. [PMID: 29679856 DOI: 10.1016/j.intimp.2018.03.020] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Revised: 03/19/2018] [Accepted: 03/20/2018] [Indexed: 01/09/2023]
Abstract
Although great progress has been made in treatment regimens, gliomas are still incurable and the 5-year survival remains poor. Studies focusing on molecules that regulate tumorigenesis or tumor immunity may provide potential therapeutic strategies for patients with glioma. B7-H6 is selectively expressed in tumor cells and plays vital roles in host immune responses. In this study, we demonstrated that B7-H6 was expressed in glioma cell lines, including CRT, U251, SHG-44, SF-295, TG-905 and U373, and tumor tissues isolated from glioma patients. Moreover, the expression levels of B7-H6 were significantly correlated with glioma grade. Previous studies reported that inflammatory mediators and cytokines induced the expression of B7 family members including programmed death-ligand 1, B7-H2 and B7-H4. Therefore, we explored the regulation of B7-H6 expression in gliomas and showed that lipopolysaccharide induced the expression of B7-H6 in glioma cells. To further analyze the roles of B7-H6 in gliomas, the expression of B7-H6 in glioma cells was knocked down. The results of cell counting kit-8, colony formation, wound healing, and transwell migration and invasion assays demonstrated that the proliferation, migration and invasion of glioma cells were inhibited after knocking down B7-H6. To elucidate the specific mechanisms of B7-H6 function in cancer progression, we examined the expression levels of proteins involved in cell apoptosis, migration and invasion. We demonstrated that the expression levels of E-cadherin and Bcl-2 associated X protein increased, and the expression levels of vimentin, N-cadherin, matrix metalloproteinase-2, matrix metalloproteinase-9 and survivin decreased after knocking down B7-H6. In conclusion, B7-H6 plays important roles in glioma, and targeting B7-H6 may provide a novel therapeutic strategy for glioma patients.
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Daud M, Rana MA, Husnain T, Ijaz B. Modulation of Wnt signaling pathway by hepatitis B virus. Arch Virol 2017; 162:2937-2947. [PMID: 28685286 DOI: 10.1007/s00705-017-3462-6] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Accepted: 05/17/2017] [Indexed: 02/08/2023]
Abstract
Hepatitis B virus (HBV) has a global distribution and is one of the leading causes of hepatocellular carcinoma. The precise mechanism of pathogenicity of HBV-associated hepatocellular carcinoma (HCC) is not yet fully understood. Viral-related proteins are known to take control of several cellular pathways like Wnt/β-catenin, TGF-β, Raf/MAPK and ROS for the virus's own replication. This affects cellular persistence, multiplication, migration, alteration and genomic instability. The Wnt/FZD/β-catenin signaling pathway plays a significant role in the pathology and physiology of the liver and has been identified as a main factor in HCC development. The role of β-catenin is linked mainly to the canonical pathway of the signaling system. Progression of liver diseases is known to be accompanied by disturbances in β-catenin expression (mainly overexpression), with its cytoplasmic or nuclear translocation. In recent years, studies have documented that the HBV X protein and hepatitis B surface antigen (HBsAg) can act as pathogenic factors that are involved in the modulation and induction of canonical Wnt signaling pathway. In the present review we explore the interaction of HBV genome products with components of the Wnt/β-catenin signaling pathway that results in the enhancement of the pathway and leads to hepatocarcinogenesis.
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Affiliation(s)
- Muhammad Daud
- Applied and Functional Genomics Lab, Centre of Excellence in Molecular Biology, University of the Punjab, 87-West Canal Road, Thokar Niaz Baig, Lahore, 53700, Pakistan
| | | | - Tayyab Husnain
- Applied and Functional Genomics Lab, Centre of Excellence in Molecular Biology, University of the Punjab, 87-West Canal Road, Thokar Niaz Baig, Lahore, 53700, Pakistan
| | - Bushra Ijaz
- Applied and Functional Genomics Lab, Centre of Excellence in Molecular Biology, University of the Punjab, 87-West Canal Road, Thokar Niaz Baig, Lahore, 53700, Pakistan.
