|
1
|
Chen C, Wang Z, Ding Y, Qin Y. Tumor microenvironment-mediated immune evasion in hepatocellular carcinoma. Front Immunol 2023; 14:1133308. [PMID: 36845131 PMCID: PMC9950271 DOI: 10.3389/fimmu.2023.1133308] [Citation(s) in RCA: 97] [Impact Index Per Article: 48.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 02/02/2023] [Indexed: 02/12/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is the third leading cause of tumor-related mortality worldwide. In recent years, the emergency of immune checkpoint inhibitor (ICI) has revolutionized the management of HCC. Especially, the combination of atezolizumab (anti-PD1) and bevacizumab (anti-VEGF) has been approved by the FDA as the first-line treatment for advanced HCC. Despite great breakthrough in systemic therapy, HCC continues to portend a poor prognosis owing to drug resistance and frequent recurrence. The tumor microenvironment (TME) of HCC is a complex and structured mixture characterized by abnormal angiogenesis, chronic inflammation, and dysregulated extracellular matrix (ECM) remodeling, collectively contributing to the immunosuppressive milieu that in turn prompts HCC proliferation, invasion, and metastasis. The tumor microenvironment coexists and interacts with various immune cells to maintain the development of HCC. It is widely accepted that a dysfunctional tumor-immune ecosystem can lead to the failure of immune surveillance. The immunosuppressive TME is an external cause for immune evasion in HCC consisting of 1) immunosuppressive cells; 2) co-inhibitory signals; 3) soluble cytokines and signaling cascades; 4) metabolically hostile tumor microenvironment; 5) the gut microbiota that affects the immune microenvironment. Importantly, the effectiveness of immunotherapy largely depends on the tumor immune microenvironment (TIME). Also, the gut microbiota and metabolism profoundly affect the immune microenvironment. Understanding how TME affects HCC development and progression will contribute to better preventing HCC-specific immune evasion and overcoming resistance to already developed therapies. In this review, we mainly introduce immune evasion of HCC underlying the role of immune microenvironment, describe the dynamic interaction of immune microenvironment with dysfunctional metabolism and the gut microbiome, and propose therapeutic strategies to manipulate the TME in favor of more effective immunotherapy.
Collapse
Affiliation(s)
| | | | | | - Yanru Qin
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| |
Collapse
|
|
2
|
Wu S, Du X, Lou G, Yu S, Lai K, Qi J, Ni S, Chen Z, Chen F. Expression changes of Tim-3 as one of supplementary indicators for monitoring prognosis of liver pathological changes in chronic HBV infection. BMC Infect Dis 2022; 22:842. [DOI: 10.1186/s12879-022-07841-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Accepted: 11/04/2022] [Indexed: 11/13/2022] Open
Abstract
Abstract
Purpose
This study was designed to analyze the liver tissue changes among the CHB patients who received treatment for at least 6 months and follow-up for at least 1 year, together with the correlation between the different disease condition and serum markers.
Methods
One-hundred and eighty-five CHB patients underwent antiviral therapy for at least 6 months were enrolled. In the 12-month follow-up, ultrasonography-guided biopsy was performed. The patients were grouped based on the serum markers and pathological changes in liver tissues. Then we determined the serum markers, virological tests and Tim-3 expression among these groups.
Results
Antiviral therapy significantly reduced liver inflammation indicators and serum Tim-3 level. However, the fibrosis process of liver tissue was not changed, and there are still disputes on the serum marker and hepatic lesion outcomes. Under normal liver function or negative hepatitis B e antigen (HBeAg) of CHB patients, there might be consensus between Tim-3 change and liver pathological outcome. According to the liver tissue inflammation and fibrosis conditions, Tim-3 was positively correlated with liver function indices. Besides, it was also related to fibrosis stage and inflammation grade.
Conclusion
There were inconsistent changes between serum markers and liver tissue conditions after anti-viral therapy. Tim-3 expression was more suitable to indicate the changes of liver inflammatory and fibrosis response to some extent than ALT and AST. It may serve as a certain indicator to predict the CHB prognosis, which could be used as one of the monitoring indicators in liver pathological changes of chronic HBV infection, especially in monitoring liver tissue inflammation.
Collapse
|
|
3
|
Li S, Li N, Yang S, Deng H, Li Y, Wang Y, Yang J, Lv J, Dong L, Yu G, Hou X, Wang G. The study of immune checkpoint inhibitors in chronic hepatitis B virus infection. Int Immunopharmacol 2022; 109:108842. [DOI: 10.1016/j.intimp.2022.108842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 04/19/2022] [Accepted: 05/04/2022] [Indexed: 11/09/2022]
|
|
4
|
Brom VC, Burger C, Wirtz DC, Schildberg FA. The Role of Immune Checkpoint Molecules on Macrophages in Cancer, Infection, and Autoimmune Pathologies. Front Immunol 2022; 13:837645. [PMID: 35418973 PMCID: PMC8995707 DOI: 10.3389/fimmu.2022.837645] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 03/02/2022] [Indexed: 12/13/2022] Open
Abstract
Immune checkpoint inhibitors have revolutionized immunotherapy against various cancers over the last decade. The use of checkpoint inhibitors results in remarkable re-activation of patients’ immune system, but is also associated with significant adverse events. In this review, we emphasize the importance of cell-type specificity in the context of immune checkpoint-based interventions and particularly focus on the relevance of macrophages. Immune checkpoint blockade alters the dynamic macrophage phenotypes and thereby substantially manipulates therapeutical outcome. Considering the macrophage-specific immune checkpoint biology, it seems feasible to ameliorate the situation of patients with severe side effects and even increase the probability of survival for non-responders to checkpoint inhibition. Apart from malignancies, investigating immune checkpoint molecules on macrophages has stimulated their fundamental characterization and use in other diseases as well, such as acute and chronic infections and autoimmune pathologies. Although the macrophage-specific effect of checkpoint molecules has been less studied so far, the current literature shows that a macrophage-centered blockade of immune checkpoints as well as a stimulation of their expression represents promising therapeutic avenues. Ultimately, the therapeutic potential of a macrophage-focused checkpoint therapy might be maximized by diagnostically assessing individual checkpoint expression levels on macrophages, thereby personalizing an effective treatment approach for each patient having cancer, infection, or autoimmune diseases.
