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Jeng LB, Shih FY, Chan WL, Teng CF. Cytokine biomarkers for independent prediction of hepatocellular carcinoma prognosis. Discov Oncol 2025; 16:421. [PMID: 40155531 PMCID: PMC11953510 DOI: 10.1007/s12672-025-02188-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Accepted: 03/20/2025] [Indexed: 04/01/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Although various therapeutic modalities have been established for HCC, the overall outcomes of patients after treatment remain unsatisfactory, highlighting the need for valuable independent prognostic biomarkers. Cytokines are a large group of multifunctional secretory proteins and play critical roles in regulating development and progression of many cancer types, including HCC. Moreover, the expression levels of many cytokines in tumor/peritumor tissues and serum/plasma samples have been validated as important biomarkers for independently predicting the prognosis of HCC patients. This review provides a comprehensive summary of literature evidence for the independent prognostic significance of cytokine biomarkers in HCC patients receiving different therapies.
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Affiliation(s)
- Long-Bin Jeng
- Organ Transplantation Center, China Medical University Hospital, Taichung, 404, Taiwan
- Department of Surgery, China Medical University Hospital, Taichung, 404, Taiwan
- Cell Therapy Center, China Medical University Hospital, Taichung, 404, Taiwan
| | - Fu-Ying Shih
- Ph.D. Program for Biotech Pharmaceutical Industry, China Medical University, Taichung, 404, Taiwan
| | - Wen-Ling Chan
- Department of Public Health, College of Public Health, China Medical University, Taichung, 404, Taiwan
- Department of Healthcare Administration, College of Medical and Health Science, Asia University, Taichung, 413, Taiwan
| | - Chiao-Fang Teng
- Organ Transplantation Center, China Medical University Hospital, Taichung, 404, Taiwan.
- Graduate Institute of Biomedical Sciences, China Medical University, No.91, Hsueh-Shih Rd., Northern Dist., Taichung, 404, Taiwan.
- Master Program for Cancer Biology and Drug Discovery, China Medical University, Taichung, 404, Taiwan.
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Zhou M, Xia Y, Wang S. IL35 modulates HBV-related HCC progression via IL6-STAT3 signaling. Sci Rep 2025; 15:6293. [PMID: 39984567 PMCID: PMC11845586 DOI: 10.1038/s41598-025-89015-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Accepted: 02/03/2025] [Indexed: 02/23/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a common malignant tumor with incidences reported worldwide along with high mortality rates. It is a significant public health concern as hepatitis B virus (HBV) infection is the leading cause of HCC. IL35, a novel heterodimeric cytokine belonging to the IL-12 family, comprises two subunits, namely IL-12p35 and Epstein-Barr virus-induced gene 3 (EBI3). They are crucial in regulating immune responses to tumors and infectious diseases. However, their function in HBV-related HCC is unclear. The objective of this study was to identify the regulatory role of IL35 in the occurrence of HBV-related HCC and its underlying molecular mechanisms. The expression of IL35 was enhanced in human HBV-related HCC tissues. HBV induction, particularly HBx, enhanced the expression of IL-35 in hepatoma cell lines. Silencing IL-35 promoted apoptosis and suppressed proliferation, cell cycle progression, migration, and invasion of HBx-induced hepatoma cells. Mechanistically, silencing IL-35 effectively inhibited the activation of the IL-6-STAT3 signaling pathway by suppressing the expression of IL-6 and nuclear import and phosphorylation of STAT3 in HBx-induced hepatoma cells. Therefore, inhibiting the IL6-STAT3 signaling pathway by silencing IL35 effectively alleviated the progression of HBV-related HCC. IL35 is a potential target for treating HBV-related HCC.
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Affiliation(s)
- Mingran Zhou
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230002, China
- Anhui Public Health Clinical Center, Hefei, 230002, China
| | - Yunhong Xia
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230002, China
- Anhui Public Health Clinical Center, Hefei, 230002, China
| | - Shuomin Wang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230002, China.
- Anhui Public Health Clinical Center, Hefei, 230002, China.
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Wang H, Wang T, Yan S, Tang J, Zhang Y, Wang L, Xu H, Tu C. Crosstalk of pyroptosis and cytokine in the tumor microenvironment: from mechanisms to clinical implication. Mol Cancer 2024; 23:268. [PMID: 39614288 PMCID: PMC11607834 DOI: 10.1186/s12943-024-02183-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Accepted: 11/22/2024] [Indexed: 12/01/2024] Open
Abstract
In the realm of cancer research, the tumor microenvironment (TME) plays a crucial role in tumor initiation and progression, shaped by complex interactions between cancer cells and surrounding non-cancerous cells. Cytokines, as essential immunomodulatory agents, are secreted by various cellular constituents within the TME, including immune cells, cancer-associated fibroblasts, and cancer cells themselves. These cytokines facilitate intricate communication networks that significantly influence tumor initiation, progression, metastasis, and immune suppression. Pyroptosis contributes to TME remodeling by promoting the release of pro-inflammatory cytokines and sustaining chronic inflammation, impacting processes such as immune escape and angiogenesis. However, challenges remain due to the complex interplay among cytokines, pyroptosis, and the TME, along with the dual effects of pyroptosis on cancer progression and therapy-related complications like cytokine release syndrome. Unraveling these complexities could facilitate strategies that balance inflammatory responses while minimizing tissue damage during therapy. This review delves into the complex crosstalk between cytokines, pyroptosis, and the TME, elucidating their contribution to tumor progression and metastasis. By synthesizing emerging therapeutic targets and innovative technologies concerning TME, this review aims to provide novel insights that could enhance treatment outcomes for cancer patients.
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Affiliation(s)
- Hua Wang
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Tao Wang
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Shuxiang Yan
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Jinxin Tang
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Yibo Zhang
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Liming Wang
- School of Biomedical Sciences, Hunan University, Changsha, Hunan, 410011, China.
| | - Haodong Xu
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China.
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China.
- Center for Precision Health, McWilliams School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
| | - Chao Tu
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China.
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China.
- Shenzhen Research Institute of Central South University, Guangdong, 518063, China.
- Hunan Engineering Research Center of AI Medical Equipment, The Second Xiangya Hospital of Central, South University, Changsha, Hunan, 410011, China.
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Nakano T, Goto S, Chen CL. Mechanisms of Tolerance Induction in Liver Transplantation: Lessons Learned from Fetomaternal Tolerance, Autoimmunity and Tumor Immunity. Int J Mol Sci 2024; 25:9331. [PMID: 39273280 PMCID: PMC11395488 DOI: 10.3390/ijms25179331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 08/08/2024] [Accepted: 08/22/2024] [Indexed: 09/15/2024] Open
Abstract
Since the first published report of experimental kidney transplantation in dogs in 1902, there were many experimental and clinical trials of organ transplantation, with many sacrifices. After the establishment of the surgical technique and the discovery of immunosuppressive drugs, transplantation became the definitive treatment strategy for patients with terminal organ failure. However, this is not a common therapy method due to the difficulty of solving the fundamental issues behind organ transplantation, including the shortage of donor graft, potential risks of transplant surgery and economic capability. The pre- and post-transplant management of recipients is another critical issue that may affect transplant outcome. Most liver transplant recipients experience post-transplant complications, including infection, acute/chronic rejection, metabolic syndrome and the recurrence of hepatocellular carcinoma. Therefore, the early prediction and diagnosis of these complications may improve overall and disease-free survival. Furthermore, how to induce operational tolerance is the key to achieving the ultimate goal of transplantation. In this review, we focus on liver transplantation, which is known to achieve operational tolerance in some circumstances, and the mechanical similarities and differences between liver transplant immunology and fetomaternal tolerance, autoimmunity or tumor immunity are discussed.
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Affiliation(s)
- Toshiaki Nakano
- Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Taoyuan 333, Taiwan
- Liver Transplantation Center and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
| | - Shigeru Goto
- Liver Transplantation Center and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
- Nobeoka Medical Check Center, Fukuoka Institution of Occupational Health, Nobeoka 882-0872, Japan
- School of Pharmacy, Shujitsu University, Okayama 703-8516, Japan
| | - Chao-Long Chen
- Liver Transplantation Center and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
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Gan W, Sun BY, Yang ZF, Ye C, Wang ZT, Zhou C, Sun GQ, Yi Y, Qiu SJ. Enhancing hepatocellular carcinoma management: prognostic value of integrated CCL17, CCR4, CD73, and HHLA2 expression analysis. J Cancer Res Clin Oncol 2024; 150:325. [PMID: 38914802 PMCID: PMC11196339 DOI: 10.1007/s00432-024-05832-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Accepted: 06/03/2024] [Indexed: 06/26/2024]
Abstract
PURPOSE Hepatocellular carcinoma (HCC) is a critical global health concern, with existing treatments benefiting only a minority of patients. Recent findings implicate the chemokine ligand 17 (CCL17) and its receptor CCR4 as pivotal players in the tumor microenvironment (TME) of various cancers. This investigation aims to delineate the roles of CCL17 and CCR4 in modulating the tumor's immune landscape, assessing their potential as therapeutic interventions and prognostic markers in HCC. METHODS 873 HCC patients post-radical surgery from 2008 to 2012 at Zhongshan Hospital, Fudan University were retrospectively examined. These individuals were stratified into a training cohort (n = 354) and a validation cohort (n = 519). Through immunohistochemical analysis on HCC tissue arrays, the expressions of CCL17, CCR4, CD73, CD47, HHLA2, and PD-L1 were quantified. Survival metrics were analyzed using the Cox model, and a prognostic nomogram was devised via R software. RESULTS The investigation confirmed the presence of CCL17 and CCR4 within the cancerous and stromal compartments of HCC tissues, associating their heightened expression with adverse clinical markers and survival outcomes. Notably, the interplay between CD73 and CCR4 expression in tumor stroma highlighted a novel cellular entity, CCR4 + CD73 + stromal cells, impacting overall and relapse-free survival. A prognostic nomogram amalgamating these immunological markers and clinical variables was established, offering refined prognostic insights and aiding in the management of HCC. The findings suggest that reduced CCR4 and CCR4 + CD73 + cell prevalence may forecast improved outcomes post-TACE. CONCLUSION This comprehensive evaluation of CCR4, CCL17, and associated markers introduces a nuanced understanding of the HCC immunological milieu, proposing CCR4 + CD73 + stromal cells as critical to HCC pathogenesis and patient stratification.
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Affiliation(s)
- Wei Gan
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Bao-Ye Sun
- Department of Liver Surgery and Transplantation & Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Zhongshan Hospital, Liver Cancer Institute, Fudan University, Shanghai, China
| | - Zhang-Fu Yang
- Department of Liver Surgery and Transplantation & Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Zhongshan Hospital, Liver Cancer Institute, Fudan University, Shanghai, China
| | - Cheng Ye
- Department of Otolaryngology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou Medical University, Wenzhou, China
| | - Zhu-Tao Wang
- Department of Liver Surgery and Transplantation & Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Zhongshan Hospital, Liver Cancer Institute, Fudan University, Shanghai, China
| | - Cheng Zhou
- Department of Liver Surgery and Transplantation & Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Zhongshan Hospital, Liver Cancer Institute, Fudan University, Shanghai, China
| | - Guo-Qiang Sun
- Department of Liver Surgery and Transplantation & Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Zhongshan Hospital, Liver Cancer Institute, Fudan University, Shanghai, China
| | - Yong Yi
- Department of Liver Surgery and Transplantation & Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Zhongshan Hospital, Liver Cancer Institute, Fudan University, Shanghai, China.
| | - Shuang-Jian Qiu
- Department of Liver Surgery and Transplantation & Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Zhongshan Hospital, Liver Cancer Institute, Fudan University, Shanghai, China.
