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Pan X, Kaminga AC, Wen SW, Liu A. Chemokines in hepatocellular carcinoma: a meta-analysis. Carcinogenesis 2021; 41:1682-1694. [PMID: 33300549 DOI: 10.1093/carcin/bgaa106] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 09/17/2020] [Accepted: 10/08/2020] [Indexed: 12/17/2022] Open
Abstract
Accumulating evidence suggests that chemokines may play an important role in the formation and mediating of the immune microenvironment of hepatocellular carcinoma (HCC). The purpose of this meta-analysis was to explore the differences in blood or tissues chemokines concentrations between HCC patients and controls. Online databases, namely PubMed, Web of Science, Embase and Cochrane Library, were systematically searched for relevant articles published on or before 15 January 2020. Standardized mean differences (SMDs) with corresponding 95% confidence intervals of the chemokines concentrations were calculated as group differences between the HCC patients and the controls. Sixty-five studies met the inclusion criteria for the meta-analysis. Altogether they consisted of 26 different chemokines compared between 5828 HCC patients and 4909 controls; and 12 different chemokines receptors compared between 2053 patients and 2285 controls. The results of meta-analysis indicated that concentrations of CCL20, CXCL8 and CXCR4 in the HCC patients were significantly higher than those in the controls (SMD of 6.18, 1.81 and 1.04, respectively). Therefore, higher concentration levels of CCL20, CXCL8 and CXCR4 may indicate the occurrence of HCC Future research should explore the putative mechanisms underlying this linkage. Meanwhile, attempts can be made to replicate the existing findings in prospective cohort populations and explore the cause-and-effect relationships pertaining to this linkage in order to develop new diagnostic and therapeutic strategies for HCC.
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Affiliation(s)
- Xiongfeng Pan
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, China
| | - Atipatsa C Kaminga
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, China.,Department of Mathematics and Statistics, Mzuzu University, Mzuzu, Malawi
| | - Shi Wu Wen
- OMNI Research Group, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Department of Obstetrics and Gynaecology, University of Ottawa Faculty of Medicine, Ottawa, Ontario, Canada.,School of Epidemiology and Public Health, University of Ottawa Faculty of Medicine, Ottawa, Ontario, Canada
| | - Aizhong Liu
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, China
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Abstract
The human liver is an organ with a diverse array of immunologic functions. Its unique anatomic position that leads to it receiving all the mesenteric venous blood, combined with its unique micro anatomy, allows it to serve as a sentinel for the body's immune system. Hepatocytes, biliary epithelial cells, Kupffer cells, stellate cells, and liver sinusoidal endothelial cells express key molecules that recruit and activate innate and adaptive immunity. Additionally, a diverse array of lymphoid and myeloid immune cells resides within and traffics to the liver in specific circumstances. Derangement of these trafficking mechanisms underlies the pathophysiology of autoimmune liver diseases, nonalcoholic steatohepatitis, and liver transplantation. Here, we review these pathways and interactions along with potential targets that have been identified to be exploited for therapeutic purposes.
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Zahran AM, Hetta HF, Rayan A, Eldin AS, Hassan EA, Fakhry H, Soliman A, El-Badawy O. Differential expression of Tim-3, PD-1, and CCR5 on peripheral T and B lymphocytes in hepatitis C virus-related hepatocellular carcinoma and their impact on treatment outcomes. Cancer Immunol Immunother 2020; 69:1253-1263. [PMID: 32170378 DOI: 10.1007/s00262-019-02465-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Accepted: 12/26/2019] [Indexed: 01/13/2023]
Abstract
BACKGROUND AND OBJECTIVE Activation of the immune checkpoints and expression of chemokines and chemokine receptors have been reported to promote HCC progression. This study aimed to assess the differential expression of Tim-3, PD-1, and CCR5 on peripheral blood lymphocytes from patients with HCV-related HCC and correlate their expression with the treatment outcomes. PATIENTS AND METHODS The study incorporated 40 patients with chronic HCV-related HCC and 40 healthy controls. Patients were radiologically assessed for hepatic focal lesions and portal vein thrombosis. Response to HCC treatment and overall survival (OS) outcomes were determined. The expression of Tim-3, PD-1, and CCR5 among CD19+, CD4+, and CD8+ lymphocytes was assessed by flow cytometry. RESULTS Higher frequencies of CD4+ and CD8+ cells expressing each of Tim-3 and PD-1 and PD-1+CD19+ cells were observed in the HCV-related HCC patients in comparison with controls. The highest expression of Tim-3 and PD-1 was by the CD8+ cells. Strong relations were detected among PD-1+CD19+, PD-1+CD4+ and PD-1+CD8+ cells. Elevated levels of PD-1+ lymphocytes were significantly associated with poor treatment response and shorter OS. CONCLUSION Modulation of the expression of immune checkpoints as Tim-3 and PD-1, and of CCR5 on T cells is somehow related to HCC. CD8+ T cells expressing PD-1 were the most relevant to HCC prognosis (OS and treatment response) and could represent a promising target for immune therapy against HCC. Future studies need to focus on exploring PD-1+ B cells and Tim-3+CD4+ cells, which seem to play a significant role in the pathogenesis of HCC.