Collapse
Affiliation(s)
- Victoria C Brom
- Clinic for Orthopedics and Trauma Surgery, University Hospital Bonn, Bonn, Germany
| | - Christof Burger
- Clinic for Orthopedics and Trauma Surgery, University Hospital Bonn, Bonn, Germany
| | - Dieter C Wirtz
- Clinic for Orthopedics and Trauma Surgery, University Hospital Bonn, Bonn, Germany
| | - Frank A Schildberg
- Clinic for Orthopedics and Trauma Surgery, University Hospital Bonn, Bonn, Germany
| |
Collapse
|
|
5
|
Tumor Immune Microenvironment and Immunosuppressive Therapy in Hepatocellular Carcinoma: A Review. Int J Mol Sci 2021; 22:ijms22115801. [PMID: 34071550 PMCID: PMC8198390 DOI: 10.3390/ijms22115801] [Citation(s) in RCA: 251] [Impact Index Per Article: 62.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 05/15/2021] [Accepted: 05/24/2021] [Indexed: 12/24/2022] Open
Abstract
Liver cancer has the fourth highest mortality rate of all cancers worldwide, with hepatocellular carcinoma (HCC) being the most prevalent subtype. Despite great advances in systemic therapy, such as molecular-targeted agents, HCC has one of the worst prognoses due to drug resistance and frequent recurrence and metastasis. Recently, new therapeutic strategies such as cancer immunosuppressive therapy have prolonged patients' lives, and the combination of an immune checkpoint inhibitor (ICI) and VEGF inhibitor is now positioned as the first-line therapy for advanced HCC. Since the efficacy of ICIs depends on the tumor immune microenvironment, it is necessary to elucidate the immune environment of HCC to select appropriate ICIs. In this review, we summarize the findings on the immune microenvironment and immunosuppressive approaches focused on monoclonal antibodies against cytotoxic T lymphocyte-associated protein 4 and programmed cell death protein 1 for HCC. We also describe ongoing treatment modalities, including adoptive cell transfer-based therapies and future areas of exploration based on recent literature. The results of pre-clinical studies using immunological classification and animal models will contribute to the development of biomarkers that predict the efficacy of immunosuppressive therapy and aid in the selection of appropriate strategies for HCC treatment.
Collapse
|
|
6
|
Dai X, Wang S, Niu C, Ji B, Liu Y. Overview of Current Progress in Immune Checkpoint Inhibitor Therapy for Advanced Hepatocellular Carcinoma. Technol Cancer Res Treat 2020. [PMCID: PMC7432969 DOI: 10.1177/1533033820947486] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Hepatocellular carcinoma (HCC) remains to a common cause of tumor mortality
worldwide and represents the most common type of lethal hepatic malignancy. The
incidence of HCC is swiftly increasing in western countries and southeast Asia.
Despite poor prognosis, traditional treatments for advanced HCC appear to be
minimally effective or even useless since patients are usually diagnosed in the
advanced stage of disease. In recent years, immune checkpoint blockade has shown
promising results in multiple pre-clinical and clinical trials of different
solid tumors, including advanced HCC. Novel drugs targeting immune checkpoints,
such as nivolumab (anti-PD-1), durvalumab (anti-PD-L1), and tremelimumab
(anti-CTLA-4) have been shown to be highly effective and relatively safe in
monotherapy or in combination treatment of advanced liver cancer. Unlike other
immunotherapies, this approach can rouse human anti-tumor immunity by relieving
T-cell exhaustion and inhibiting the evasion of HCC by blocking co-inhibitory
signaling transduction accurately. In this review, we will provide current
knowledge of several major immune checkpoints and summarize recent data from
clinical trials that applied immune checkpoint inhibitors alone or in
combination. In addition, this review will discuss the limitations and future
prospective of immune checkpoint-targeted therapy for advanced HCC.
Collapse
Affiliation(s)
- Xinlun Dai
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin
University, Changchun, Jilin, People’s Republic of China
| | - Shupeng Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin
University, Changchun, Jilin, People’s Republic of China
| | - Chunyuan Niu
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin
University, Changchun, Jilin, People’s Republic of China
| | - Bai Ji
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin
University, Changchun, Jilin, People’s Republic of China
- Yahui Liu and Bai Ji, Department of
Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, 1
Xinmin Street, Changchun, Jilin 130021, People’s Republic of China. Emails:
;
| | - Yahui Liu
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin
University, Changchun, Jilin, People’s Republic of China
- Yahui Liu and Bai Ji, Department of
Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, 1
Xinmin Street, Changchun, Jilin 130021, People’s Republic of China. Emails:
;
| |
Collapse
|
|
7
|
Chen H, Zhao W, Zhang Y, Guo Y, Luo W, Wang X, Nie Y, Ye M, Huang C, Wang D, Chen M, He X, Zhao Q. Systematic analysis on multiple Gene Expression Omnibus data sets reveals fierce immune response in hepatitis B virus-related acute liver failure. J Cell Mol Med 2020; 24:9798-9809. [PMID: 32686296 PMCID: PMC7520256 DOI: 10.1111/jcmm.15561] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 05/26/2020] [Accepted: 06/14/2020] [Indexed: 12/17/2022] Open
Abstract
Acute liver failure (ALF) caused by hepatitis B virus (HBV) is common type of liver failure in the world, with high morbidity and mortality rates. However, the prevalence, genetic background and factors determining the development of HBV‐related ALF are rarely studied. In this study, we examined three Gene Expression Omnibus (GEO) data sets by bioinformatics analysis to identify differentially expressed genes (DEGs), key biological processes and pathways. Immune infiltration analysis showed high immune cells infiltration in HBV‐related ALF tissue. We then confirmed natural killer cells and macrophages infiltration in clinical samples by immunohistochemistry assay, implying these cells play a significant role in HBV‐ALF. We found 1277 genes were co‐up‐regulated and that 1082 genes were co‐down‐regulated in the 3 data sets. Inflammation‐related pathways were enriched in the co‐up‐regulated genes and synthetic metabolic pathways were enriched in the co‐down‐regulated genes. WGCNA also revealed a key module enriching in immune inflammation response and identified 10 hub genes, differentially expressed in an independent data set. In conclusion, we identified fierce immune inflammatory response to elucidate the immune‐driven mechanism of HBV‐ALF and 10 hub genes based on gene expression profiles.