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Yang C, Dong L, Zhong J. Immunomodulatory effects of iTr35 cell subpopulation and its research progress. Clin Exp Med 2024; 24:41. [PMID: 38386086 PMCID: PMC10884179 DOI: 10.1007/s10238-024-01303-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 01/24/2024] [Indexed: 02/23/2024]
Abstract
The spotlight in recent years has increasingly focused on inducible regulatory T cells 35 (iTr35), a novel subpopulation of regulatory T cells characterized by phenotypic stability, heightened reactivity, and potent immunosuppressive function through the production of IL-35. Despite being in the exploratory phase, research on iTr35 has garnered significant interest. In this review, we aim to consolidate our understanding of the biological characteristics and immunomodulatory mechanisms of iTr35, offering fresh perspectives that may pave the way for its potential applications in disease diagnosis and treatment.
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Affiliation(s)
- Chenxi Yang
- Department of Rheumatology and Immunology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Lingli Dong
- Department of Rheumatology and Immunology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
| | - Jixin Zhong
- Department of Rheumatology and Immunology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
- Institute of Allergy and Clinical Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
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Wang X, Yuan Z, Li Z, He X, Zhang Y, Wang X, Su J, Wu X, Li M, Du F, Chen Y, Deng S, Zhao Y, Shen J, Yi T, Xiao Z. Key oncogenic signaling pathways affecting tumor-infiltrating lymphocytes infiltration in hepatocellular carcinoma: basic principles and recent advances. Front Immunol 2024; 15:1354313. [PMID: 38426090 PMCID: PMC10902128 DOI: 10.3389/fimmu.2024.1354313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 01/29/2024] [Indexed: 03/02/2024] Open
Abstract
The incidence of hepatocellular carcinoma (HCC) ranks first among primary liver cancers, and its mortality rate exhibits a consistent annual increase. The treatment of HCC has witnessed a significant surge in recent years, with the emergence of targeted immune therapy as an adjunct to early surgical resection. Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) has shown promising results in other types of solid tumors. This article aims to provide a comprehensive overview of the intricate interactions between different types of TILs and their impact on HCC, elucidate strategies for targeting neoantigens through TILs, and address the challenges encountered in TIL therapies along with potential solutions. Furthermore, this article specifically examines the impact of oncogenic signaling pathways activation within the HCC tumor microenvironment on the infiltration dynamics of TILs. Additionally, a concise overview is provided regarding TIL preparation techniques and an update on clinical trials investigating TIL-based immunotherapy in solid tumors.
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Affiliation(s)
- Xiang Wang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Zijun Yuan
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Zhengbo Li
- Department of Laboratory Medicine, The Longmatan District People’s Hospital, Luzhou, China
| | - Xinyu He
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Yinping Zhang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Xingyue Wang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Jiahong Su
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Fukuan Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Yu Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Shuai Deng
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Tao Yi
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, Hong Kong SAR, China
| | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
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Yi P, Yu W, Xiong Y, Dong Y, Huang Q, Lin Y, Du Y, Hua F. IL-35: New Target for Immunotherapy Targeting the Tumor Microenvironment. Mol Cancer Ther 2024; 23:148-158. [PMID: 37988561 DOI: 10.1158/1535-7163.mct-23-0242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 08/15/2023] [Accepted: 11/10/2023] [Indexed: 11/23/2023]
Abstract
Interleukin 35(IL-35) is a newly discovered inhibitory cytokine of the IL12 family. More recently, IL-35 was found to be increased in the tumor microenvironment (TME) and peripheral blood of many patients with cancer, indicating that it plays an important role in the TME. Tumors secrete cytokines that recruit myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Treg) into the TME to promote malignant progression, which is a great challenge for cancer treatment. Radiotherapy causes serious adverse effects, and tumor resistance to immune checkpoint inhibitors is still an unsolved challenge. Thus, new cancer therapy approaches are urgently needed. Numerous studies have shown that IL-35 can recruit immunosuppressive cells to enable tumor immune escape by promoting the conversion of immune cells into a tumor growth-promoting phenotype as well as facilitating tumor angiogenesis. IL-35-neutralizing antibodies were found to boost the chemotherapeutic effect of gemcitabine and considerably reduce the microvascular density of pancreatic cancer in mice. Therefore, targeting IL-35 in the TME provides a promising cancer treatment target. In addition, IL-35 may be used as an independent prognostic factor for some tumors in the near future. This review intends to reveal the interplay of IL-35 with immune cells in the TME, which may provide new options for the treatment of cancer.
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Affiliation(s)
- Pengcheng Yi
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, P.R. China
- Key Laboratory of Anesthesiology of Jiangxi Province, Nanchang City, Jiangxi Province, P.R. China
| | - Wenjun Yu
- Fuzhou First People's Hospital of Jiangxi Province, Fuzhou City, Jiangxi Province, P.R. China
| | - Yanhong Xiong
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, P.R. China
- Key Laboratory of Anesthesiology of Jiangxi Province, Nanchang City, Jiangxi Province, P.R. China
| | - Yao Dong
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, P.R. China
- Key Laboratory of Anesthesiology of Jiangxi Province, Nanchang City, Jiangxi Province, P.R. China
| | - Qiang Huang
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, P.R. China
- Key Laboratory of Anesthesiology of Jiangxi Province, Nanchang City, Jiangxi Province, P.R. China
| | - Yue Lin
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, P.R. China
- Key Laboratory of Anesthesiology of Jiangxi Province, Nanchang City, Jiangxi Province, P.R. China
| | - Yunfei Du
- Department of Anesthesiology, Nanchang Central Hospital, Nanchang, Jiangxi, China
| | - Fuzhou Hua
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, P.R. China
- Key Laboratory of Anesthesiology of Jiangxi Province, Nanchang City, Jiangxi Province, P.R. China
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Li X, Zhu Q, Ye B, Zhu C, Dong Y, Ni Q. JNK/c-Jun pathway activation is essential for HBx-induced IL-35 elevation to promote persistent HBV infection. J Clin Lab Anal 2023; 37:e24860. [PMID: 36916737 PMCID: PMC10098067 DOI: 10.1002/jcla.24860] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 02/16/2023] [Accepted: 03/02/2023] [Indexed: 03/15/2023] Open
Abstract
BACKGROUND Immunoregulation plays pivotal roles during chronic hepatitis B virus (HBV) infection. Studies have shown that Interleukin (IL)-35 is an important molecule associated with inadequate immune response against HBV. However, the mechanisms involved in the up-regulation of IL-35 expression during persistent HBV infection remain unknown. METHODS In this study, we constructed a plasmid expressing the HBV X protein (pCMV-HBx) to evaluate the relationship between HBx and IL-35. Activation of the JNK/c-Jun pathway was analyzed and chromatin immunoprecipitation followed by sequencing and luciferase reporter assays were performed to determine whether c-Jun could regulate IL-35 transcription. RESULTS HBx can significantly activate IL-35 promoter in both LO2 and HepG2 cells compared to the control plasmid (pCMV-Tag2) using the dual-luciferase assay. Whereas other viral proteins, such as S, preS1, the core protein, had no significant effect on IL-35 expression. Similarly, WB and qRT-PCR also showed that HBx can significantly promote IL-35 expression at protein and mRNA levels in the aforementioned cells. The relevant pathway mechanism showed that the expression of JNK and c-Jun genes was significantly higher in transfected cells carrying pCMV-HBx than in the pCMV-Tag2-transfected and -untransfected cells. WB analysis revealed that phosphorylated JNK and c-Jun were overexpressed after HBx action. Conversely, the addition of the JNK/c-Jun signaling pathway inhibitor could significantly suppress HBx-induced IL-35 expression in a dose-dependent manner. CONCLUSIONS A novel molecular mechanism of HBV-induced IL-35 expression was revealed, which involves JNK/c-Jun signaling in up-regulating IL-35 expression via HBx, resulting in transactivation of the IL-35 subunit EBI3 and p35 promoter.
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Affiliation(s)
- Xuefen Li
- Department of Laboratory Medicine, Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qiaoyun Zhu
- Central Laboratory, Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Bo Ye
- Department of Laboratory Medicine, Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Chunxia Zhu
- Department of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yuejiao Dong
- Department of Laboratory Medicine, Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qin Ni
- Department of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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10
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Xia C, Yin S, To KKW, Fu L. CD39/CD73/A2AR pathway and cancer immunotherapy. Mol Cancer 2023; 22:44. [PMID: 36859386 PMCID: PMC9979453 DOI: 10.1186/s12943-023-01733-x] [Citation(s) in RCA: 109] [Impact Index Per Article: 54.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 01/26/2023] [Indexed: 03/03/2023] Open
Abstract
Cancer development is closely associated with immunosuppressive tumor microenvironment (TME) that attenuates antitumor immune responses and promotes tumor cell immunologic escape. The sequential conversion of extracellular ATP into adenosine by two important cell-surface ectonucleosidases CD39 and CD73 play critical roles in reshaping an immunosuppressive TME. The accumulated extracellular adenosine mediates its regulatory functions by binding to one of four adenosine receptors (A1R, A2AR, A2BR and A3R). The A2AR elicits its profound immunosuppressive function via regulating cAMP signaling. The increasing evidence suggests that CD39, CD73 and A2AR could be used as novel therapeutic targets for manipulating the antitumor immunity. In recent years, monoclonal antibodies or small molecule inhibitors targeting the CD39/CD73/A2AR pathway have been investigated in clinical trials as single agents or in combination with anti-PD-1/PD-L1 therapies. In this review, we provide an updated summary about the pathophysiological function of the adenosinergic pathway in cancer development, metastasis and drug resistance. The targeting of one or more components of the adenosinergic pathway for cancer therapy and circumvention of immunotherapy resistance are also discussed. Emerging biomarkers that may be used to guide the selection of CD39/CD73/A2AR-targeting treatment strategies for individual cancer patients is also deliberated.
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Affiliation(s)
- Chenglai Xia
- Affiliated Foshan Maternity and Child Healthcare Hospital, Southern Medical University, Foshan, 528000, China. .,School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 515150, China.
| | - Shuanghong Yin
- grid.284723.80000 0000 8877 7471Affiliated Foshan Maternity and Child Healthcare Hospital, Southern Medical University, Foshan, 528000 China ,grid.488530.20000 0004 1803 6191State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Sun Yat-sen University Cancer Center, Guangzhou, 510060 China
| | - Kenneth K. W. To
- grid.10784.3a0000 0004 1937 0482School of Pharmacy, The Chinese University of Hong Kong, Hong Kong, China
| | - Liwu Fu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
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11
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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.