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Huang ZY, Xu P, Li JH, Zeng CH, Song HF, Chen H, Zhu YB, Song YY, Lu HL, Shen CP, Zhang XG, Wu MY, Wang XF. Clinical Significance of Dynamics of Programmed Death Ligand-1 Expression on Circulating CD14 + Monocytes and CD19 + B Cells with the Progression of Hepatitis B Virus Infection. Viral Immunol 2016; 30:224-231. [PMID: 28005469 DOI: 10.1089/vim.2016.0122] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Programmed death-1 (PD-1) expression has been revealed to be upregulated on T cells and contributes to T cell exhaustion in patients with hepatitis B virus (HBV) infection. In this study, we investigated the dynamic expression of programmed death ligand-1 (PD-L1), the ligand of PD-1, on circulating CD14+ monocytes and CD19+ B cells of HBV-infected patients at the stages of chronic HBV (CHB) infection, liver cirrhosis (LC), and hepatocellular carcinoma (HCC), respectively. The results showed that compared with healthy controls, the levels of PD-L1 expression on CD14+ and CD19+ populations were both upregulated in CHB, LC, and HCC groups. Although there was no significant difference of PD-L1 expression on CD14+ population among three disease groups, further analysis demonstrated that the frequency of CD14+PD-L1+ population was negatively correlated with HBV DNA load, the levels of alanine aminotransaminase (ALT), and the levels of aspartate aminotransferase (AST), respectively, at CHB stage, while it did not present significant correlation with such parameters at LC stage and was only positively correlated with HBV DNA load at HCC stage. Similarly, the levels of PD-L1 expression on CD19+ population also did not present much difference among three disease groups. Intriguingly, the frequencies of CD19+PD-L1+ population at CHB and LCC stages were both positively correlated with the levels of ALT and AST, but they were not significantly correlated with HBV DNA load. Thereby, the current study elucidated the dynamics of PD-L1 expression on monocytes and B cells, along with the dynamic regulation of PD-1 on T cells, which had a close relationship during the progression of HBV infection. Collectively, our findings demonstrated that in the course of HBV infection development, PD-L1 expression on CD14+ monocytes and CD19+ B cells varied and significantly correlated with clinical parameters, which could be utilized as a potential clinical indicator.
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Affiliation(s)
- Zi-Yi Huang
- 1 Department of Biochemistry and Molecular Biology, School of Biology and Basic Medical Sciences, Soochow University , Suzhou, China .,2 Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University , Suzhou, China
| | - Ping Xu
- 3 The Affiliated Infectious Hospital of Soochow University , Suzhou, China
| | - Jian-Hua Li
- 4 Central Blood Station of Jiaxing , Zhejiang, China
| | - Chen-Hua Zeng
- 1 Department of Biochemistry and Molecular Biology, School of Biology and Basic Medical Sciences, Soochow University , Suzhou, China
| | - Hua-Feng Song
- 3 The Affiliated Infectious Hospital of Soochow University , Suzhou, China
| | - Hui Chen
- 3 The Affiliated Infectious Hospital of Soochow University , Suzhou, China
| | - Yi-Bei Zhu
- 1 Department of Biochemistry and Molecular Biology, School of Biology and Basic Medical Sciences, Soochow University , Suzhou, China
| | - Ying-Ying Song
- 1 Department of Biochemistry and Molecular Biology, School of Biology and Basic Medical Sciences, Soochow University , Suzhou, China
| | - Han-Lin Lu
- 1 Department of Biochemistry and Molecular Biology, School of Biology and Basic Medical Sciences, Soochow University , Suzhou, China
| | - Chun-Ping Shen
- 1 Department of Biochemistry and Molecular Biology, School of Biology and Basic Medical Sciences, Soochow University , Suzhou, China
| | - Xue-Guang Zhang
- 1 Department of Biochemistry and Molecular Biology, School of Biology and Basic Medical Sciences, Soochow University , Suzhou, China .,2 Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University , Suzhou, China
| | - Mei-Ying Wu
- 3 The Affiliated Infectious Hospital of Soochow University , Suzhou, China
| | - Xue-Feng Wang
- 1 Department of Biochemistry and Molecular Biology, School of Biology and Basic Medical Sciences, Soochow University , Suzhou, China
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Hepatitis B core antigen upregulates B7-H1 on dendritic cells by activating the AKT/ERK/P38 pathway: a possible mechanism of hepatitis B virus persistence. J Transl Med 2016; 96:1156-1164. [PMID: 27617403 DOI: 10.1038/labinvest.2016.96] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Revised: 07/12/2016] [Accepted: 08/02/2016] [Indexed: 02/06/2023] Open