Collapse
Affiliation(s)
- Huadi Chen
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Wenting Zhao
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Yixi Zhang
- Liver Transplantation Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yiwen Guo
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Weixin Luo
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Xiaobo Wang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Yu Nie
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Maodong Ye
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Changjun Huang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Dongping Wang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Maogen Chen
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Xiaoshun He
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Qiang Zhao
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| |
Collapse
|
|
8
|
Zhao L, Liang J, Rao W, Cui M, Ren S, Zhang L, Xu D, Han Q, Zang YJ, Zhang B. Cross-regulation by TLR4 and T cell Ig mucin-3 determines severity of liver injury in a CCl4-induced mouse model. Scand J Immunol 2019; 91:e12851. [PMID: 31733121 DOI: 10.1111/sji.12851] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 10/06/2019] [Accepted: 11/10/2019] [Indexed: 11/30/2022]
Abstract
Acute liver injury is a common pathological basis for a variety of acute liver diseases in the clinic, which can eventually lead to liver fibrosis and even liver failure. In this study, we found that T cell Ig and mucin domain protein 3 (Tim-3) and TLR4 receptors play important roles in CCl4-induced acute liver injury. Tim-3 is a negative regulator that is expressed by T cells and macrophages. Using antibodies against Tim-3 (anti-Tim-3 Ab), we studied the Tim-3 signal in an animal model of acute liver injury and found that a large number of inflammatory factors were upregulated. In vitro experimental data shown that anti-Tim-3 Ab treatment increased interferon-ɣ production by concanavalin A (ConA)-stimulated spleen T cells, and we found that the expression level of interleukin (IL)-6 was increased in a macrophage/spleen T cell coculture system, while administration of galectin-9 (Gal-9, a Tim-3 ligand) reduced the IL-6 production. This indicates the importance of the Tim-3/Gal-9 signalling pathway in maintaining hepatic homeostasis. The Tim-3 signalling pathway inhibits TLR4-mediated NF-κB activity, and an anti-Tim-3 Ab does not affect the liver injury in TLR4-deficient mice. Regulation between Tim-3 and TLR4 determines the severity of liver damage. The negative regulation of Tim-3 reflects the protective mechanisms of patients with impaired liver function, and these results provide important information about innate and adaptive responses in the regulation of liver damage. This finding is potentially important for the study of early liver injury.
Collapse
Affiliation(s)
- Lizhen Zhao
- Department of Immunology, College of Basic Medicine, Qingdao University, Qingdao, Shandong, China
| | - Jie Liang
- Department of Immunology, College of Basic Medicine, Qingdao University, Qingdao, Shandong, China
| | - Wei Rao
- Division of Liver Transplantation, Organ Transplantation Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Mengli Cui
- Department of Immunology, College of Basic Medicine, Qingdao University, Qingdao, Shandong, China
| | - Shurong Ren
- Department of Immunology, College of Basic Medicine, Qingdao University, Qingdao, Shandong, China
| | - Li Zhang
- Department of Immunology, College of Basic Medicine, Qingdao University, Qingdao, Shandong, China
| | - Dan Xu
- Department of Immunology, College of Basic Medicine, Qingdao University, Qingdao, Shandong, China
| | - Qi Han
- Department of Immunology, College of Basic Medicine, Qingdao University, Qingdao, Shandong, China
| | - Yun-Jin Zang
- Division of Liver Transplantation, Organ Transplantation Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Bei Zhang
- Department of Immunology, College of Basic Medicine, Qingdao University, Qingdao, Shandong, China
| |
Collapse
|
|
9
|
Fu Y, Liu S, Zeng S, Shen H. From bench to bed: the tumor immune microenvironment and current immunotherapeutic strategies for hepatocellular carcinoma. J Exp Clin Cancer Res 2019; 38:396. [PMID: 31500650 PMCID: PMC6734524 DOI: 10.1186/s13046-019-1396-4] [Citation(s) in RCA: 288] [Impact Index Per Article: 48.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Accepted: 08/27/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) ranks the most common primary liver malignancy and the third leading cause of tumor-related mortality worldwide. Unfortunately, despite advances in HCC treatment, less than 40% of HCC patients are eligible for potentially curative therapies. Recently, cancer immunotherapy has emerged as one of the most promising approaches for cancer treatment. It has been proven therapeutically effective in many types of solid tumors, such as non-small cell lung cancer and melanoma. As an inflammation-associated tumor, it's well-evidenced that the immunosuppressive microenvironment of HCC can promote immune tolerance and evasion by various mechanisms. Triggering more vigorous HCC-specific immune response represents a novel strategy for its management. Pre-clinical and clinical investigations have revealed that various immunotherapies might extend current options for needed HCC treatment. In this review, we provide the recent progress on HCC immunology from both basic and clinical perspectives, and discuss potential advances and challenges of immunotherapy in HCC.