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Affiliation(s)
| | | | | | - Yanru Qin
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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12
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Hao Y, Dong H, Li W, Lv X, Shi B, Gao P. The Molecular Role of IL-35 in Non-Small Cell Lung Cancer. Front Oncol 2022; 12:874823. [PMID: 35719927 PMCID: PMC9204334 DOI: 10.3389/fonc.2022.874823] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Accepted: 04/25/2022] [Indexed: 12/24/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and a common cause of cancer-related death. Better understanding of the molecular mechanisms, pathogenesis, and treatment of NSCLC can help improve patient outcomes. Significant progress has been made in the treatment of NSCLC, and immunotherapy can prolong patient survival. However, the overall cure and survival rates are low, especially in patients with advanced metastases. Interleukin-35 (IL-35), an immunosuppressive factor, is associated with the onset and prognosis of various cancers. Studies have shown that IL-35 expression is elevated in NSCLC, and it is closely related to the progression and prognosis of NSCLC. However, there are few studies on the mechanism of IL-35 in NSCLC. This study discusses the role of IL-35 and its downstream signaling pathways in the pathogenesis of NSCLC and provides new insights into its therapeutic potential.
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Affiliation(s)
- Yuqiu Hao
- Department of Respiratory Medicine, Second Hospital of Jilin University, Changchun, China
| | - Hongna Dong
- Department of Respiratory Medicine, Second Hospital of Jilin University, Changchun, China
| | - Wei Li
- Department of Respiratory Medicine, Second Hospital of Jilin University, Changchun, China
| | - Xuejiao Lv
- Department of Respiratory Medicine, Second Hospital of Jilin University, Changchun, China
| | - Bingqing Shi
- Department of Respiratory Medicine, Second Hospital of Jilin University, Changchun, China
| | - Peng Gao
- Department of Respiratory Medicine, Second Hospital of Jilin University, Changchun, China
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13
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Tang Y, Ma T, Jia S, Zhang Q, Liu S, Qi L, Yang L. The Mechanism of Interleukin-35 in Chronic Hepatitis B. Semin Liver Dis 2021; 41:516-524. [PMID: 34233371 DOI: 10.1055/s-0041-1731708] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Interleukin-35 (IL-35) is a newly identified inhibitory cytokine. It has recently been found to play an extremely important role in chronic hepatitis B disease, which makes it likely to be a target for new therapies for hepatitis B malady. IL-35 modulates a variety of immune mechanisms to cause persistent viral infections, such as affecting the ratio of helper T cells, reducing the activity of cytotoxic T cells, hindering the antigen presentation capacity for dendritic cells, and increasing the transcription level of hepatitis B virus. On the other hand, IL-35 can control the inflammation caused by hepatitis B liver injury. Therefore, to seek a breakthrough in curing hepatitis B disease, the contradictory part of IL-35 in the occurrence and development of this sickness is worthy of further discussion and research. This article will systematically review the biological effects of IL-35 and the specific mechanisms affecting the disease.
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Affiliation(s)
- Ying Tang
- Diseases Center, Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, Changchun, China
| | - Tianyi Ma
- Diseases Center, Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, Changchun, China
| | - Shengnan Jia
- Diseases Center, Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, Changchun, China
| | - Qian Zhang
- Diseases Center, Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, Changchun, China
| | - Siqi Liu
- Diseases Center, Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, Changchun, China
| | - Ling Qi
- Department of Core Medical Laboratory, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
| | - Lanlan Yang
- Diseases Center, Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, Changchun, China
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14
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Liu S, Yang L, Jia S, Zhao R, Jin Z. Interleukin-35 suppresses the activity of natural killer-like B cells in patients with hepatocellular carcinoma. Int Immunopharmacol 2021; 100:108161. [PMID: 34555643 DOI: 10.1016/j.intimp.2021.108161] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 08/31/2021] [Accepted: 09/14/2021] [Indexed: 02/07/2023]
Abstract
Natural killer-like B (NKB) cells are newly identified lymphocyte subset, which present immunomodulatory property in infectious diseases through secretion of interleukin-18 (IL-18). However, the role of NKB cells function and its regulation in hepatocellular carcinoma (HCC) is not elucidated. Seventy-two HCC patients and twenty-five controls were enrolled. Peripheral and liver-infiltrating CD3-CD19+CD56+NKp46+ cells were investigated by flow cytometry. Serum IL-35 and NKB cell-secreting cytokine level was measured by ELISA. The regulatory activity of IL-35 to peripheral and liver-infiltrating NKB cells was assessed in direct co-culture system between CD8+ T cells and HepG2 cells. Peripheral NKB cells and IL-18 secretion were reduced in HCC patients, while liver-infiltrating NKB cells and IL-18 secretion were also decreased in HCC tumor sites. Increased IL-35 level was negatively correlated with NKB cell percentage and IL-18 production in HCC. NKB cells induced the elevation of CD8+ T cell cytotoxicty, and this enhancement could be inhibited by IL-18 binding protein. IL-35 stimulation dampened NKB cell percentage and IL-18 production, leading to the suppression of NKB cell-mediated CD8+ T cell cytotoxicity in HCC patients. Our current data revealed that IL-35 might suppress NKB cell activity in HCC patients.
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Affiliation(s)
- Siqi Liu
- Digestive Diseases Center, Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, Changchun, Jilin Province 130041, People's Republic of China
| | - Lanlan Yang
- Digestive Diseases Center, Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, Changchun, Jilin Province 130041, People's Republic of China
| | - Shengnan Jia
- Digestive Diseases Center, Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, Changchun, Jilin Province 130041, People's Republic of China
| | - Rui Zhao
- Digestive Diseases Center, Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, Changchun, Jilin Province 130041, People's Republic of China
| | - Zhenjing Jin
- Digestive Diseases Center, Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, Changchun, Jilin Province 130041, People's Republic of China.
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15
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Liu W, Xu C, Meng Q, Kang P. The clinical value of kinesin superfamily protein 2A in hepatocellular carcinoma. Clin Res Hepatol Gastroenterol 2021; 45:101527. [PMID: 33713978 DOI: 10.1016/j.clinre.2020.08.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 07/28/2020] [Accepted: 08/24/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND This study aimed to investigate the clinical value of kinesin superfamily protein 2A (KIF2A) in hepatocellular carcinoma (HCC) patients. METHODS This study retrospectively analyzed 196 HCC patients who underwent hepatic resection, and their preoperative clinical characteristics were collected from the medical records. Immunohistochemical (IHC) assay was performed to detect KIF2A expression, subsequently KIF2A expression was evaluated by a semi-quantitative IHC score (according to IHC staining density and intensity of positively stained cells) and then graded as KIF2A-/KIF2A+/KIF2A++/KIF2A+++ for analysis. Overall survival (OS) was calculated from the date of resection to the date of death. RESULTS Compared to adjacent tissue, both KIF2A IHC score and grade were higher in tumor tissue (Both P < 0.001). Tumor KIF2A expression was positively correlated with performance status score (P = 0.001), multifocal tumor nodule (P = 0.018), largest tumor size (P = 0.015) and Barcelona clinic liver cancer stage (P < 0.001). Regarding live function indexes, tumor KIF2A expression was positively associated with aspartate aminotransferase (P = 0.006). As to tumor markers, tumor KIF2A expression showed a trend to be positively correlated with alpha fetoprotein (P = 0.060) and carbohydrate antigen 199 (P = 0.053), but no statistical significance. Kaplan-Meier curve showed that tumor higher KIF2A expression was associated with worse OS (P < 0.001), which was further validated by multivariate Cox's regression analysis as higher an independent factor predicting shorter OS (P = 0.001). CONCLUSION KIF2A is upregulated in tumor tissue than adjacent tissue, importantly, tumor KIF2A is associated with worse liver function, raised tumor stage and poor OS in HCC patients.
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Affiliation(s)
- Wenjuan Liu
- Department of Infectious Diseases, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Chunlin Xu
- Department of Infectious Diseases, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Qingyang Meng
- Department of Infectious Diseases, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Peng Kang
- Department of Infectious Diseases, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
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16
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Granito A, Muratori L, Lalanne C, Quarneti C, Ferri S, Guidi M, Lenzi M, Muratori P. Hepatocellular carcinoma in viral and autoimmune liver diseases: Role of CD4+ CD25+ Foxp3+ regulatory T cells in the immune microenvironment. World J Gastroenterol 2021; 27:2994-3009. [PMID: 34168403 PMCID: PMC8192285 DOI: 10.3748/wjg.v27.i22.2994] [Citation(s) in RCA: 122] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 04/09/2021] [Accepted: 05/07/2021] [Indexed: 02/06/2023] Open
Abstract
More than 90% of cases of hepatocellular carcinoma (HCC) occurs in patients with cirrhosis, of which hepatitis B virus and hepatitis C virus are the leading causes, while the tumor less frequently arises in autoimmune liver diseases. Advances in understanding tumor immunity have led to a major shift in the treatment of HCC, with the emergence of immunotherapy where therapeutic agents are used to target immune cells rather than cancer cells. Regulatory T cells (Tregs) are the most abundant suppressive cells in the tumor microenvironment and their presence has been correlated with tumor progression, invasiveness, as well as metastasis. Tregs are characterized by the expression of the transcription factor Foxp3 and various mechanisms ranging from cell-to-cell contact to secretion of inhibitory molecules have been implicated in their function. Notably, Tregs amply express checkpoint molecules such as cytotoxic T lymphocyte-associated antigen 4 and programmed cell-death 1 receptor and therefore represent a direct target of immune checkpoint inhibitor (ICI) immunotherapy. Taking into consideration the critical role of Tregs in maintenance of immune homeostasis as well as avoidance of autoimmunity, it is plausible that targeting of Tregs by ICI immunotherapy results in the development of immune-related adverse events (irAEs). Since the use of ICI becomes common in oncology, with an increasing number of new ICI currently under clinical trials for cancer treatment, the occurrence of irAEs is expected to dramatically rise. Herein, we review the current literature focusing on the role of Tregs in HCC evolution taking into account their opposite etiological function in viral and autoimmune chronic liver disease, and we discuss their involvement in irAEs due to the new immunotherapies.