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Affiliation(s)
- Asmaa M Zahran
- Clinical Pathology Department, South Egypt Cancer Institute, Assiut, Egypt
| | - Helal F Hetta
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt. .,Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
| | - Amal Rayan
- Clinical Oncology Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Abeer Sharaf Eldin
- Department of Gastroenterology and Tropical Medicine, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Elham Ahmed Hassan
- Department of Gastroenterology and Tropical Medicine, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Hussein Fakhry
- Surgical Oncology Department, South Egypt Cancer Institute, Assiut University, Assiut, Egypt
| | - Ahmed Soliman
- General Surgery Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Omnia El-Badawy
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
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Wiedemann GM, Röhrle N, Makeschin MC, Fesseler J, Endres S, Mayr D, Anz D. Peritumoural CCL1 and CCL22 expressing cells in hepatocellular carcinomas shape the tumour immune infiltrate. Pathology 2019; 51:586-592. [PMID: 31445808 DOI: 10.1016/j.pathol.2019.06.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 05/16/2019] [Accepted: 06/06/2019] [Indexed: 12/21/2022]
Abstract
Development, course of disease and prognosis of hepatocellular carcinomas (HCC) are strongly influenced by the immune system. Immunosuppressive regulatory T cells (Treg) have been shown to negatively impact disease progression and survival. To further understand the mechanisms of Treg attraction to HCC lesions, this study provides an analysis of Treg attracting chemokines in human HCC tissues. We analysed the expression of the Treg attracting chemokines CCL1 and CCL22 as well as the infiltration of FoxP3+ Treg and CD8+ T cells in paraffin-embedded tissue sections of 62 HCC patients. Expression of both chemokines was detected in 47 of 62 tissue slides. Chemokine expression was generally higher in tumour stroma and peritumoural liver tissue than in the tumour tissue itself. CD8+ T cells and FoxP3+ Treg were found at high levels in many tumour tissues. Intratumoural infiltration of Treg positively correlated with CCL22 levels in peritumoural liver tissue. In contrast, no correlation of Treg numbers and expression of CCL1 was detected. In summary, we describe here that the chemokines CCL1 and CCL22 are expressed in HCC tissues and, to a higher extent, in the stroma and peritumoural liver tissue. CCL22 may contribute to Treg recruitment and immunosuppression, whereas the role of CCL1 remains to be defined. It will be interesting to investigate the potential of these chemokines as drug targets for cancer therapy.
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Affiliation(s)
- Gabriela M Wiedemann
- Center of Integrated Protein Science Munich (CIPS-M), Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany; Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Natascha Röhrle
- Center of Integrated Protein Science Munich (CIPS-M), Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
| | - Marie-Christine Makeschin
- Pathologisches Institut, Medizinische Fakultät der Ludwig-Maximilians Universität München, Munich, Germany
| | - Julia Fesseler
- Center of Integrated Protein Science Munich (CIPS-M), Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
| | - Stefan Endres
- Center of Integrated Protein Science Munich (CIPS-M), Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
| | - Doris Mayr
- Pathologisches Institut, Medizinische Fakultät der Ludwig-Maximilians Universität München, Munich, Germany
| | - David Anz
- Center of Integrated Protein Science Munich (CIPS-M), Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany; Department of Medicine II, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.