Collapse
MESH Headings
- Adaptive Immunity
- Animals
- Antineoplastic Agents, Immunological/pharmacology
- Antineoplastic Agents, Immunological/therapeutic use
- Biomarkers, Tumor
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/therapy
- Clinical Trials as Topic
- Combined Modality Therapy/methods
- Humans
- Immunity, Innate
- Immunotherapy/adverse effects
- Immunotherapy/methods
- Liver Neoplasms/immunology
- Liver Neoplasms/pathology
- Liver Neoplasms/therapy
- Lymphocytes, Tumor-Infiltrating/immunology
- Lymphocytes, Tumor-Infiltrating/metabolism
- Lymphocytes, Tumor-Infiltrating/pathology
- Translational Research, Biomedical
- Treatment Outcome
- Tumor Microenvironment/immunology
Collapse
Affiliation(s)
- Yaojie Fu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008 Hunan China
| | - Shanshan Liu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008 Hunan China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008 Hunan China
| | - Shan Zeng
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008 Hunan China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, 410008 Hunan China
| | - Hong Shen
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008 Hunan China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008 Hunan China
| |
Collapse
|
|
10
|
Wang J, Li C, Fu J, Wang X, Feng X, Pan X. Tim-3 regulates inflammatory cytokine expression and Th17 cell response induced by monocytes from patients with chronic hepatitis B. Scand J Immunol 2019; 89:e12755. [PMID: 30729555 DOI: 10.1111/sji.12755] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Revised: 02/02/2019] [Accepted: 02/03/2019] [Indexed: 02/06/2023]
Abstract
Tim-3 is expressed on monocytes/macrophages and is involved in the regulation of inflammatory responses. The aim of this study was to determine the effect of Tim-3 on inflammatory response triggered by peripheral monocytes from patients with chronic hepatitis B (CHB). Tim-3 expression on peripheral monocytes and frequency of Th17 cells in peripheral blood mononuclear cells (PBMCs) derived from CHB patients were detected. Followed by lipopolysaccharides (LPS) activation of circulating monocytes from CHB patients, expression of inflammatory cytokines including TNF-α，IL-1β and IL-6 were examined in the presence and absence of Galectin-9 which is the ligand for Tim-3. Subsequently, after purified CD4+T cells were cocultured with LPS-activated monocytes from CHB patients in the presence of anti-Tim-3 antibody, percentage of Th17 cells and production of IL-17 were measured. Tim-3 expression was significantly upregulated and closely correlated to the frequency of Th17 cells in patients with CHB. Expression of TNF-α，IL-1β and IL-6 increased significantly in monocytes stimulated with LPS and Galectin-9, compared to LPS stimulation alone. LPS-activated monocytes from CHB patients could drive differentiation of memory CD4+T cells to Th17 cells. However, under the blockade of Tim-3 signalling by anti-Tim-3 antibody, percentage of Th17 cells and production of IL-17 decreased significantly. Our results demonstrate that upregulated expression of Tim-3 on circulating monocytes accelerates inflammatory response by promoting production of inflammatory cytokines and Th17 responses in CHB.
Collapse
Affiliation(s)
- Junyan Wang
- Department of Infectious Disease, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Chan Li
- Department of Infectious Disease, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Juanjuan Fu
- Department of Infectious Disease, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Xia Wang
- Department of Infectious Disease, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Xia Feng
- Central Laboratory of the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Xiucheng Pan
- Department of Infectious Disease, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| |
Collapse
|
|
11
|
Xu Y, Wang Z, Du X, Liu Y, Song X, Wang T, Tan S, Liang X, Gao L, Ma C. Tim-3 blockade promotes iNKT cell function to inhibit HBV replication. J Cell Mol Med 2018; 22:3192-3201. [PMID: 29602251 PMCID: PMC5980221 DOI: 10.1111/jcmm.13600] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2017] [Accepted: 02/06/2018] [Indexed: 12/23/2022] Open
Abstract
Increased expression of T cell immunoglobulin and mucin domain-3 (Tim-3) on invariant natural killer T (iNKT) cells is reported in chronic hepatitis B virus (HBV) infection. However, whether Tim-3 regulates iNKT cells in chronic HBV condition remains unclear. In this study, our results showed that the expression of Tim-3 was up-regulated on hepatic iNKT cells from HBV-transgenic (Tg) mice or iNKT cells stimulated with α-galactosylceramide (α-Galcer). Compared with Tim-3- iNKT cells, Tim-3+ iNKT cells expressed more IFN-γ, IL-4 and CD107a, indicating a strong relationship between Tim-3 and iNKT cell activation. Constantly, treatment of Tim-3 blocking antibodies significantly enhanced the production of IFN-γ, TNF-α, IL-4 and CD107a in iNKT cells both in vivo and in vitro. This Tim-3- mediated suppression of iNKT cells was further confirmed in Tim-3 knockout (KO) mice. Moreover, Tim-3 blockade promoted α-Galcer-triggered inhibition of HBV replication, displaying as the decreased HBV DNA and HBsAg level in serum, and down-regulated pgRNA expression in liver tissues. Collectively, our data, for the first time, demonstrated the potential role of Tim-3 blockade in promoting iNKT cell-mediated HBV inhibition. Therefore, combination of α-Galcer with Tim-3 blockade might be a promising approach in chronic hepatitis B therapy.
Collapse
Affiliation(s)
- Yong Xu
- Key Laboratory for Experimental Teratology of Ministry of EducationKey Laboratory of Infection and Immunity of Shandong ProvinceDepartment of ImmunologySchool of Basic Medical SciencesShandong UniversityJinanChina
| | - Zehua Wang
- Key Laboratory for Experimental Teratology of Ministry of EducationKey Laboratory of Infection and Immunity of Shandong ProvinceDepartment of ImmunologySchool of Basic Medical SciencesShandong UniversityJinanChina
| | - Xianhong Du
- Key Laboratory for Experimental Teratology of Ministry of EducationKey Laboratory of Infection and Immunity of Shandong ProvinceDepartment of ImmunologySchool of Basic Medical SciencesShandong UniversityJinanChina
| | - Yuan Liu
- Key Laboratory for Experimental Teratology of Ministry of EducationKey Laboratory of Infection and Immunity of Shandong ProvinceDepartment of ImmunologySchool of Basic Medical SciencesShandong UniversityJinanChina
| | - Xiaojia Song
- Key Laboratory for Experimental Teratology of Ministry of EducationKey Laboratory of Infection and Immunity of Shandong ProvinceDepartment of ImmunologySchool of Basic Medical SciencesShandong UniversityJinanChina
| | - Tixiao Wang
- Key Laboratory for Experimental Teratology of Ministry of EducationKey Laboratory of Infection and Immunity of Shandong ProvinceDepartment of ImmunologySchool of Basic Medical SciencesShandong UniversityJinanChina
| | - Siyu Tan
- Key Laboratory for Experimental Teratology of Ministry of EducationKey Laboratory of Infection and Immunity of Shandong ProvinceDepartment of ImmunologySchool of Basic Medical SciencesShandong UniversityJinanChina
| | - Xiaohong Liang
- Key Laboratory for Experimental Teratology of Ministry of EducationKey Laboratory of Infection and Immunity of Shandong ProvinceDepartment of ImmunologySchool of Basic Medical SciencesShandong UniversityJinanChina
| | - Lifen Gao
- Key Laboratory for Experimental Teratology of Ministry of EducationKey Laboratory of Infection and Immunity of Shandong ProvinceDepartment of ImmunologySchool of Basic Medical SciencesShandong UniversityJinanChina
| | - Chunhong Ma
- Key Laboratory for Experimental Teratology of Ministry of EducationKey Laboratory of Infection and Immunity of Shandong ProvinceDepartment of ImmunologySchool of Basic Medical SciencesShandong UniversityJinanChina
| |
Collapse
|
|
12
|
Immunomodulatory effects of Tim-3 and PD-1 on chronic hepatitis B virus infection. INFECTION INTERNATIONAL 2018. [DOI: 10.2478/ii-2018-0012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Abstract
In patients with chronic hepatitis B virus (HBV) infection, the immune cells are dysfunctional, and the immune function cannot work normally. T-cell immunoglobulin mucin-3 (Tim-3) and programmed death receptor-1 (PD-1) are overexpressed on the surface of immune cells, such as cluster of differentiation (CD)4+, CD8+ T-lymphocytes, and natural killer (NK) cells. Many studies indicate that this phenomenon is closely related to the persistence, occurrence, development, and prognosis of HBV. Tim-3 and PD-1 may be used as new immune targets for the treatment of chronic hepatitis B.