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Affiliation(s)
- Alessandro Granito
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, University of Bologna, Bologna 40138, Italy
- Center for the Study and Treatment of Autoimmune Diseases of the Liver and Biliary System, Department of Medical and Surgical Sciences, University of Bologna, Bologna 40138, Italy
| | - Luigi Muratori
- Division of Internal Medicine and Immunorheumatology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Center for the Study and Treatment of Autoimmune Diseases of the Liver and Biliary System, University of Bologna, Bologna 40138, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna 40138, Italy
| | - Claudine Lalanne
- Division of Internal Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Center for the Study and Treatment of Autoimmune Diseases of the Liver and Biliary System, Bologna 40138, Italy
| | - Chiara Quarneti
- Division of Internal Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Center for the Study and Treatment of Autoimmune Diseases of the Liver and Biliary System, Bologna 40138, Italy
| | - Silvia Ferri
- Division of Internal Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Center for the Study and Treatment of Autoimmune Diseases of the Liver and Biliary System, Bologna 40138, Italy
| | - Marcello Guidi
- Division of Internal Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Center for the Study and Treatment of Autoimmune Diseases of the Liver and Biliary System, Bologna 40138, Italy
| | - Marco Lenzi
- Division of Internal Medicine and Immunorheumatology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Center for the Study and Treatment of Autoimmune Diseases of the Liver and Biliary System, University of Bologna, Bologna 40138, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna 40138, Italy
| | - Paolo Muratori
- Division of Internal Medicine, Morgagni-Pierantoni Hospital, Forlì 47100, Italy
- Department of Science for the Quality of Life, University of Bologna, Bologna 40138, Italy
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17
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Liu K, Huang A, Nie J, Tan J, Xing S, Qu Y, Jiang K. IL-35 Regulates the Function of Immune Cells in Tumor Microenvironment. Front Immunol 2021; 12:683332. [PMID: 34093586 PMCID: PMC8176033 DOI: 10.3389/fimmu.2021.683332] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Accepted: 05/11/2021] [Indexed: 12/20/2022] Open
Abstract
Interleukin-35 (IL-35) is a heterodimeric cytokine composed of Epstein-Barr virus-induced gene 3 (EBI3) and IL-12p35 that has recently been shown to play diverse and important roles in the tumor microenvironment (TME). Owing to its immunosuppressive activity and ability to promote tumor growth and progression, IL-35 is widely recognized as a key mediator of TME status. Immune cells are key mediators of diverse tumor-related phenotypes, and immunosuppressive cytokines such as IL-35 can promote tumor growth and metastasis in TME. These influences should be considered together. Since tumor immunotherapy based on immune checkpoint blockade remains ineffective in many patients due to tumoral resistance, a new target or efficacy enhancing factor is urgently needed. Suppressing IL-35 production and activity has been demonstrated as an effective factor that inhibits tumor cells viability, and further investigation of this cytokine is warranted. However, the mechanistic basis for IL-35-mediated regulation of immune cells in the TME remains to be fully clarified. In the present review, we explore the roles of IL-35 in regulating immune cells within the TME. In addition, we highlight IL-35 as a specific immunological target and discuss its possible relevance in the context of immunotherapy. Lastly, we sought to summarize potential future research directions that may guide the advancement of current understanding regarding the role of this important cytokine as a regulator of oncogenesis.
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Affiliation(s)
| | | | | | | | | | | | - Ke Jiang
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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18
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Li X, Liu X, Wang W. IL-35: A Novel Immunomodulator in Hepatitis B Virus-Related Liver Diseases. Front Cell Dev Biol 2021; 9:614847. [PMID: 33777929 PMCID: PMC7990793 DOI: 10.3389/fcell.2021.614847] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 02/19/2021] [Indexed: 12/13/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection is a risk factor for liver cirrhosis (LC) and hepatocellular carcinoma (HCC), however, little is known about the mechanisms involved in the progression of HBV-related diseases. It has been well acknowledged that host immune response was closely related to the clinical outcomes of patients with HBV infection. As the factors closely related to the immunomodulatory process, cytokines are crucial in the cell-cell communication and the host responses to HBV infection. Recently, a newly discovered cytokine, designated as interleukin-35 (IL-35), has been proved to be essential for the progression of chronic HBV infection, the development of cirrhosis, the transformation of cirrhosis to HCC, and the metastasis of HCC. Specifically, it showed various biological activities such as inhibiting the HBV-specific cytotoxic T lymphocyte (CTL) proliferation and cytotoxicity, deactivating the immature effector T-cells (Teffs), as well as delaying the proliferation of dendritic cells. It regulated the immune responses by acting as a “brake” on the activation of Teffs, which subsequently played important roles in the pathogenesis of various inflammatory diseases and malignancies. In this review, we focused on the most recent data on the relationship between IL-35 and chronic HBV infection, LC and HCC.
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Affiliation(s)
- Xuefen Li
- Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, Department of Laboratory Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xia Liu
- Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou, China
| | - Weilin Wang
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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19
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Malik A, Thanekar U, Amarachintha S, Mourya R, Nalluri S, Bondoc A, Shivakumar P. "Complimenting the Complement": Mechanistic Insights and Opportunities for Therapeutics in Hepatocellular Carcinoma. Front Oncol 2021; 10:627701. [PMID: 33718121 PMCID: PMC7943925 DOI: 10.3389/fonc.2020.627701] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 12/22/2020] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and a leading cause of death in the US and worldwide. HCC remains a global health problem and is highly aggressive with unfavorable prognosis. Even with surgical interventions and newer medical treatment regimens, patients with HCC have poor survival rates. These limited therapeutic strategies and mechanistic understandings of HCC immunopathogenesis urgently warrant non-palliative treatment measures. Irrespective of the multitude etiologies, the liver microenvironment in HCC is intricately associated with chronic necroinflammation, progressive fibrosis, and cirrhosis as precedent events along with dysregulated innate and adaptive immune responses. Central to these immunological networks is the complement cascade (CC), a fundamental defense system inherent to the liver which tightly regulates humoral and cellular responses to noxious stimuli. Importantly, the liver is the primary source for biosynthesis of >80% of complement components and expresses a variety of complement receptors. Recent studies implicate the complement system in liver inflammation, abnormal regenerative responses, fibrosis, carcinogenesis, and development of HCC. Although complement activation differentially promotes immunosuppressive, stimulant, and angiogenic microenvironments conducive to HCC development, it remains under-investigated. Here, we review derangement of specific complement proteins in HCC in the context of altered complement regulatory factors, immune-activating components, and their implications in disease pathogenesis. We also summarize how complement molecules regulate cancer stem cells (CSCs), interact with complement-coagulation cascades, and provide therapeutic opportunities for targeted intervention in HCC.
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Affiliation(s)
- Astha Malik
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Unmesha Thanekar
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Surya Amarachintha
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Reena Mourya
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Shreya Nalluri
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Alexander Bondoc
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Pranavkumar Shivakumar
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
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20
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Zhao N, Liu X, Guo H, Zhao X, Qiu Y, Wang W. Interleukin-35: An emerging player in the progression of liver diseases. Clin Res Hepatol Gastroenterol 2021; 45:101518. [PMID: 33387857 DOI: 10.1016/j.clinre.2020.07.023] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 07/31/2020] [Indexed: 02/04/2023]
Abstract
Interleukin-35(IL-35), a newly identified immunosuppressive cytokine, has recently been shown to play a significant role in the progression of various autoimmune diseases and malignant tumors. The liver is the largest organ in the body and is generally regarded as an important lymphoid organ by an increasing number of immunologists. A number of reports have demonstrated that IL-35 plays essential roles in maintaining the immune homeostasis of the liver microenvironment. This review summarizes the existing studies of IL-35 in liver diseases, including viral hepatitis, immune liver injury, liver cirrhosis and carcinoma. We aimed to provide a comprehensive overview of the vital roles of IL-35 in hepatic damage and explore new alternative therapeutic targets for these diseases.
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Affiliation(s)
- Na Zhao
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China.
| | - Xin Liu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Hao Guo
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Xiangnan Zhao
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Yujie Qiu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Wei Wang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
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21
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Yang L, Zhang Q, Song J, Wang W, Jin Z. Interleukin-35 Suppresses CD8 + T Cell Activity in Patients with Viral Hepatitis-Induced Acute-on-Chronic Liver Failure. Dig Dis Sci 2020; 65:3614-3623. [PMID: 31974915 DOI: 10.1007/s10620-020-06077-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 01/13/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Interleukin (IL)-35 is a newly indentified cytokine and induces immunotolerance via suppression of CD8+ T cell activity in chronic viral hepatitis. AIMS To investigate the modulatory function of IL-35 to CD8+ T cells in viral hepatitis-induced acute-on-chronic liver failure (ACLF). METHODS Fifty-five ACLF patients and 21 healthy controls were enrolled. Serum IL-35 concentration was measured by ELISA. Absolute accounts for T cells, immune checkpoint molecules, and cytotoxic molecules in CD8+ T cells were measured by flow cytometry and real-time PCR, respectively. Direct and indirect contact co-culture systems between CD8+ T cells and HepG2 cells were set up. The regulatory function of IL-35 to CD8+ T cells was assessed by measuring lactate dehydrogenase expression and cytokine production. RESULTS Serum IL-35 concentration was elevated in ACLF patients and positively correlated with total bilirubin, but negatively correlated with prothrombin time activity. Peripheral CD8+ T cells showed exhausted phenotype in ACLF patients, which manifested as up-regulation of programmed death-1 (PD-1), cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), and lymphocyte activation gene-3 (LAG-3) but down-regulation of perforin, granzyme B, and FasL. Recombinant IL-35 stimulation dampened cytotoxicity and interferon-γ production in both direct and indirect contact co-culture systems. This process was accompanied by elevation of PD-1, CTLA-4, and LAG3, as well as reduction of perforin, granzyme B, and FasL in CD8+ T cells. CONCLUSION Elevated IL-35 suppressed both cytolytic and non-cytolytic activity of CD8+ T cells in ACLF patients.
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Affiliation(s)
- Lanlan Yang
- Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, No. 218 Ziqiang St, Nanguan District, Changchun, 130041, Jilin Province, China
| | - Qian Zhang
- Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, No. 218 Ziqiang St, Nanguan District, Changchun, 130041, Jilin Province, China
| | - Jie Song
- Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, No. 218 Ziqiang St, Nanguan District, Changchun, 130041, Jilin Province, China
| | - Wudong Wang
- Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, No. 218 Ziqiang St, Nanguan District, Changchun, 130041, Jilin Province, China
| | - Zhenjing Jin
- Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, No. 218 Ziqiang St, Nanguan District, Changchun, 130041, Jilin Province, China.
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22
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Liu X, Ren H, Guo H, Wang W, Zhao N. Interleukin-35 has a tumor-promoting role in hepatocellular carcinoma. Clin Exp Immunol 2020; 203:219-229. [PMID: 33030251 DOI: 10.1111/cei.13535] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 08/19/2020] [Accepted: 09/18/2020] [Indexed: 12/31/2022] Open
Abstract
Hepatic inflammatory response is a risk factor for liver cancer initiation and progression. Interleukin (IL)-35 is the newest member of the IL-12 cytokine family, and has been reported to play an essential role in the immunosuppressive liver microenvironment. Herein we focus on the expression profiles of IL-35 in hepatocellular carcinoma (HCC) and effects on local immune status. HCC transcriptome array data were downloaded from Gene Expression Omnibus (GEO). Analysis was performed by BRB-Array Tools and Ingenuity Pathway Analysis (IPA) software. Serum IL-35 level was detected by AimPlet bead-based immunoassay. In-situ IL-35 detection was performed by immunohistochemical staining and Western blot. The n-vitro effect of IL-35 on CD4+ or CD8+ T cell function was detected by flow cytometry. Our results showed that there were large amounts of IL-35 expressed in HCC serum and tumor tissues. IL-35 expression affects the transcript of thousands of genes, most differentially expressed genes (DEGs), in tumor tissues correlated with T cell immunity. The IL-35 high-expression group exhibited enhancement of regulatory T cells (Tregs ) and impairment of cytolytic T cells. In-vitro experiments proved that exogenous IL-35 stimulated the expression of programmed cell death 1 (PD-1) and lymphocyte activation gene-3 (LAG3) in CD4+ and CD8+ T cells. In addition, the stimulating effect was time-dependent. Furthermore, IL-35 inhibited interferon (IFN)-γ secretion by CD4+ and CD8+ T cells. Elevated IL-35 had an immune suppressive role in HCC tumor microenvironments through affecting inhibitor receptor expression and cytokine secretion of CD4+ and CD8+ T cells. Dissection of the precise targets and underlying molecular mechanisms would mean alternative treatments for HCC patients.