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Nakagawa S, Umezaki N, Yamao T, Kaida T, Okabe H, Mima K, Imai K, Hashimoto D, Yamashita YI, Ishiko T, Chikamoto A, Baba H. Survival impact of lymphocyte infiltration into the tumor of hepatocellular carcinoma in hepatitis B virus-positive or non-B non-C patients who underwent curative resection. Hepatol Res 2018; 48:E126-E132. [PMID: 28696046 DOI: 10.1111/hepr.12936] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2017] [Revised: 06/17/2017] [Accepted: 07/10/2017] [Indexed: 02/08/2023]
Abstract
AIM The prognostic value of lymphocyte infiltration into hepatocellular carcinoma (HCC) is still controversial, and it has not been reported in hepatitis B virus (HBV)-positive or non-B non-C (NBNC) HCC. The aim of this study is to assess the prognostic significance of lymphocyte infiltrate in tumor for HBV-positive and NBNC HCC patients. METHODS This study investigated 145 HBV-positive or NBNC patients who underwent hepatectomy for HCC between January 2001 and May 2009. Cumulative recurrence rate, overall survival (OS), and clinicopathological parameters were analyzed according to lymphocyte infiltration in tumor. RESULTS In patients with low lymphocyte infiltration, the 5-year recurrence rate was higher and OS was poor (86.4 and 44.1%, respectively) than that of the patients with high lymphocyte infiltration (55.3 and 83.7%, respectively). Multivariate analyses revealed that independent risk factors for recurrence were low albumin value (hazard ratio [HR] 2.33, P = 0.009), high American Joint Committee on Cancer (AJCC) T stage (HR 2.31, P < 0.0001), high α-fetoprotein (AFP) value (HR 2.06, P = 0.005), and low lymphocyte infiltration (HR 2.50, P = 0.0001). The independent risk factors for OS were low albumin value (HR 3.69, P = 0.003), high AJCC T stage (HR 2.10, P = 0.049), high AFP value (HR 3.98, P < 0.001), and low lymphocyte infiltration (HR 3.47, P = 0.001). CONCLUSIONS Lymphocyte infiltrate in tumor is significantly associated high recurrence rate and poor overall survival. Evaluation of the infiltrating lymphocyte could improve the prediction of prognosis in HCC patients after curative resection.
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Affiliation(s)
- Shigeki Nakagawa
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Naoki Umezaki
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Takanobu Yamao
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Takayoshi Kaida
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Hirohisa Okabe
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Kosuke Mima
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Katsunori Imai
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Daisuke Hashimoto
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Yo-Ichi Yamashita
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Takatoshi Ishiko
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Akira Chikamoto
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
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Sachdeva M, Chawla YK, Arora SK. Immunology of hepatocellular carcinoma. World J Hepatol 2015; 7:2080-2090. [PMID: 26301050 PMCID: PMC4539401 DOI: 10.4254/wjh.v7.i17.2080] [Citation(s) in RCA: 86] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Revised: 05/28/2015] [Accepted: 07/22/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is primarily a malignancy of the liver, advancing from a damaged, cirrhotic liver to HCC. Globally, HCC is the sixth most prevalent cancer and the third-most prevalent reason for neoplastic disease-related deaths. A diverse array of infiltrating immunocytes regulates the development and progression of HCC, as is the case in many other cancers. An understanding of the various immune components during HCC becomes necessary so that novel therapeutic strategies can be designed to combat the disease. A dysregulated immune system (including changes in the number and/or function of immune cells, cytokine levels, and the expression of inhibitory receptors or their ligands) plays a key role in the development of HCC. Alterations in either the innate or adaptive arm of the immune system and cross-talk between them make the immune system tolerant to tumors, leading to disease progression. In this review, we have discussed the status and roles of various immune effector cells (e.g., dendritic cells, natural killer cells, macrophages, and T cells), their cytokine profile, and the chemokine-receptor axis in promoting or impeding HCC.