Collapse
|
|
13
|
Increased Tim-3 expression alleviates liver injury by regulating macrophage activation in MCD-induced NASH mice. Cell Mol Immunol 2018; 16:878-886. [PMID: 29735977 DOI: 10.1038/s41423-018-0032-0] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2017] [Revised: 04/03/2018] [Accepted: 04/03/2018] [Indexed: 02/07/2023] Open
Abstract
As an immune checkpoint, Tim-3 plays roles in the regulation of both adaptive and innate immune cells including macrophages and is greatly involved in chronic liver diseases. However, the precise roles of Tim-3 in nonalcoholic steatohepatitis (NASH) remain unstated. In the current study, we analyzed Tim-3 expression on different subpopulations of liver macrophages and further investigated the potential roles of Tim-3 on hepatic macrophages in methionine and choline-deficient diet (MCD)-induced NASH mice. The results of flow cytometry demonstrated the significantly increased expression of Tim-3 on all detected liver macrophage subsets in MCD mice, including F4/80+CD11b+, F4/80+CD68+, and F4/80+CD169+ macrophages. Remarkably, Tim-3 knockout (KO) significantly accelerated MCD-induced liver steatosis, displaying higher serum ALT, larger hepatic vacuolation, more liver lipid deposition, and more severe liver fibrosis. Moreover, compared with wild-type C57BL/6 mice, Tim-3 KO MCD mice demonstrated an enhanced expression of NOX2, NLRP3, and caspase-1 p20 together with increased generation of IL-1β and IL-18 in livers. In vitro studies demonstrated that Tim-3 negatively regulated the production of reactive oxygen species (ROS) and related downstream pro-inflammatory cytokine secretion of IL-1β and IL-18 in macrophages. Exogenous administration of N-Acetyl-L-cysteine (NAC), a small molecular inhibitor of ROS, remarkably suppressed caspase-1 p20 expression and IL-1β and IL-18 production in livers of Tim-3 KO mice, thus significantly reducing the severity of steatohepatitis induced by MCD. In conclusion, Tim-3 is a promising protector in MCD-induced steatohepatitis by controlling ROS and the associated pro-inflammatory cytokine production in macrophages.
Collapse
|
|
14
|
Li F, Li N, Sang J, Fan X, Deng H, Zhang X, Han Q, Lv Y, Liu Z. Highly elevated soluble Tim-3 levels correlate with increased hepatocellular carcinoma risk and poor survival of hepatocellular carcinoma patients in chronic hepatitis B virus infection. Cancer Manag Res 2018; 10:941-951. [PMID: 29760564 PMCID: PMC5937498 DOI: 10.2147/cmar.s162478] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Background and objective Upregulated T-cell immunoglobulin and mucin domain containing molecule-3 (Tim-3) in hepatitis B virus (HBV)-specific CD8+ T-cells contributes to CD8+ T-cell exhaustion during chronic HBV infection. The membrane-bound Tim-3 can be cleaved from the cell surface by sheddase, yielding soluble Tim-3 (sTim-3). This study investigated serum sTim-3 levels in patients with chronic HBV infection of various liver diseases. Methods Serum sTim-3 levels were quantitatively determined in 288 patients with chronic HBV infection of various liver diseases. The sTim-3 levels were analyzed in relation to liver diseases including HBV-related hepatocellular carcinoma (HCC) and overall survival of HCC patients. Results Serum sTim-3 levels in the patients with chronic HBV infection were significantly elevated compared with healthy controls (P<0.001) and the levels from asymptomatic HBV carrier status, chronic hepatitis, liver cirrhosis to HCC were progressively increased. Serum sTim-3 levels were closely associated with the severity of liver function abnormalities. Importantly, serum sTim-3 levels were independently associated with HCC risk (OR, 4.310; 95% CI, 2.141–8.676, P<0.001) in comparison to non-HCC diseases in chronic HBV infection and significantly associated with the overall survival of HCC patients, with a level >3000 pg/mL being related to shorter overall survival than a level ≤3000 pg/mL (P=0.019). Conclusion Serum sTim-3 is involved in disease progression and HCC development in chronic HBV infection and its quantitative determination may be potentially used as a marker for monitoring the disease progression and predicting the HCC prognosis in chronic HBV infection.
Collapse
Affiliation(s)
- Fang Li
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Na Li
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Jiao Sang
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Xiude Fan
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Huan Deng
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Xiaoge Zhang
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Qunying Han
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Yi Lv
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.,Institute of Advanced Surgical Technology and Engineering, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Zhengwen Liu
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.,Institute of Advanced Surgical Technology and Engineering, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| |
Collapse
|
|
15
|
Zhang N, Zhang M, Liu RT, Zhang P, Yang CL, Yue LT, Li H, Li YK, Duan RS. Statins reduce the expressions of Tim-3 on NK cells and NKT cells in atherosclerosis. Eur J Pharmacol 2017; 821:49-56. [PMID: 29288118 DOI: 10.1016/j.ejphar.2017.12.050] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2017] [Revised: 12/20/2017] [Accepted: 12/21/2017] [Indexed: 12/20/2022]
Abstract
3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) have an immuno-regulatory effect in addition to lowing-lipids. Accumulated evidence showed that the expressions of T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) on natural killer (NK) cells increased in atherosclerotic patients and animal models. In this study, 14 patients treated with rosuvastatin and 12 patients with atorvastatin for more than 3 months were included and 20 patients without statins treatment as control. Both statins treatment reduced the expressions of Tim-3 on NK cells and their subtypes, natural killer T (NKT) cells and CD3+ T cells, and increased the proportions of NKT cells among peripheral blood mononuclear cells, accompanied by the decreased levels of total cholesterol, low density lipoprotein, and increased ratios of high density lipoprotein to cholesterol. These may contribute to the functions of statins in the treatment of atherosclerosis.