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Affiliation(s)
- X Liu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - H Ren
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - H Guo
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - W Wang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - N Zhao
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
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23
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Zhu J, Wang Y, Li D, Zhang H, Guo Z, Yang X. Interleukin-35 promotes progression of prostate cancer and inhibits anti-tumour immunity. Cancer Cell Int 2020; 20:487. [PMID: 33041668 PMCID: PMC7541216 DOI: 10.1186/s12935-020-01583-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 09/28/2020] [Indexed: 12/16/2022] Open
Abstract
Background Interleukin-35 (IL-35) has been reported to play an important role in the progression of cancers. The role of IL-35 in prostate cancer (PCA) is not well understood. In this study, we investigated the effects of IL-35 on PCA and its immunoregulatory effect on PCA. Methods The protein and mRNA expression of IL-35 in PCA cells was detected by western blot and RT-PCR. The invasion and migration of cells were detected using transwell and wound-healing assays. A CCK-8 assay was conducted to observe cell proliferation. In vivo, IL-35 plasma concentration was test by enzyme-linked immunosorbent assay. The role of IL-35 in tumour cell proliferation and angiogenesis of mice was detected by immunohistochemical stains. The mouse survival and tumour volumes were calculated, and lung metastasis rate was detected by HE staining. The modulatory effects of IL-35 on myeloid-derived inhibitory cells (MDSCs), regulatory T cells (Tregs), CD4+ T cells and CD8+ T cells from PCA mice were investigated by immunohistochemical stains and flow cytometry. Results High levels of IL-35 significantly promoted the migration, invasion and cell proliferation of PCA cells in vitro. IL-35 was associated with tumour growth, metastasis and poor prognosis in PCA mice. Additionally, high levels of IL-35 significantly increased the proportions of MDSCs and Tregs and decreased the proportions of CD4+ and CD8+ T cells in the spleen, blood and tumour microenvironment. The IL-35 neutralizing antibody played the opposite role. Conclusions IL-35 contributed to the progression of PCA through promoting cell proliferation and tumour angiogenesis. IL-35 might limit the anti-tumour immune response by upregulating the proportions of Tregs and MDSCs and by reducing the proportions of CD4+ and CD8+ T cells. IL-35 might serve as a novel therapeutic target for PCA.
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Affiliation(s)
- Jialin Zhu
- Department of Ultrasound Diagnosis and Treatment, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060 China
| | - Yan Wang
- Department of Radiology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310000 China
| | - Dai Li
- Department of Geriatrics, Laboratory of Neuro-Trauma and Neurodegenerative Disorders, Tianjin Geriatrics Institute, Tianjin Medical University General Hospital, Tianjin, 300000 China
| | - Haonan Zhang
- Department of Interventional Therapy, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Huan Hu West Road, Tianjin, 300060 China
| | - Zhi Guo
- Department of Interventional Therapy, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Huan Hu West Road, Tianjin, 300060 China
| | - Xueling Yang
- Department of Interventional Therapy, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Huan Hu West Road, Tianjin, 300060 China
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24
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Takeda A, Hasegawa E, Nakao S, Ishikawa K, Murakami Y, Hisatomi T, Arima M, Yawata N, Oda Y, Kimura K, Yoshikawa H, Sonoda KH. Vitreous levels of interleukin-35 as a prognostic factor in B-cell vitreoretinal lymphoma. Sci Rep 2020; 10:15715. [PMID: 32973297 PMCID: PMC7519124 DOI: 10.1038/s41598-020-72962-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Accepted: 09/07/2020] [Indexed: 02/06/2023] Open
Abstract
Vitreoretinal lymphoma (VRL) is a rare disease of B-cell origin with poor prognosis. Regulatory cytokines promote tumor development by suppressing antitumor immunity in several cancer types, including B-cell malignancies. To identify the regulatory cytokines associated with poor prognosis in patients with B-cell VRL, we determined the regulatory cytokines profiles in the vitreous humor of patients with VRL. This retrospective study included 22 patients with VRL, 24 with non-infectious uveitis (NIU), and 20 with idiopathic epiretinal membrane (control). Vitreous concentrations of regulatory cytokines were assessed using a cytometric beads assay and association with clinical data was examined. IL-35 and soluble IL-2 receptor α levels were significantly higher in patients with VRL and NIU than those in the control group. The 5-year overall survival (OS) rates for the group with high intravitreal IL-35 was significantly poorer than those for the group with low intravitreal IL-35, who were diagnosed with VRL at the onset (P = 0.024, log-rank test). The 5-year OS rates with intravitreal IL-35 levels above and below the median were 40.0% and 83.3%, respectively. Our results suggest that high intravitreal IL-35 levels indicate poor prognosis for patients diagnosed with B-cell VRL at the onset.
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Affiliation(s)
- Atsunobu Takeda
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan. .,Department of Ophthalmology,Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
| | - Eiichi Hasegawa
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan
| | - Shintaro Nakao
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan
| | - Keijiro Ishikawa
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan
| | - Yusuke Murakami
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan
| | - Toshio Hisatomi
- Department of Ophthalmology, Chikushi Hospital, Fukuoka University, Chikushino, Fukuoka, Japan
| | - Mitsuru Arima
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan
| | - Nobuyo Yawata
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan.,Department of Ocular Pathology and Imaging Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kazuhiro Kimura
- Department of Ophthalmology, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi, Japan
| | - Hiroshi Yoshikawa
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan
| | - Koh-Hei Sonoda
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan.,Department of Ocular Pathology and Imaging Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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25
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Khamoushi T, Ahmadi M, Ali-Hassanzadeh M, Zare M, Hesampour F, Gharesi-Fard B, Amooee S. Evaluation of Transforming Growth Factor-β1 and Interleukin-35 Serum Levels in Patients with Placenta Accreta. Lab Med 2020; 52:245-249. [PMID: 32926163 DOI: 10.1093/labmed/lmaa071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
OBJECTIVE Placenta accreta is a pregnancy-related disorder with extreme trophoblast invasion and the adherence of the placenta to the uterine wall. This study aimed to investigate the serum level of transforming growth factor-beta 1 (TGF-β1) and interleukin (IL)-35 in patients with placenta accreta. METHODS Thirty-one women with placenta accreta and 57 healthy pregnant women were enrolled. The serum levels of TGF-β1 and IL-35 were measured using the enzyme-linked immunosorbent assay method. RESULTS The serum levels of both TGF-β and IL-35 were significantly higher in the placenta accreta group compared with the group of healthy women (1082.48 pg/mL vs 497.33 pg/mL and 4541.14 pg/mL vs 1306.04 pg/mL; P <.001, respectively). Moreover, the level of TGF-β1 positively correlated with the IL-35 level but other factors such as age, gestations, live births, and abortions did not correlate with IL-35 and TGF-β1 levels. CONCLUSION The serum levels of IL-35 and TGF-β1 may contribute to the pathogenesis of placenta accreta and could be considered as potential targets in clinical and diagnostic approaches.
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Affiliation(s)
- Tayyebe Khamoushi
- Department of Obstetrics and Gynecology, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Moslem Ahmadi
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Ali-Hassanzadeh
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Immunology, School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Maryam Zare
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Fateme Hesampour
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Behrouz Gharesi-Fard
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.,Infertility Research Center, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sedigheh Amooee
- Department of Obstetrics and Gynecology, Shiraz University of Medical Sciences, Shiraz, Iran
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26
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Wang S, Gao S, Zhou D, Qian X, Luan J, Lv X. The role of the CD39-CD73-adenosine pathway in liver disease. J Cell Physiol 2020; 236:851-862. [PMID: 32648591 DOI: 10.1002/jcp.29932] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 06/30/2020] [Accepted: 07/01/2020] [Indexed: 02/06/2023]
Abstract
Extracellular adenosine triphosphate (ATP) is a danger signal released by dying and damaged cells, and it functions as an immunostimulatory signal that promotes inflammation. The ectonucleotidases CD39/ectonucleoside triphosphate diphosphohydrolase-1 and CD73/ecto-5'-nucleotidase are cell-surface enzymes that breakdown extracellular ATP into adenosine. This drives a shift from an ATP-driven proinflammatory environment to an anti-inflammatory milieu induced by adenosine. The CD39-CD73-adenosine pathway changes dynamically with the pathophysiological context in which it is embedded. Accumulating evidence suggests that CD39 and CD73 play important roles in liver disease as critical components of the extracellular adenosinergic pathway. Recent studies have shown that the modification of the CD39-CD73-adenosine pathway alters the liver's response to injury. Moreover, adenosine exerts different effects on the pathophysiology of the liver through different receptors. In this review, we aim to describe the role of the CD39-CD73-adenosine pathway and adenosine receptors in liver disease, highlighting potential therapeutic targets in this pathway, which will facilitate the development of therapeutic strategies for the treatment of liver disease.
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Affiliation(s)
- Sheng Wang
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, China.,The Key Laboratory of Anti-Inflammatory and Immune Medicines, Ministry of Education, School of Pharmacy, Institute for Liver Disease, Anhui Medical University, Hefei, Anhui, China
| | - Songsen Gao
- Department of Orthopedics (Spinal Surgery), The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Dexi Zhou
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, China
| | - Xueyi Qian
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, China
| | - Jiajie Luan
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, China
| | - Xiongwen Lv
- The Key Laboratory of Anti-Inflammatory and Immune Medicines, Ministry of Education, School of Pharmacy, Institute for Liver Disease, Anhui Medical University, Hefei, Anhui, China
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27
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Yang H, Xuefeng Y, Jianhua X. Systematic review of the roles of interleukins in hepatocellular carcinoma. Clin Chim Acta 2020; 506:33-43. [PMID: 32142718 DOI: 10.1016/j.cca.2020.03.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 03/02/2020] [Accepted: 03/02/2020] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is a primary liver cancer with high morbidity and mortality that is often accompanied by immune system disorders and local lymphocyte infiltration. Tumor-infiltrating lymphocytes, cancer cells, stromal cells, and the numerous cytokines they produce, such as chemokines, interferons, tumor necrosis factors, and interleukins, collectively constitute the tumor microenvironment. As a main type of immune effector, interleukin plays opposing roles in regulating tumor cell progression, adhesion, and migration according to its different subtypes. Many reports have concentrated on the roles that interleukins play in HCC, but understanding them systematically remains challenging. This study reviewed the current data to comprehensively summarize the relationships between HCC progression and human interleukin gene families.