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Liang CM, Chen L, Hu H, Ma HY, Gao LL, Qin J, Zhong CP. Chemokines and their receptors play important roles in the development of hepatocellular carcinoma. World J Hepatol 2015; 7:1390-1402. [PMID: 26052384 PMCID: PMC4450202 DOI: 10.4254/wjh.v7.i10.1390] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 11/08/2014] [Accepted: 04/07/2015] [Indexed: 02/06/2023] Open
Abstract
The chemokine system consists of four different subclasses with over 50 chemokines and 19 receptors. Their functions in the immune system have been well elucidated and research during the last decades unveils their new roles in hepatocellular carcinoma (HCC). The chemokines and their receptors in the microenvironment influence the development of HCC by several aspects including: inflammation, effects on immune cells, angiogenesis, and direct effects on HCC cells. Regarding these aspects, pre-clinical research by targeting the chemokine system has yielded promising data, and these findings bring us new clues in the chemokine-based therapies for HCC.
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Tsai HT, Yang SF, Chen DR, Chan SE. CCL5-28, CCL5-403, and CCR5 genetic polymorphisms and their synergic effect with alcohol and tobacco consumptions increase susceptibility to hepatocellular carcinoma. Med Oncol 2012; 29:2771-9. [PMID: 22374185 DOI: 10.1007/s12032-012-0189-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2011] [Accepted: 02/06/2012] [Indexed: 12/20/2022]
Abstract
The aim of this study was to estimate the relationship between gene polymorphisms of CCL5-28, CCL5-403, and CCR5 to the susceptibility of hepatocellular carcinoma (HCC). A total of 449 subjects, including 347 healthy controls and 102 patients with HCC, were recruited in this study and subjected to polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to investigate the impact of these two polymorphic variants on HCC. A significant association between HCC susceptibility and genetic polymorphism, CG heterozygotes of CCL5-28 (AOR=2.35; 95% CI=1.27-4.33, p=0.006), AA homozygotes of CCL5-403 (AOR=5.18; 95% CI=2.25-11.91, p=0.0001), and AA homozygotes of CCR5 (AOR=2.47; 95% CI=1.24-4.90, p=0.009), was found compared with wild genotype after adjusting for other confounders. It was detected that synergistic effect between gene-to-gene polymorphisms increased the risk to have HCC among individuals with CG or GG of CCL5-28, and GA or AA of CCL-403, and GA or AA of CCR5 (AOR=3.42; 95% CI=1.39-8.38, p=0.007) compared to individuals with wild genotypes of CCL5-28, CCL-403, and CCR5. Also, alcohol or tobacco consumption increased the risk to have HCC among subjects with CG heterozygotes of CCL5-28 (alcohol: p=0.001; tobacco: p=0.006), AA homozygotes (alcohol: p=0.0004; tobacco: p≤0.0001) or GA heterozygotes (tobacco: p=0.03) of CCL5-403, and AA homozygotes of CCR5 (alcohol: p=0.02; tobacco: p=0.02), respectively. Gene polymorphisms of CCL5-28, CCL5-403, and CCR5 play an important factor for the susceptibility of HCC, respectively. The synergic effects of these two gene polymorphisms to tobacco or alcohol consumption significantly increase the risk to develop HCC.
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Affiliation(s)
- Hsiu-Ting Tsai
- School of Nursing, Chung Shan Medical University, 110, Section 1, Chien-Kuo N. Road, Taichung, Taiwan, ROC.