Collapse
Affiliation(s)
- Na Zhang
- Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, PR China
| | - Min Zhang
- Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, PR China
| | - Ru-Tao Liu
- Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, PR China
| | - Peng Zhang
- Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, PR China
| | - Chun-Lin Yang
- Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, PR China
| | - Long-Tao Yue
- Central laboratory, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, PR China
| | - Heng Li
- Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, PR China
| | - Yong-Kang Li
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, PR China
| | - Rui-Sheng Duan
- Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, PR China.
| |
Collapse
|
|
16
|
Michel JJ, Griffin P, Vallejo AN. Functionally Diverse NK-Like T Cells Are Effectors and Predictors of Successful Aging. Front Immunol 2016; 7:530. [PMID: 27933066 PMCID: PMC5121286 DOI: 10.3389/fimmu.2016.00530] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Accepted: 11/10/2016] [Indexed: 12/16/2022] Open
Abstract
The fundamental challenge of aging and long-term survivorship is maintenance of functional independence and compression of morbidity despite a life history of disease. Inasmuch as immunity is a determinant of individual health and fitness, unraveling novel mechanisms of immune homeostasis in late life is of paramount interest. Comparative studies of young and old persons have documented age-related atrophy of the thymus, the contraction of diversity of the T cell receptor (TCR) repertoire, and the intrinsic inefficiency of classical TCR signaling in aged T cells. However, the elderly have highly heterogeneous health phenotypes. Studies of defined populations of persons aged 75 and older have led to the recognition of successful aging, a distinct physiologic construct characterized by high physical and cognitive functioning without measurable disability. Significantly, successful agers have a unique T cell repertoire; namely, the dominance of highly oligoclonal αβT cells expressing a diverse array of receptors normally expressed by NK cells. Despite their properties of cell senescence, these unusual NK-like T cells are functionally active effectors that do not require engagement of their clonotypic TCR. Thus, NK-like T cells represent a beneficial remodeling of the immune repertoire with advancing age, consistent with the concept of immune plasticity. Significantly, certain subsets are predictors of physical/cognitive performance among older adults. Further understanding of the roles of these NK-like T cells to host defense, and how they integrate with other physiologic domains of function are new frontiers for investigation in Aging Biology. Such pursuits will require a research paradigm shift from the usual young-versus-old comparison to the analysis of defined elderly populations. These endeavors may also pave way to age-appropriate, group-targeted immune interventions for the growing elderly population.
Collapse
Affiliation(s)
- Joshua J Michel
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Patricia Griffin
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Abbe N Vallejo
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Claude Pepper Older Americans Independence Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| |
Collapse
|
|
17
|
Zou ZQ, Wang L, Wang K, Yu JG. Innate immune targets of hepatitis B virus infection. World J Hepatol 2016; 8:716-725. [PMID: 27330680 PMCID: PMC4911505 DOI: 10.4254/wjh.v8.i17.716] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Revised: 04/29/2016] [Accepted: 06/03/2016] [Indexed: 02/06/2023] Open
Abstract
Approximately 400 million people are chronically infected with hepatitis B virus (HBV) globally despite the widespread immunization of HBV vaccine and the development of antiviral therapies. The immunopathogenesis of HBV infection is initiated and driven by complexed interactions between the host immune system and the virus. Host immune responses to viral particles and proteins are regarded as the main determinants of viral clearance or persistent infection and hepatocyte injury. Innate immune system is the first defending line of host preventing from virus invasion. It is acknowledged that HBV has developed active tactics to escape innate immune recognition or actively interfere with innate immune signaling pathways and induce immunosuppression, which favor their replication. HBV reduces the expression of pattern-recognition receptors in the innate immune cells in humans. Also, HBV may interrupt different parts of antiviral signaling pathways, leading to the reduced production of antiviral cytokines such as interferons that contribute to HBV immunopathogenesis. A full comprehension of the mechanisms as to how HBV inactivates various elements of the innate immune response to initiate and maintain a persistent infection can be helpful in designing new immunotherapeutic methods for preventing and eradicating the virus. In this review, we aimed to summarize different branches the innate immune targeted by HBV infection. The review paper provides evidence that multiple components of immune responses should be activated in combination with antiviral therapy to disrupt the tolerance to HBV for eliminating HBV infection.
Collapse
|
|
18
|
Guo C, Shen X, Fu B, Liu Y, Chen Y, Ni F, Ye Y, Sun R, Li J, Tian Z, Wei H. CD3(bright)CD56(+) T cells associate with pegylated interferon-alpha treatment nonresponse in chronic hepatitis B patients. Sci Rep 2016; 6:25567. [PMID: 27174425 PMCID: PMC4865958 DOI: 10.1038/srep25567] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2015] [Accepted: 04/19/2016] [Indexed: 12/26/2022] Open
Abstract
Chronic hepatitis B (CHB) infection is a serious and prevalent health concern worldwide, and the development of effective drugs and strategies to combat this disease is urgently needed. Currently, pegylated interferon-alpha (peg-IFNα) and nucleoside/nucleotide analogues (NA) are the most commonly prescribed treatments. However, sustained response rates in patients remain low, and the reasons are not well understood. Here, we observed that CHB patients preferentially harbored CD3brightCD56+ T cells, a newly identified CD56+ T cell population. Patients with this unique T cell population exhibited relatively poor responses to peg-IFNα treatment. CD3brightCD56+ T cells expressed remarkably high levels of the inhibitory molecule NKG2A as well as low levels of CD8. Even if patients were systematically treated with peg-IFNα, CD3brightCD56+ T cells remained in an inhibitory state throughout treatment and exhibited suppressed antiviral function. Furthermore, peg-IFNα treatment rapidly increased inhibitory TIM-3 expression on CD3brightCD56+ T cells, which negatively correlated with IFNγ production and might have led to their dysfunction. This study identified a novel CD3brightCD56+ T cell population preferentially shown in CHB patients, and indicated that the presence of CD3brightCD56+ T cells in CHB patients may be useful as a new indicator associated with poor therapeutic responses to peg-IFNα treatment.