Abstract
B7-H1 binding to programmed death-1 may deliver a coinhibitory signal to T cells that is involved in the regulation of T-cell activation and tolerance. B7-H1 plays a key role in dysfunction of dendritic cells (DCs) during chronic HBV infection, but the expression mechanism of B7-H1 remains unclear. One hundred and twenty-nine patients with chronic HBV infection were categorized into either the immune tolerance phase (HBV-IT), the immune clearance phase (HBV-IC), or the inactive carrier phase (HBV-IA). Twenty healthy volunteers were enrolled as controls. Another 16 patients with HBeAg-positive chronic Hepatitis B were enrolled, and entecavir was administrated at 0.5 mg per day for 6 months. The B7-H1 expression level on peripheral DCs was tested by flow cytometry. In vitro, expression levels of B7-H1 and signaling molecules on monocyte-derived DC (MO-DC) induced by recombinant hepatitis B virus C antigen (rhHBcAg) were examined by RT-PCR, flow cytometry, and western blotting, and the apoptosis rate was tested by flow cytometry. The percentages of peripheral DCs and myeloid DCs (mDCs) were decreased and B7-H1 levels were increased in patients compared with controls. Serum HBV-DNA levels were positively correlated with B7-H1 levels on mDCs in patients with HBV-IT. B7-H1 levels on peripheral DCs from patients with chronic hepatitis B decreased after antiviral therapy. In vitro studies demonstrated that the B7-H1 level on MO-DC was upregulated by rhHBcAg, which resulted from the activation of PI3K-AKT, ERK, and P38 signaling pathways, and the percentage of MO-DC was downregulated by rhHBcAg. In addition, rhHBcAg promoted the apoptosis of MO-DC. The data suggest that HBcAg induced B7-H1 upregulation by activating AKT, ERK, and P38 signaling pathways, which inhibited the clearance of HBV-DNA and the reduction of DCs contributed to immune tolerance, which may correlate with apoptosis.
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Hong B, Qian Y, Zhang H, Sang YW, Cheng LF, Wang Q, Gao S, Zheng M, Yao HP. Expression of B7-H4 and hepatitis B virus X in hepatitis B virus-related hepatocellular carcinoma. World J Gastroenterol 2016; 22:4538-4546. [PMID: 27182163 PMCID: PMC4858635 DOI: 10.3748/wjg.v22.i18.4538] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Revised: 02/27/2016] [Accepted: 03/18/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the expression and clinical significance of B7-H4 and hepatitis B virus X (HBx) protein in hepatitis B virus-related hepatocellular carcinoma (HBV-HCC).
METHODS: The expression of B7-H4 in the human HCC cell lines HepG2 and HepG2.2.15 were detected by western blot, flow cytometry, and immunofluorescence. The expression of B7-H4 and HBx in 83 HBV-HCC was detected by immunohistochemistry, and the relationship with clinicopathological features was analyzed. Paraffin sections were generated from 83 HBV-HCC patients (22 females and 61 males) enrolled in this study. The age of these patients ranged from 35 to 77 years, with an average of 52.5 ± 11.3 years. All experiments were approved by the Ethics Committees of the Second Affiliated Hospital, Zhejiang University School of Medicine.
RESULTS: B7-H4 was significantly upregulated in HepG2.2.15 cells compared to HepG2 cells. Specifically, the protein expression of B7-H4 in the lysates of HepG2 cells was more than that in HepG2.2.15 cells. In addition, HBx was expressed only in HepG2.2.15 cells. Similar data were obtained by flow cytometry. The positive rates of B7-H4 and HBx in the tissues of 83 HBV-HCC patients were 68.67% (57/83) and 59.04% (49/83), respectively. The expression of HBx was correlated with tumor node metastases (TNM) stage, and the expression of B7-H4 was positively correlated with HBx (rs = 0.388; P < 0.01). The expression level of B7-H4 in HBx-positive HBV-HCC tissues was substantially higher than that in HBx-negative HBV-HCC tissues. The expression level of B7H4 was negatively related to tumor TNM stage.
CONCLUSION: Higher expression of HBx and B7-H4 was correlated with tumor progression of HBV-HCC, suggesting that B7-H4 may be involved in facilitating HBV-related hepatocarcinogenesis.
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Lan S, Wu L, Wang X, Wu J, Lin X, Wu W, Huang Z. Impact of HBeAg on the maturation and function of dendritic cells. Int J Infect Dis 2016; 46:42-8. [DOI: 10.1016/j.ijid.2016.03.024] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Revised: 12/16/2015] [Accepted: 03/24/2016] [Indexed: 02/06/2023] Open
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