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Zhu J, Feng A, Sun J, Jiang Z, Zhang G, Wang K, Hu S, Qu X. Increased CD4(+) CD69(+) CD25(-) T cells in patients with hepatocellular carcinoma are associated with tumor progression. J Gastroenterol Hepatol 2011; 26:1519-26. [PMID: 21557772 DOI: 10.1111/j.1440-1746.2011.06765.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIM A new subset of Treg cells, CD4(+) CD69(+) CD25(-) T cells, has been identified in mice. Herein, we aimed to identify this subset of T cells and to evaluate its function in patients with hepatocellular carcinoma (HCC). METHODS We detected CD4(+) CD69(+) CD25(-) T cells and its expression of CCR6 and transforming growth factor-β1 (TGF-β1) in peripheral blood of 91 HCC patients, 38 chronic hepatitis patients and 34 healthy donors by flow cytometry. CD4(+) CD69(+) CD25(-) T cells in HCC tissues were also analyzed. RESULTS CD4(+) CD69(+) CD25(-) T cells were significantly increased in peripheral blood of HCC patients compared with healthy persons and chronic hepatitis patients (8.74% ± 0.42% vs 4.55% ± 0.33% and 5.15% ± 0.36%, P < 0.0001). The percentage of peripheral CD4(+) CD69(+) CD25(-) T cells was significantly higher in HCC patients with Tumor Node Metastasis (TNM) stage III plus IV (P < 0.05). Patients with large tumor size and tumor vascular invasion were inclined to obtain high percentage of CD4(+) CD69(+) CD25(-) T cells (P < 0.05). The frequency of membrane-bound TGF-β1 positive cells in CD4(+) CD69(+) CD25(-) T cells from HCC patients was higher than that from the other two groups (P < 0.0001). A considerable proportion of CD4(+) CD69(+) CD25(-) T cells were present in HCC tissues, which has significant correlation with tumor size and TNM stage. Few CD4(+) CD69(+) CD25(-) T cells express CCR6 both in peripheral blood and tumor tissues from HCC patients. CONCLUSIONS Increased CD4(+) CD69(+) CD25(-) T cells in HCC patients are significantly correlated with tumor size, vascular invasion and TNM stage. Thus, increased CD4(+) CD69(+) CD25(-) T cells exert a critical role in HCC progression and might be a clinically aggressive phenotype of HCC.
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Affiliation(s)
- Jiankang Zhu
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
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Maeda M, Nishimura Y, Hayashi H, Kumagai N, Chen Y, Murakami S, Miura Y, Hiratsuka JI, Kishimoto T, Otsuki T. Decreased CXCR3 expression in CD4+ T cells exposed to asbestos or derived from asbestos-exposed patients. Am J Respir Cell Mol Biol 2011; 45:795-803. [PMID: 21357438 DOI: 10.1165/rcmb.2010-0435oc] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Asbestos causes malignant tumors such as lung cancer and malignant mesothelioma (MM). To determine whether asbestos exposure causes reduction of antitumor immunity, we established an in vitro T-cell line model of low-dose and continuous exposure to asbestos using an human adult T-cell leukemia virus-1 immortalized human polyclonal T-cell line, MT-2, and revealed that MT-2 cells exposed continuously to asbestos showed resistance to asbestos-induced apoptosis. In addition, the cells presented reduction of surface CXCR3 chemokine receptor expression and IFN-γ production. In this study, to confirm that these findings are suitable for clinical translation, surface CXCR3 and IFN-γ expression were analyzed using freshly isolated human CD4(+) T cells derived from healthy donors and patients with pleural plaque (PP) or MM. The results revealed that CXCR3 and IFN-γ expression in the ex vivo model were reduced in some cases. Additionally, CXCR3 expression in CD4(+) T cells from PPs and MMs was significantly reduced compared with that from healthy donors, and CD4(+) T cells from patients with MMs exhibited a marked reduction in IFN-γ mRNA levels after stimulation in vitro. Moreover, CD4(+)CXCR3(+) T cells in lymphocytes from MMs showed a tendency for an inverse correlation with its ligand CXCL10/IP10 in plasma. These findings show reduction of antitumor immune function in asbestos-exposed patients and indicate that CXCR3, IFN-γ, and CXCL10/IP10 may be candidates to detect and monitor disease status.
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Affiliation(s)
- Megumi Maeda
- Department of Hygiene, Kawasaki Medical School, Okayama, Japan.
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Low expression of chemokine receptor CCR5 in human colorectal cancer correlates with lymphatic dissemination and reduced CD8+ T-cell infiltration. Int J Colorectal Dis 2010; 25:417-24. [PMID: 20054600 DOI: 10.1007/s00384-009-0868-y] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/24/2009] [Indexed: 02/04/2023]
Abstract
BACKGROUND Chemokines and their receptors have been proposed to distinctly contribute to tumor growth, dissemination, and local immune escape. The aim of this study was to evaluate the relevance of the chemokine receptor CCR5 expression for the progression of human colorectal cancer. METHODS CCR5 expression was assessed by RT-PCR analysis in 103 colorectal cancer patients. Intensity of CCR5 expression was correlated with both tumor and patient characteristics. Infiltration of tumor margins with CD8(+) T cells in the context of CCR5 expression was analyzed by immunohistochemistry in additional 18 colorectal cancer specimens. RESULTS Human colorectal cancer revealed variable intensities of CCR5 expression ranging from absent (48/103: 47%), weak (30/103: 29%), intermediate (13/103: 13%), to strong (12/103: 12%). Absent or weak CCR5 expression was significantly associated with advanced UICC stages (P=0.02) and lymphatic metastasis (P=0.05). In addition, CCR5 expression positively correlated with CD8(+) T-cell infiltration in tumor margins (P=0.001). CONCLUSION In summary, intermediate and strong CCR5 expression was significantly associated with nonmetastatic colorectal cancer and increased CD8(+) T-cell infiltration.