Collapse
Affiliation(s)
- Chuang Guo
- Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Science and Medical Center, University of Science and Technology of China, Hefei 230027, People's Republic of China
| | - Xiaokun Shen
- Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Science and Medical Center, University of Science and Technology of China, Hefei 230027, People's Republic of China
| | - Binqing Fu
- Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Science and Medical Center, University of Science and Technology of China, Hefei 230027, People's Republic of China.,Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui, People's Republic of China
| | - Yanyan Liu
- Department of Infectious Diseases, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People's Republic of China
| | - Yongyan Chen
- Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Science and Medical Center, University of Science and Technology of China, Hefei 230027, People's Republic of China
| | - Fang Ni
- Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Science and Medical Center, University of Science and Technology of China, Hefei 230027, People's Republic of China
| | - Ying Ye
- Department of Infectious Diseases, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People's Republic of China
| | - Rui Sun
- Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Science and Medical Center, University of Science and Technology of China, Hefei 230027, People's Republic of China.,Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui, People's Republic of China
| | - Jiabin Li
- Department of Infectious Diseases, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People's Republic of China
| | - Zhigang Tian
- Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Science and Medical Center, University of Science and Technology of China, Hefei 230027, People's Republic of China.,Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui, People's Republic of China
| | - Haiming Wei
- Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Science and Medical Center, University of Science and Technology of China, Hefei 230027, People's Republic of China.,Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui, People's Republic of China
| |
Collapse
|
|
19
|
Liu Y, Gao LF, Liang XH, Ma CH. Role of Tim-3 in hepatitis B virus infection: An overview. World J Gastroenterol 2016; 22:2294-2303. [PMID: 26900291 PMCID: PMC4735003 DOI: 10.3748/wjg.v22.i7.2294] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2015] [Revised: 10/08/2015] [Accepted: 12/21/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection has received increasing public attention. HBV is the prototypical member of hepadnaviruses, which naturally infect only humans and great apes and induce the acute and persistent chronic infection of hepatocytes. A large body of evidence has demonstrated that dysfunction of the host anti-viral immune response is responsible for persistent HBV replication, unresolved inflammation and disease progression. Many regulatory factors are involved in immune dysfunction. Among these, T cell immunoglobulin domain and mucin domain-3 (Tim-3), one of the immune checkpoint proteins, has attracted increasing attention due to its critical role in regulating both adaptive and innate immune cells. In chronic HBV infection, Tim-3 expression is elevated in many types of immune cells, such as T helper cells, cytotoxic T lymphocytes, dendritic cells, macrophages and natural killer cells. Tim-3 over-expression is often accompanied by impaired function of the above-mentioned immunocytes, and Tim-3 inhibition can at least partially rescue impaired immune function and thus promote viral clearance. A better understanding of the regulatory role of Tim-3 in host immunity during HBV infection will shed new light on the mechanisms of HBV-related liver disease and suggest new therapeutic methods for intervention.
Collapse
|
|
20
|
Hato T, Zhu AX, Duda DG. Rationally combining anti-VEGF therapy with checkpoint inhibitors in hepatocellular carcinoma. Immunotherapy 2016; 8:299-313. [PMID: 26865127 DOI: 10.2217/imt.15.126] [Citation(s) in RCA: 97] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a fatal disease with rising incidence in the world. For advanced HCC, sorafenib, a multikinase inhibitor, is the only systemic therapy with proven survival benefits. Sorafenib is a pan-VEGF receptor inhibitor, and thus many studies have focused its antivascular effects. But VEGF also acts as an immunosuppressive molecule. VEGF can inhibit maturation of dendritic cells, promote immune suppressive cell infiltration and enhance immune checkpoint molecules expression. On the other hand, potent VEGF inhibition may increase tumor hypoxia, which could hinder antitumor immunity or immunotherapy. Thus, achieving synergy when combining anti-VEGF therapy with immunotherapy may require proper polarization of the tumor microenvironment by dose titration or combination with other immunomodulating agents.
Collapse
Affiliation(s)
- Tai Hato
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.,Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Andrew X Zhu
- Hematology/Oncology, Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA
| | - Dan G Duda
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| |
Collapse
|
|
21
|
Downregulation of T cell immunoglobulin and mucin protein 3 in the pathogenesis of intracranial aneurysm. Inflammation 2015; 38:368-74. [PMID: 25342285 DOI: 10.1007/s10753-014-0040-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Evidence has shown that inflammation acts as a critical contributor to the pathogenesis of intracranial aneurysm (IA), a potentially devastating clinical problem. T cell immunoglobulin and mucin protein 3 (Tim-3) is a negative regulatory molecule and plays important roles in the inflammation process. In the current study, we investigated the expression of Tim-3 and its correlation with tumor necrosis factor alpha (TNF-α) in IA patients. Data showed that both messenger RNA (mRNA) level and protein level of Tim-3 were significantly decreased in CD4+ T cells and CD8+ T cells from IA patients than from healthy controls (P < 0.001). However, expression of Tim-3 was not altered in monocytes between patients and healthy donors. Further analyses revealed that patients with ruptured aneurysm had significantly lower level of Tim-3 in CD8+ T cells than those with un-ruptured aneurysm. In addition, a negative correlation between serum level of TNF-α and the expression of Tim-3 in CD4+ T cells was observed in IA patients. Similar correlation was also identified in CD8+ T cells from IA patients. Our study suggests that Tim-3 may participate in the development and progression of IA by probably its negative regulation on TNF-α.