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Affiliation(s)
- Hu Yang
- Institute of Pathogenic Biology, Hengyang Medical College, University of South China, Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang 421001, Hunan, China; Department of Gastroenterology, Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan 421002, China
| | - Yang Xuefeng
- Department of Gastroenterology, Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan 421002, China
| | - Xiao Jianhua
- Institute of Pathogenic Biology, Hengyang Medical College, University of South China, Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang 421001, Hunan, China.
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28
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Yu SJ, Greten TF. Deciphering and Reversing Immunosuppressive Cells in the Treatment of Hepatocellular Carcinoma. JOURNAL OF LIVER CANCER 2020; 20:1-16. [PMID: 37383056 PMCID: PMC10035699 DOI: 10.17998/jlc.20.1.1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 11/06/2019] [Accepted: 11/10/2019] [Indexed: 06/30/2023]
Abstract
Use of immune checkpoint inhibitors (ICIs) in hepatocellular carcinoma (HCC) has been partially successful. However, most HCC patients do not respond to immunotherapy. HCC has been shown to induce several immune suppressor mechanisms in patients. These suppressor mechanisms include involvement of myeloid-derived suppressor cells, regulatory T-cells, functionally impaired dendritic cells (DCs), neutrophils, monocytes, and tumor associated macrophages. The accumulation of immunosuppressive cells may lead to an immunosuppressive tumor microenvironment as well as the dense fibrotic stroma which may contribute to immune tolerance. Our laboratory has been investigating different cellular mechanisms of immune suppression in HCC patients. In vitro as well as in vivo studies have demonstrated that abrogation of the suppressor cells enhances or unmasks tumor-specific antitumor immune responses. Two or three effective systemic therapies including ICIs and/or molecular targeted therapies and the addition of innovative combination therapies targeting immune suppressor cells may lead to increased immune recognition with a greater tumor response. We reviewed the literature for the latest research on immune suppressor cells in HCC, and here we provide a comprehensive summary of the recent studies in this field.
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Affiliation(s)
- Su Jong Yu
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Tim F. Greten
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, USA
- NCI CCR Liver Cancer Program, Bethesda, USA
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29
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Targeting adenosinergic pathway enhances the anti-tumor efficacy of sorafenib in hepatocellular carcinoma. Hepatol Int 2019; 14:80-95. [DOI: 10.1007/s12072-019-10003-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2019] [Accepted: 11/02/2019] [Indexed: 12/24/2022]
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30
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Yazdani Z, Rafiei A, Golpour M, Zafari P, Moonesi M, Ghaffari S. IL‐35, a double‐edged sword in cancer. J Cell Biochem 2019; 121:2064-2076. [DOI: 10.1002/jcb.29441] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Accepted: 10/08/2019] [Indexed: 12/11/2022]
Affiliation(s)
- Zahra Yazdani
- Department of Immunology, School of Medicine Mazandaran University of Medical Sciences Sari Iran
| | - Alireza Rafiei
- Department of Immunology, School of Medicine Mazandaran University of Medical Sciences Sari Iran
| | - Monireh Golpour
- Students Research Committee Mazandaran University of Medical Sciences Sari Iran
| | - Parisa Zafari
- Department of Immunology, School of Medicine Mazandaran University of Medical Sciences Sari Iran
- Students Research Committee Mazandaran University of Medical Sciences Sari Iran
| | - Mohammadreza Moonesi
- Department of Hematology, School of Medicine Tabriz University of Medical Science, Tabriz Iran
| | - Sasan Ghaffari
- Student Scientific Research Center Tehran University of Medical Sciences Tehran Iran
- Cell‐Based Therapies Research Center, Digestive Disease Research Institute Tehran University of Medical Sciences Tehran Iran
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31
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Fu Y, Liu S, Zeng S, Shen H. From bench to bed: the tumor immune microenvironment and current immunotherapeutic strategies for hepatocellular carcinoma. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 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] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Accepted: 08/27/2019] [Indexed: 02/07/2023]
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.
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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.
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32
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Yang M, Zhang Z, Chen J, Xu M, Huang J, Wang M, Li W, Wan X, Yuen MF, Luo X, Xi D, Ning Q. Soluble fibrinogen-like protein 2 promotes the growth of hepatocellular carcinoma via attenuating dendritic cell-mediated cytotoxic T cell activity. J Exp Clin Cancer Res 2019; 38:351. [PMID: 31409352 PMCID: PMC6693134 DOI: 10.1186/s13046-019-1326-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Accepted: 07/15/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Soluble fibrinogen-like protein 2 (sFGL2), a secretory protein expressed by regulatory T cells (Tregs) with immunosuppressive activity, is highly expressed in both the peripheral blood and tumor tissue of patients with hepatocellular carcinoma (HCC); however, sFGL2 function in HCC remains largely unknown. Here, we elucidated the potential role of sFGL2 in HCC progression. METHODS T cells, dendritic cells (DCs), and related cytokines in the tumor microenvironment were comparatively analyzed in BALB/c and C57BL/6 mice bearing transplanted hepatomas harboring Fgl2-knockout or receiving sFGL2-antibody treatment. Additionally, the effects of sFGL2 on DCs and T cells were evaluated in vivo and ex vivo. RESULTS The growth of both subcutaneously and orthotopically transplanted hepatomas was inhibited in Fgl2-knockout mice and those treated with the sFGL2 antibody, respectively, as compared with controls. Moreover, sFGL2 depletion enhanced the proportion and cytotoxicity of cytotoxic T cells, promoted DC maturation, and improved DC activity to proliferate T cells in the tumor microenvironment. Furthermore, we detected lower levels of interleukin (IL)-35 in both types of transplanted hepatomas and higher level of IL-6 in orthotopically transplanted hepatomas following sFGL2 depletion. Mechanistically, we found that sFGL2 impaired bone-marrow-derived DC (BMDCs) function by inhibiting phosphorylation of Akt, nuclear factor-kappaB, cAMP response element binding protein, and p38 and downregulating the expression of major histocompatibility complex II, CD40, CD80, CD86, and CD83 on BMDCs in vitro. CONCLUSIONS Our data suggest that sFGL2 promotes hepatoma growth by attenuating DC activity and subsequent CD8+ T cell cytotoxicity, suggesting sFGL2 as a novel potential therapeutic target for HCC treatment.
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MESH Headings
- Animals
- Antibodies, Monoclonal/pharmacology
- Biomarkers
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/mortality
- Carcinoma, Hepatocellular/pathology
- Cell Line, Tumor
- Cytokines/metabolism
- Cytotoxicity, Immunologic/drug effects
- Dendritic Cells/immunology
- Dendritic Cells/metabolism
- Disease Models, Animal
- Female
- Fibrinogen/antagonists & inhibitors
- Fibrinogen/genetics
- Fibrinogen/metabolism
- Fibrinogen/pharmacology
- Heterografts
- Humans
- Immunophenotyping
- Liver Neoplasms/genetics
- Liver Neoplasms/immunology
- Liver Neoplasms/mortality
- Liver Neoplasms/pathology
- Mice
- Mice, Knockout
- Phosphorylation
- Proto-Oncogene Proteins c-akt/metabolism
- Signal Transduction/drug effects
- T-Lymphocytes, Cytotoxic/immunology
- T-Lymphocytes, Cytotoxic/metabolism
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Affiliation(s)
- Muyang Yang
- Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Zhongwei Zhang
- Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Jiajia Chen
- Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Mengying Xu
- Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Jiaquan Huang
- Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
- Department of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Ming Wang
- Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
- Department of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Weina Li
- Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
- Department of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Xiaoyang Wan
- Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Man-Fung Yuen
- Department of Medicine, the University of Hong Kong, Queen Mary Hospital, Hong Kong, China
| | - Xiaoping Luo
- Department of Pediatrics, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dong Xi
- Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Qin Ning
- Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
- Department of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
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A nomogram predicting the prognosis of young adult patients diagnosed with hepatocellular carcinoma: A population-based analysis. PLoS One 2019; 14:e0219654. [PMID: 31295310 PMCID: PMC6623961 DOI: 10.1371/journal.pone.0219654] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Accepted: 06/28/2019] [Indexed: 02/08/2023] Open
Abstract
Background Few studies have reported the clinical characteristics and outcomes of young adult patients diagnosed with hepatocellular carcinoma (HCC). This study aimed to formulate a nomogram to predict the prognosis of young adult HCC patients. Methods Young adult patients diagnosed with HCC from 2004 to 2015 were screened from the Surveillance, Epidemiology, and End Results (SEER) database. Based on the multivariate analysis results, a nomogram was constructed. The concordance index (c-index) and calibration were used to assess the predictive performance of the nomogram. The clinical benefit was measured by using decision curve analysis (DCA). Results The mean follow-up time of the patients was 25.0±34.0 months. Gender, race, AFP level, Edmondson–Steiner classification, treatment and TNM stage were selected as independent prognostic factors and integrated into the nomogram. The c-indexes of the two sets were 0.786 and 0.775, respectively. The calibration curves showed good agreement between the nomogram-predicted probability and the actual observations. Furthermore, the DCA indicated that the nomogram had positive net benefits compared with the conventional staging system. Conclusions The nomogram could accurately predict the prognosis of young adult HCC patients.
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Liu MX, Liu QY, Liu Y, Cheng ZM, Liu L, Zhang L, Sun DH. Interleukin-35 suppresses antitumor activity of circulating CD8 + T cells in osteosarcoma patients. Connect Tissue Res 2019; 60:367-375. [PMID: 30616389 DOI: 10.1080/03008207.2018.1552267] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Purpose/Aim of the study: Interleukin (IL)-35 is a newly identified IL-12 cytokine family member and reveals immunosuppressive activity to CD8+ T cells in inflammation, infectious diseases, and cancers. However, little is known regarding IL-35 function in osteosarcoma. Thus, the aim of the current study was to investigate the regulatory function of IL-35 to CD8+ T cells in osteosarcoma. Materials and methods: Thirty-five osteosarcoma patients and 20 healthy individuals were enrolled. Serum CD4+CD25+CD127dim/- regulatory T cells (Tregs) and CD8+ T cells were purified. IL-35 concentration in serum and cultured supernatants was measured by enzyme-linked immunosorbent assay. Osteosarcoma cell line MG-63 cells and CD8+ T cells were stimulated with recombinant IL-35 in vitro, and modulatory function of IL-35 on these cells was assessed by investigation of cellular proliferation, cell cycle, apoptosis, and cytokine production. Results: Serum IL-35 and Treg-secreting IL-35 were significantly elevated in osteosarcoma patients. IL-35 stimulation did not affect proliferation, apoptosis, or cell cycle of MG-63 cells. Purified peripheral CD8+ T cells from osteosarcoma patients revealed dysfunctional property, which presented as decreased mRNA expressions for perforin, granzyme B, and granulysin, as well as reduced cytolytic (direct lysis of target MG-63 cells) and noncytolytic (interferon-γ and tumor necrosis factor-α production) function in coculture systems. Moreover, IL-35 stimulation further diminished cytolytic and noncytolytic activity of CD8+ T cells from osteosarcoma patients. Conclusions: The current data indicated that IL-35 contributed to CD8+ T-cell dysfunction and limited antitumor immune response in osteosarcoma.