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12
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Lee JS, Lee JY, Son JW, Oh JH, Shin DM, Yuk JM, Song CH, Paik TH, Jo EK. Expression and regulation of the CC-chemokine ligand 20 during human tuberculosis. Scand J Immunol 2007; 67:77-85. [PMID: 18052967 DOI: 10.1111/j.1365-3083.2007.02040.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
CC-chemokine ligand 20 (CCL20), a unique chemokine ligand of CC-chemokine receptor 6 (CCR6), play roles in various pathologic conditions. However, the characteristic expression profiles of CCL20 during human tuberculosis (TB) have been largely unknown. The present study analyzed the production and regulatory mechanisms of CCL20 in peripheral blood mononuclear cells (PBMC) and monocyte-derived macrophages (MDM) from active pulmonary TB patients and healthy controls (HC). The 30-kDa antigen (Ag) of Mycobacterium tuberculosis actively induced the production of CCL20 by human PBMC and MDM. A comparative analysis revealed that the expression of CCL20 protein was prominently up-regulated in PBMC, MDM, bronchoalveolar lavage fluids (not in sera) from TB patients compared with the corresponding cells or body fluids from HC. Blockade of either tumour necrosis factor-alpha or interferon-gamma, but not interleukin-10, significantly attenuated the CCL20 production. In addition, recombinant CCL20 induced CCR6 expression by CD45RO+ T lymphocytes in a dose-dependent manner. Furthermore, the expression of CCR6 was significantly increased in CD45RO+ T lymphocytes from TB patients, as compared with those from HC. Pharmacological inhibition studies showed that the 30-kDa Ag-induced CCL20 mRNA expression involves mitogen-activated protein kinases (MAPK; extracellular signal-regulated kinase 1/2 and p38)- and NF-kappaB-dependent signalling. Collectively, the present study demonstrated that TB patients show the up-regulated expression of CCL20, which is modulated by proinflammatory cytokines, and through MAPK/NF-kappaB-mediated transcriptional mechanisms. The findings suggest important implications of potential roles of CCL20-CCR6 in immunopathogenesis of TB.
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Affiliation(s)
- J-S Lee
- Department of Microbiology, College of Medicine, Chungnam National University, Daejeon, South Korea
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Wald O, Weiss ID, Galun E, Peled A. Chemokines in hepatitis C virus infection: Pathogenesis, prognosis and therapeutics. Cytokine 2007; 39:50-62. [PMID: 17629707 DOI: 10.1016/j.cyto.2007.05.013] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2007] [Revised: 05/20/2007] [Accepted: 05/25/2007] [Indexed: 12/20/2022]
Abstract
Hepatitis C virus infection and its associated liver inflammatory disease is a major global health problem affecting over 170 million people worldwide. Following viral infection, multiple pro-inflammatory mediators contribute to recruitment of immune cells to the liver and to the generation of an anti-viral immune response. However, when this vigorous immune response fails to eliminate the virus, chronic infection is established. This in turn, results in an ongoing process of inflammation, regeneration and fibrosis that in many cases leads to the development of cirrhosis and of hepatocellular carcinoma. Multiple recent publications mark chemokines and their receptors as key players in leukocyte recirculation through the inflamed liver. Furthermore, chemokines may also be involved in liver regeneration, fibrosis, and in malignant transformation, which is induced by the persistence of inflammation. Accumulating data indicates that distinct chemokines and chemokine receptors may be associated with different stages of the chronic hepatitis C virus infection-associated liver disease. Multiple small molecules and peptide antagonizing chemokines and their receptors are in advanced phase 3 and phase 2 clinical trials. In the near future, such drugs are expected to enter clinical use raising the question whether they may be applicable for the treatment of chronic viral infection-associated liver disease. In this review, recent advances in understanding the role of chemokines and their receptors in the pathogenesis of chronic viral infection-associated liver disease are presented. Furthermore, the clinical implications of these novel findings, which mark chemokines as prognostic markers and therapeutic targets for immune-modulation during chronic liver viral infection, are documented.