Collapse
|
|
22
|
Shi Y, Wu W, Yang Y, Yang Q, Song G, Wu Y, Wei L, Chen Z. Decreased Tim-3 expression is associated with functional abnormalities of monocytes in decompensated cirrhosis without overt bacterial infection. J Hepatol 2015; 63:60-7. [PMID: 25701694 DOI: 10.1016/j.jhep.2015.02.020] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2014] [Revised: 01/22/2015] [Accepted: 02/09/2015] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Patients with advanced cirrhosis usually exhibit altered monocyte function. However, the molecular mechanisms underlying the functional changes of monocytes are poorly understood. METHODS We investigated the role of T-cell immunoglobulin domain and mucin domain-containing molecule-3 (Tim-3) in regulating monocyte function in 94 patients with decompensated liver cirrhosis (DC-LC) (decompensation was defined by ascites, hepatic encephalopathy or upper gastrointestinal bleeding), 58 with compensated liver cirrhosis (C-LC) and 52 healthy controls (HC) by characterizing the frequency of Tim-3(+) monocytes, their phagocytosis capacity, HLA-DR expression, cytokine secretion and MAP kinase activation induced by lipopolysaccharide (LPS). RESULTS Tim-3 expression on CD14(+) monocytes in DC-LC group were significantly lower than that in C-LC and HC and were associated with increased levels of plasma endotoxin, enhanced cytokine production, decreased phagocytic capacity, and reduced HLA-DR expression. Tim-3 expression on monocytes and monocyte function did not differ between C-LC and HC group. Tim-3(+)CD14(+) cells had more potent phagocytic capacity, higher levels of HLA-DR, CD86, CD80, CD163, and CD206 expression, but lower levels of CD1a and CD83, related to that of Tim-3(-)CD14(+) monocytes. In addition, Tim-3(+)CD14(+) cells produced less TNF-α but higher levels of IL-10 in response to LPS. Treatment with anti-Tim-3 antibody significantly reduced phagocytic capacity, but enhanced LPS-stimulated TNF-α, IL-6, and IL-10 secretion. Furthermore, blocking Tim-3 signaling increased p38 MAP kinase phosphorylation in monocytes upon LPS stimulation. CONCLUSIONS Downregulation of Tim-3 expression was associated with endotoxemia and functional alterations of monocytes in patients with decompensated cirrhosis.
Collapse
Affiliation(s)
- Yu Shi
- State Key Lab of Diagnostic and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wei Wu
- State Key Lab of Diagnostic and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ying Yang
- State Key Lab of Diagnostic and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qiao Yang
- Department of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Guangzhong Song
- Department of Laboratory Medicine, Zhejiang Medical College, Hangzhou, China
| | - Yihua Wu
- Department of Epidemiology and Healthy Statistics, Zhejiang University School of Public Health, Hangzhou, China
| | - Li Wei
- State Key Lab of Diagnostic and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhi Chen
- State Key Lab of Diagnostic and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| |
Collapse
|
|
23
|
Lawrenczyk A, Kim S, Wen X, Xiong R, Yuan W. Exploring the Therapeutic Potentials of iNKT Cells for Anti-HBV Treatment. Pathogens 2014; 3:563-76. [PMID: 25438012 PMCID: PMC4243429 DOI: 10.3390/pathogens3030563] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2014] [Revised: 06/23/2014] [Accepted: 06/23/2014] [Indexed: 12/14/2022] Open
Abstract
CD1d-restricted invariant NKT (iNKT) cells are a group of innate-like regulatory T cells that recognize lipid antigens. Both mouse modeling experiments and human clinical studies have suggested a key role for iNKT cells in anti-HBV immunity and these potent T cells can be explored as a novel therapeutic target for anti-HBV treatment. We aim to humanize mice in the CD1d/iNKT cell lipid presentation system and provide new research tools for identifying novel anti-HBV agents.
Collapse
Affiliation(s)
- Agnieszka Lawrenczyk
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
| | - Seil Kim
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
| | - Xiangshu Wen
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
| | - Ran Xiong
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
| | - Weiming Yuan
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
| |
Collapse
|
|
24
|
Wang M, Ji B, Wang J, Cheng X, Zhou Q, Zhou J, Cao C, Guo Q. Tim-3 polymorphism downregulates gene expression and is involved in the susceptibility to ankylosing spondylitis. DNA Cell Biol 2014; 33:723-8. [PMID: 24905803 DOI: 10.1089/dna.2014.2456] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Ankylosing spondylitis (AS) is a chronic inflammatory disorder primarily affecting the sacroiliac joints and the spine. T-cell immunoglobulin- and mucin-domain-containing molecule 3 (TIM-3) has been established as a negative regulatory molecule that plays a critical role in controlling inflammation. Studies have shown that polymorphisms in TIM-3 gene may be associated with inflammatory diseases. The current study investigated the association between polymorphisms in the TIM-3 gene and susceptibility to AS, and it examined the effects of these polymorphisms on gene expression. Two polymorphisms in TIM-3 -574G/T and +4259T/G polymorphisms were identified by polymerase chain reaction-restriction fragment length polymorphism in 282 AS patients and 298 healthy controls. Results showed that frequency of the TIM-3 -574GT genotype was significantly increased in cases than in controls (Odd ratio [OR]=2.50, 95% confidence interval [CI]: 1.39-4.48, p=0.002). Similarly, TIM-3 -574T allele revealed a positive association with the disease (OR=2.39, p=0.002). The TIM-3 +4259T/G polymorphism did not show any correlation with AS. We further evaluated TIM-3 mRNA and protein levels in CD4(+) T cells, CD8(+) T cells, and monocytes from subjects carrying different TIM-3 genotypes. Results revealed that subjects carrying polymorphic -574GT genotype had significantly lower TIM-3 mRNA and protein levels in CD4(+) T cells, CD8(+) T cells, and monocytes than those with wild-type GG genotype. These data suggest that TIM-3 polymorphism is associated with increased susceptibility to AS possibly by downregulating gene expression.
Collapse
Affiliation(s)
- Mingfei Wang
- 1 Department of Orthopedic Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine , Shanghai, China
| | | | | | | | | | | | | | | |
Collapse
|
|
25
|
Tim-3 expression is increased on peripheral T cells from diffuse large B cell lymphoma. Tumour Biol 2014; 35:7951-6. [DOI: 10.1007/s13277-014-2080-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2014] [Accepted: 05/08/2014] [Indexed: 11/25/2022] Open
|