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Affiliation(s)
- Ming-Xi Liu
- a Department of Orthopaedic Traumatology , The First Hospital of Jilin University , Changchun , China
| | - Qing-Yu Liu
- b Department of Orthopaedic Traumatology , 208th Hospital of PLA , Changchun , China
| | - Ye Liu
- c Intensive Care Unit , 208th Hospital of PLA , Changchun , China
| | - Zhi-Ming Cheng
- b Department of Orthopaedic Traumatology , 208th Hospital of PLA , Changchun , China
| | - Lei Liu
- b Department of Orthopaedic Traumatology , 208th Hospital of PLA , Changchun , China
| | - Lei Zhang
- b Department of Orthopaedic Traumatology , 208th Hospital of PLA , Changchun , China
| | - Da-Hui Sun
- a Department of Orthopaedic Traumatology , The First Hospital of Jilin University , Changchun , China
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35
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Larousserie F, Kebe D, Huynh T, Audebourg A, Tamburini J, Terris B, Devergne O. Evidence for IL-35 Expression in Diffuse Large B-Cell Lymphoma and Impact on the Patient's Prognosis. Front Oncol 2019; 9:563. [PMID: 31316915 PMCID: PMC6611226 DOI: 10.3389/fonc.2019.00563] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2019] [Accepted: 06/10/2019] [Indexed: 12/23/2022] Open
Abstract
IL-35 is an immunosuppressive cytokine of the IL-12 family consisting of two subunits, EBV-induced gene 3 (EBI3) and p35. It has been shown to play a pro-tumor role in murine tumor models, and in various types of human cancer such as colorectal, pancreatic, or liver carcinoma, its expression has been associated with a worse clinical outcome. Here, we show by analyzing gene expression data from public databases and by immunohistochemical studies that IL-35 is overexpressed by tumor cells in diffuse-large B-cell lymphoma (DLBCL) compared to another type of mature aggressive B-cell lymphoma, Burkitt lymphoma. However, while high IL-35 expression was significantly associated with a worse overall survival in DLBCL patients treated with chemotherapy only (cyclophosphamide, doxorubicin, vincristine, prednisone, CHOP), no significant correlation between IL-35 expression levels and the patient outcome was observed in DLBCL patients treated with CHOP combined to rituximab (R-CHOP), the current conventional treatment. In addition, we found that an anti-IL-35 antibody, clone 15k8D10, used to assess IL-35 expression by immunohistochemistry in various human tissues including tumors does not recognize IL-35 heterodimer, nor its individual subunits EBI3 and p35, but cross-reacts with human IgG1, indicating that IL-35 expression in human cancers needs to be re-evaluated.
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Affiliation(s)
- Frédérique Larousserie
- Sorbonne Université, INSERM, CNRS, Centre D'Immunologie et des Maladies Infectieuses (Cimi-Paris), Paris, France.,Pathology Department, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes, Paris, France
| | - Diakho Kebe
- Institut Necker Enfants Malades, INSERM, CNRS, Université Paris Descartes, Paris, France
| | - Tony Huynh
- Hematology Department, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes, Paris, France
| | - Anne Audebourg
- Pathology Department, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes, Paris, France
| | - Jérôme Tamburini
- Hematology Department, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes, Paris, France
| | - Benoît Terris
- Pathology Department, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes, Paris, France
| | - Odile Devergne
- Sorbonne Université, INSERM, CNRS, Centre D'Immunologie et des Maladies Infectieuses (Cimi-Paris), Paris, France
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36
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Tian MX, Liu WR, Wang H, Zhou YF, Jin L, Jiang XF, Tao CY, Tang Z, Zhou PY, Fang Y, Qu WF, Ding ZB, Peng YF, Dai Z, Qiu SJ, Zhou J, Lau WY, Fan J, Shi YH. Tissue-infiltrating lymphocytes signature predicts survival in patients with early/intermediate stage hepatocellular carcinoma. BMC Med 2019; 17:106. [PMID: 31164128 PMCID: PMC6549297 DOI: 10.1186/s12916-019-1341-6] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Accepted: 05/07/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Intratumoral immune infiltrates have manifested a robust prognostic signature in patients with hepatocellular carcinoma (HCC). We hypothesized that a novel tissue-related immune signature (TRIS) could improve the prediction of postoperative survival for patients diagnosed with early/intermediate HCC. METHODS Twenty-eight immune features were immunohistochemically examined on 352 HCC specimens. The LASSO Cox regression model was used to construct a five-feature-based TRIS. The univariate and multivariate Cox analyses were performed. Based on independent predictors, the immune-clinical prognostic index (ICPI) was established. Performance assessment was measured with C-index and compared with seven traditional staging systems. The independent validation cohort (n = 393) was included to validate the model. RESULTS By using the LASSO method, the TRIS were constructed on the basis of five immune features, CD3intratumoral (T), CD27T, CD68peritumoral (P), CD103T, and PD1T. Multivariate Cox analysis showed that the TRIS was an independent prognostic predictor. In the training cohort, γ-glutamyl transferase, tumor diameter, tumor differentiation, and TRIS were incorporated into the ICPI. The ICPI presented satisfactory discrimination ability, with C-index values of 0.691 and 0.686 in the training and validation cohorts, respectively. Compared with seven conventional staging systems (C-index, training cohort, 0.548-0.597; validation cohort, 0.519-0.610), the ICPI exhibited better performance for early/intermediate-stage HCCs. Further, the patients were categorized into three subgroups with X-tile software, and the stratified ICPI presented a superior corrected Akaike information criterion and homogeneity in both cohorts. CONCLUSIONS Our ICPI was a useful and reliable prognostic tool which may offer good individualized prediction capability for HCC patients with early/intermediate stage.
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Affiliation(s)
- Meng-Xin Tian
- Department of Liver Surgery, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Wei-Ren Liu
- Department of Liver Surgery, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Han Wang
- Department of Liver Surgery, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Yu-Fu Zhou
- Department of Liver Surgery, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Lei Jin
- Department of Liver Surgery, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Xi-Fei Jiang
- Department of Liver Surgery, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Chen-Yang Tao
- Department of Liver Surgery, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Zheng Tang
- Department of Liver Surgery, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Pei-Yun Zhou
- Department of Liver Surgery, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Yuan Fang
- Department of Liver Surgery, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Wei-Feng Qu
- Department of Liver Surgery, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Zhen-Bin Ding
- Department of Liver Surgery, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Yuan-Fei Peng
- Department of Liver Surgery, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Zhi Dai
- Department of Liver Surgery, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Shuang-Jian Qiu
- Department of Liver Surgery, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Jian Zhou
- Department of Liver Surgery, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China.,Institutes of Biomedical Sciences, Fudan University, Shanghai, People's Republic of China
| | - Wan Yee Lau
- Department of Liver Surgery, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China.,Faculty of Medicine, the Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, SAR, China
| | - Jia Fan
- Department of Liver Surgery, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China.,Institutes of Biomedical Sciences, Fudan University, Shanghai, People's Republic of China
| | - Ying-Hong Shi
- Department of Liver Surgery, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China.
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Xue W, Yan D, Kan Q. Interleukin-35 as an Emerging Player in Tumor Microenvironment. J Cancer 2019; 10:2074-2082. [PMID: 31205568 PMCID: PMC6548173 DOI: 10.7150/jca.29170] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2018] [Accepted: 03/05/2019] [Indexed: 12/15/2022] Open
Abstract
IL-35 is the newest member of IL-12 family. A dimeric protein consisting of two separate subunits has manifested suppressive actions on immune system, which is counterproductive in the context of cancers. Various reports have confirmed its inhibitory role on immune system which is carried out via formation of IL-35-producing regulatory T cells (iTr35), increased Treg development and suppressive Th17 cells growth. Although last decade has seen a great deal of scientific interest on this subject, the exact role, precise signal transduction and elaborative functions of IL-35 in tumor microenvironment (TME) remained elusive. Search for anti-IL-35 therapies have exhibited limited success in animal models. Contrarily, few studies have denied the idea that IL-35 plays a role in cancer. The purpose of this review is to analyze the reported scientific data on continuous symphony of IL-35 in cancers since the inception of former.
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Affiliation(s)
- Wenhua Xue
- Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Dan Yan
- Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Quancheng Kan
- Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
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38
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Yang L, Shao X, Jia S, Zhang Q, Jin Z. Interleukin-35 Dampens CD8 + T Cells Activity in Patients With Non-viral Hepatitis-Related Hepatocellular Carcinoma. Front Immunol 2019; 10:1032. [PMID: 31134088 PMCID: PMC6514160 DOI: 10.3389/fimmu.2019.01032] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2019] [Accepted: 04/23/2019] [Indexed: 12/12/2022] Open
Abstract
Interleukin (IL)-35 is a newly identified IL-12 cytokine family member, which has been demonstrated to induce immunotolerance by suppression of CD8+ T cells function in chronic viral hepatitis. However, the role of IL-35 in modulating CD8+ T cells activity in non-viral hepatitis-related hepatocellular carcinoma (HCC) was not fully elucidated. Forty-four patients with non-viral hepatitis-related HCC and 20 healthy individuals were enrolled. Serum IL-35 concentration was measured by ELISA. CD8+ T cells were purified from peripheral bloods and liver tissues. mRNA expression of cytotoxic/inhibitory molecules in CD8+ T cells with IL-35 stimulation was semi-quantified by real-time PCR. Direct and indirect contact co-culture systems of CD8+ T cells and HCC cell lines were set up. The modulatory function of IL-35 on peripheral and liver-resident CD8+ T cells was assessed by measurement of lactate dehydrogenase release and cytokine production in the co-culture supernatants. Serum IL-35 was notably elevated in HCC patients, while effective anti-tumor therapies down-regulated IL-35 concentration. Recombinant IL-35 stimulation suppressed cytotoxicity and proinflammatory cytokine secretion of peripheral and liver-resident CD8+ T cells in direct and indirect contact co-culture systems. This process was accompanied by reduction of perforin expression and interferon-γ production, as well as programmed death-1 and cytotoxic T-lymphocyte-associated protein 4 elevation in CD8+ T cells. The current data suggested that IL-35 inhibited both cytolytic and non-cytolytic function of CD8+ T cells to non-viral hepatitis-related HCC probably via repression of perforin expression. IL-35 might be considered to be one of the therapeutic targets for patients with HCC.