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Affiliation(s)
- Ori Wald
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, P.O. Box 12000, Jerusalem 91120, Israel.
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Rubie C, Frick VO, Wagner M, Weber C, Kruse B, Kempf K, König J, Rau B, Schilling M. Chemokine expression in hepatocellular carcinoma versus colorectal liver metastases. World J Gastroenterol 2006; 12:6627-33. [PMID: 17075975 PMCID: PMC4125667 DOI: 10.3748/wjg.v12.i41.6627] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate and compare the expression profiles of CXCL12 (SDF-1), CCL19 (MIP-3β), CCL20 (MIP-3α) and CCL21 (6Ckine, Exodus2) and their receptors on RNA and protein levels in hepatocellular carcinoma (HCC) versus colorectal liver metastases (CRLM) and to elucidate their impact on the carcinogenesis and progression of malignant liver diseases.
METHODS: Chemokine expression was analyzed by RT-PCR and ELISA in 11 cases of HCC specimens and in 23 cases of CRLM and corresponding adjacent non-tumorous liver tissues, respectively. Expressions of their receptors CXCR4, CCR6 and CCR7 were analyzed by RT-PCR and Western blot analysis in the same cases of HCC and CRLM.
RESULTS: Significant up-regulation for CCL20/CCR6 was detected in both cancer types. Moreover, CCL20 demonstrated significant overexpression in CRLM in relation to the HCC tissues. Being significantly up-regulated only in CRLM, CXCR4 displayed an aberrant expression pattern with respect to the HCC tissues.
CONCLUSION: Correlation of CXCR4 expression with CRLM suggests CXCR4 as a potential predictive factor for CRLM. High level expression of CCL20 and its receptor CCR6 in HCC and CRLM with marked up-regulation of CCL20 in CRLM in relation to HCC tissues indicates involvement of the CCL20/CCR6 ligand-receptor pair in the carcinogenesis and progression of hepatic malignancies.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Chemokine CCL20
- Chemokine CXCL12
- Chemokines/genetics
- Chemokines/metabolism
- Chemokines, CC/genetics
- Chemokines, CC/metabolism
- Chemokines, CXC/genetics
- Chemokines, CXC/metabolism
- Colorectal Neoplasms/genetics
- Colorectal Neoplasms/metabolism
- Colorectal Neoplasms/pathology
- Female
- Gene Expression Regulation, Neoplastic/genetics
- Humans
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/secondary
- Macrophage Inflammatory Proteins/genetics
- Macrophage Inflammatory Proteins/metabolism
- Male
- Middle Aged
- Neoplasm Metastasis/genetics
- Neoplasm Metastasis/pathology
- Predictive Value of Tests
- Receptors, CCR6
- Receptors, CXCR4/genetics
- Receptors, CXCR4/metabolism
- Receptors, Chemokine/genetics
- Receptors, Chemokine/metabolism
- Up-Regulation
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Affiliation(s)
- Claudia Rubie
- Department of General-, Visceral-, Vascular- and Paediatric Surgery, Universitatsklinikum des Saarlandes, Chirurgische Klinik, Gebaude 57, Homburg/Saar 66421, Germany.
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Rubie C, Frick VO, Wagner M, Rau B, Weber C, Kruse B, Kempf K, Tilton B, König J, Schilling M. Enhanced expression and clinical significance of CC-chemokine MIP-3 alpha in hepatocellular carcinoma. Scand J Immunol 2006; 63:468-77. [PMID: 16764701 DOI: 10.1111/j.1365-3083.2006.001766.x] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most frequent visceral neoplasms worldwide. Using RT-PCR, ELISA, microdissection and immunohistochemistry, we investigated the expression profiles of CCL19, CCL20, CCL21 and CXCL12 and their receptors in tumourous and tumour neighbouring tissues from patients with HCC and in nonmalignant liver lesions, respectively. All chemokines were found to be expressed in normal liver and HCC tissues, yet CCL20 was the only chemokine showing significant upregulation in HCC tissues. Clinicopathological analysis revealed a distinct increase in CCL20 expression rates in HCC tissues of grade III tumours in comparison to HCC tissues from grade II tumours. On mRNA level, only chemokine receptor CCR6 revealed significant upregulation in HCC tissues. However, immunohistochemical studies indicated a marked CCR6 expression accumulated in a streak of normal cells along the tumour invasion front in all our HCC specimens which could provide a stimulative signal for the tumour to further expand. The present findings show significant overexpression of CCL20 in the tumour tissues and marked overexpression of the corresponding receptor CCR6 in the tumour invasion front of HCC patients in comparison to normal liver. Moreover, CCL20 expression was found to correlate with tumour grade and therefore, we suggest that the CCL20/CCR6 system may be involved in hepatocarcinogenesis.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Biomarkers, Tumor/biosynthesis
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/physiology
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Chemokine CCL20
- Chemokines, CC/biosynthesis
- Chemokines, CC/genetics
- Chemokines, CC/physiology
- Female
- Humans
- Liver Neoplasms/immunology
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Macrophage Inflammatory Proteins/biosynthesis
- Macrophage Inflammatory Proteins/genetics
- Macrophage Inflammatory Proteins/physiology
- Male
- Middle Aged
- Receptors, CCR6
- Receptors, Chemokine/physiology
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Affiliation(s)
- C Rubie
- Department of General-, Visceral-, Vascular- and Paediatric Surgery, University of the Saarland, Homburg/Saar, Germany.
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Liu YQ, Poon RT, Hughes J, Li QY, Yu WC, Fan ST. Desensitization of T lymphocyte function by CXCR3 ligands in human hepatocellular carcinoma. World J Gastroenterol 2005; 11:164-70. [PMID: 15633209 PMCID: PMC4205395 DOI: 10.3748/wjg.v11.i2.164] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Despite the presence of lymphocyte infiltration, human hepatocellular carcinoma (HCC) is typically a rapidly progressive disease. The mechanism of regulation of lymphocyte migration is poorly understood. In this study, we investigated various factors regulating T cell migration in HCC patients. We examined serum CXC chemokine levels in HCC patients and demonstrated the production of CXC chemokines by HCC cell lines. We determined the effect of both HCC patient serum and tumor cell conditioned supernatant upon lymphocyte expression of chemokine receptor CXCR3 as well as lymphocyte migration. Lastly, we examined the chemotactic responses of lymphocytes derived from HCC patients.
METHODS: The serum chemokines IP-10 (CXCL10) and Mig (CXCL9) levels were measured by cytometric bead array (CBA) and the tumor tissue IP-10 concentration was measured by ELISA. The surface expression of CXCR3 on lymphocytes was determined by flow cytometry. The migratory function of lymphocytes to the corresponding chemokines was assessed using an in vitro chemotactic assay. Phosphorylation of extracellular signal-regulated kinase (ERK) was determined by Western blot analysis.
RESULTS: Increased levels of IP-10 and Mig were detected in HCC patient serum and culture supernatants of HCC cell lines. The IP-10 concentration in the tumor was significantly higher than that in the non-involved adjacent liver tissues. HCC cell lines secreted functional chemokines that induced a CXCR3-specific chemotactic response of lymphocytes. Furthermore, tumor-cell-derived chemokines induced initial rapid phosphorylation of lymphocyte ERK followed by later inhibition of ERK phosphorylation. The culture of normal lymphocytes with HCC cell line supernatants or medium containing serum from HCC patients resulted in a significant reduction in the proportion of lymphocytes exhibiting surface expression of CXCR3. The reduction in T cell expression of CXCR3 resulted in reduced migration toward the ligand IP-10, and both CD4+ and CD8+ T cells from HCC patients exhibited diminished chemotactic responses to IP-10 in vitro compared to T cells from healthy control subjects.
CONCLUSION: This study demonstrates functional desensitization of the chemokine receptor CXCR3 in lymphocytes from HCC patients by CXCR3 ligands secreted by tumor cells. This may cause lymphocyte dysfunction and subsequently impaired immune defense against the tumor.
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Affiliation(s)
- Yu-Qing Liu
- Centre for the Study of Liver Disease and Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong, China
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