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Affiliation(s)
- Lanlan Yang
- Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, Changchun, China
| | - Xue Shao
- Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, Changchun, China
| | - Shengnan Jia
- Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, Changchun, China
| | - Qian Zhang
- Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, Changchun, China
| | - Zhenjing Jin
- Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, Changchun, China
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39
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Interleukin-35 is associated with the tumorigenesis and progression of prostate cancer. Oncol Lett 2019; 17:5094-5102. [PMID: 31186721 PMCID: PMC6507472 DOI: 10.3892/ol.2019.10208] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Accepted: 03/04/2019] [Indexed: 12/24/2022] Open
Abstract
Interleukin (IL)-35 is a novel member of the IL-12 cytokine family, which exhibits a unique immune regulatory function. Previously, it was demonstrated that IL-35 expression is significantly increased in a wide range of tumor tissues, promoting angiogenesis and inhibiting the anti-tumor immune response. In the present study, the IL-35 protein expression levels were measured in the plasma and tumor tissue of patients with prostate cancer (PCA), and its role was determined in the occurrence and progression of PCA. Plasma IL-35 expression levels were measured using ELISA, and the associations of plasma IL-35 and clinicopathological parameters were analyzed. Receiver operating characteristic curves were plotted to analyze the role of IL-35 as a clinical biomarker for the diagnosis of PCA. Survival curve analysis demonstrated a significant decrease in the survival time in months in patients with PCA and increased expression levels of IL-35 compared with the participants with relatively lower IL-35 protein expression levels. IL-35 expression was detected using immunohistochemical staining of a human PCA tissue microarray. Plasma IL-35 expression levels in the patients with PCA were significantly increased compared with the patients with benign prostatic hyperplasia and the healthy controls. An increase in the plasma concentration of IL-35 was associated with progression of PCA stage and an increase in the Gleason score. Significant differences in AUCs for IL-35 and prostate-specific antigen were observed with regard to the presence of lymph node and distant metastases in patients with PCA. The expression levels of Epstein-barr virus-induced gene 3 (EBI3) and IL-12A (p35; the subunits which together form IL-35) were significantly increased in the tumor tissue compared with the adjacent normal tissue. An association was identified between the Gleason score and the expression of EBI3 and p35. Therefore, increased expression of IL-35 in the plasma and tumor tissues may contribute to the progression and metastasis of PCA, and IL-35 may serve as a novel prognostic biomarker or therapeutic target for the treatment of PCA.
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40
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Jing CY, Fu YP, Yi Y, Zhang MX, Zheng SS, Huang JL, Gan W, Xu X, Lin JJ, Zhang J, Qiu SJ, Zhang BH. HHLA2 in intrahepatic cholangiocarcinoma: an immune checkpoint with prognostic significance and wider expression compared with PD-L1. J Immunother Cancer 2019; 7:77. [PMID: 30885276 PMCID: PMC6421676 DOI: 10.1186/s40425-019-0554-8] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 02/28/2019] [Indexed: 02/08/2023] Open
Abstract
Background Intrahepatic cholangiocarcinoma (ICC) is a highly mortal malignancy with limited therapeutic options. Immunotherapies targeting PD-1/PD-L1 pathway represent a promising treatment for ICC. However, PD-L1 expression and microsatellite instability are not common in ICC. This study aimed to investigate whether HHLA2, a newly identified B7 family immune checkpoint for T cells, could be a therapeutic target next to PD-L1 in ICC. Methods Expression levels of PD-L1 and HHLA2 as well as infiltrations of CD3+, CD8+, CD4 + Foxp3+, CD68+, CD163+ and CD20+ cells were evaluated by immunohistochemistry in 153 resected ICC samples. Comprehensive comparisons were made between PD-L1 and HHLA2 in terms of the expression rates, clinicopathological features and infiltrations of different immune cells. The expression level and prognostic significance of HHLA2 were further validated in an independent cohort. Results Expression of HHLA2 is more frequent than PD-L1 in ICC (49.0% vs 28.1%). Co-expression of both immune checkpoints was infrequent (13.1%) and 50% PD-L1 negative cases were with elevated HHLA2. HHLA2 overexpression was associated with sparser CD3+ tumor infiltrating lymphocytes (TILs), CD8+ TILs and a higher CD4 + Foxp3+/CD8+ TIL ratio, whereas PD-L1 expression was associated with prominent T cells and CD163+ tumor associated macrophages infiltrations. PD-L1 failed to stratify overall survival (OS) but HHLA2 was identified as an independent prognostic indicator for OS in two independent cohorts. Conclusions Compared with PD-L1, HHLA2 is more prevalent and possesses more explicit prognostic significance, which confer the rationale for HHLA2 as a potential immunotherapeutic target next to PD-L1 for ICC patients. Electronic supplementary material The online version of this article (10.1186/s40425-019-0554-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Chu-Yu Jing
- Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, People's Republic of China.,The Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Yi-Peng Fu
- Department of breast surgery, The Obstetrics & Gynecology Hospital of Fudan University, 419 Fangxie Road, Shanghai, 200090, People's Republic of China
| | - Yong Yi
- The Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Mei-Xia Zhang
- The Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Su-Su Zheng
- The Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Jin-Long Huang
- The Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Wei Gan
- The Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Xin Xu
- The Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Jia-Jia Lin
- The Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Juan Zhang
- The Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Shuang-Jian Qiu
- The Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, 180 Fenglin Road, Shanghai, 200032, People's Republic of China.
| | - Bo-Heng Zhang
- The Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, 180 Fenglin Road, Shanghai, 200032, People's Republic of China. .,Center for evidence-based medicine, Shanghai Medical School, Fudan University, Shanghai, 200032, People's Republic of China.
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Ding W, Xu X, Qian Y, Xue W, Wang Y, Du J, Jin L, Tan Y. Prognostic value of tumor-infiltrating lymphocytes in hepatocellular carcinoma: A meta-analysis. Medicine (Baltimore) 2018; 97:e13301. [PMID: 30557978 PMCID: PMC6320107 DOI: 10.1097/md.0000000000013301] [Citation(s) in RCA: 76] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND In patients with hepatocellular carcinoma (HCC), the prognostic role of tumor-infiltrating lymphocytes (TILs) for survival is still controversial. A meta-analysis was performed to investigate the prognostic effect of TILs in HCC. METHODS We identify studies from PubMed, Embase, and the Cochrane Library to evaluate the prognostic value of TILs in patients with HCC. A meta-analysis was conducted to estimate overall survival and disease-free survival. The hazard ratio (HR) and 95% confidence interval (CI) were calculated employing fixed-effect or random-effect models depending on the heterogeneity of the included trials. RESULTS A total of 7905 patients from 46 observational studies were enrolled. For TILs subsets, the density of CD8+, FOXP3+, CD3+, and Granzyme B+ lymphocytes was significantly associated with improved survival (P < .05). The density of FOXP3+ TILs in intratumor (IT) was the most significant prognostic marker (pooled HR = 1.894; 95% CI = 1.659-2.164; P < .001). Patients with high infiltration of CD8+ TILs in IT (pooled HR = 0.676; 95% CI = 0.540-0.845; P = .001) or in margin of tumor (MT) (pooled HR = 0.577; 95% CI = 0.437-0.760; P < .001) had better OS. The pooled analysis revealed that high density of Granzyme B+ T-lymphocytes in IT was statistically significant associated with better OS (pooled HR = 0.621; 95% CI = 0.516-0.748; P < .001) and DFS (pooled HR = 0.678; 95% CI = 0.563-0.815; P < .001). It was interesting that high density of CD3+ in IT foreboded worse OS (pooled HR = 1.008; 95% CI = 1.000-1.015; P = .037), but better DFS (pooled HR = 0.596; 95% CI = 0.374-0.948; P = .029). CONCLUSION Our findings suggested that some TIL subsets could serve as prognostic biomarkers in HCC. High-quality randomized controlled trials are needed to determine if these TILs could serve as targets for immunotherapy in HCC.
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Affiliation(s)
- Wei Ding
- Department of General Surgery, Wujin Hospital Affiliated to Jiangsu University, Changzhou, Jiangsu Province
| | - Xuezhong Xu
- Department of General Surgery, Wujin Hospital Affiliated to Jiangsu University, Changzhou, Jiangsu Province
| | - Yan Qian
- Department of respiration, Changzhou Second People's Hospital Affiliated to Nanjing Medical University, Changzhou, China
| | - Wenbo Xue
- Department of General Surgery, Wujin Hospital Affiliated to Jiangsu University, Changzhou, Jiangsu Province
| | - Yibo Wang
- Department of General Surgery, Wujin Hospital Affiliated to Jiangsu University, Changzhou, Jiangsu Province
| | - Jianguo Du
- Department of General Surgery, Wujin Hospital Affiliated to Jiangsu University, Changzhou, Jiangsu Province
| | - Lei Jin
- Department of General Surgery, Wujin Hospital Affiliated to Jiangsu University, Changzhou, Jiangsu Province
| | - Yulin Tan
- Department of General Surgery, Wujin Hospital Affiliated to Jiangsu University, Changzhou, Jiangsu Province
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Taylor AE, Carey AN, Kudira R, Lages CS, Shi T, Lam S, Karns R, Simmons J, Shanmukhappa K, Almanan M, Chougnet CA, Miethke AG. Interleukin 2 Promotes Hepatic Regulatory T Cell Responses and Protects From Biliary Fibrosis in Murine Sclerosing Cholangitis. Hepatology 2018; 68:1905-1921. [PMID: 29698570 PMCID: PMC6203671 DOI: 10.1002/hep.30061] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Accepted: 04/14/2018] [Indexed: 12/25/2022]
Abstract
In the multidrug resistance protein 2 (Mdr2)-/- mouse model, low phospholipid bile instigates biliary epithelial injury, sterile inflammation, and fibrosis, thereby recapitulating disease mechanisms implicated in biliary atresia (BA) and primary sclerosing cholangitis. We hypothesize that T lymphocytes contribute to the biliary injury and fibrosis in murine sclerosing cholangitis (SC) and that they are susceptible to suppression by regulatory T cells (Tregs). In juvenile Mdr2-/- mice, intrahepatic CD8+ lymphocytes were expanded, and contraction of intrahepatic Tregs coincided with rising serum alanine transferase and alkaline phosphatase (ALP) levels between days 14-30 of life. Antibody-mediated depletion of intrahepatic CD8+ lymphocytes during that time reduced ALP levels and the expression of osteopontin (Opn), a pro-fibrogenic cytokine. Depletion of intrahepatic Tregs with anti-CD25 antibody between days 7-30 increased intrahepatic CD8+ T cells, Opn expression, and fibrosis. Conversely, expansion of intrahepatic Tregs with interleukin 2/anti-interleukin 2 immune complexes (IL-2c) downregulated hepatic expression of Opn and Tnf, reduced frequency of intrahepatic CD8+ lymphocytes, and diminished biliary injury and fibrosis. Treatment with IL-2c upregulated hepatic Treg expression of CD39, an ectonucleotidase capable of hydrolyzing pro-inflammatory adenosine triphosphate. In vitro, Tregs expressing CD39 suppressed the proliferation of hepatic CD8+ lymphocytes from Mdr2-/- mice more efficiently than those lacking CD39. In infants with BA, infiltration of interlobular bile ducts with CD8+ cells was associated with biliary expression of Opn and its transcription was negatively correlated with mRNA expression of Treg-associated genes. Conclusion: Hepatic CD8+ T lymphocytes drive biliary injury and fibrosis in murine SC. Their proliferation is controlled by hepatic Tregs through the purinergic pathway, which is responsive to IL-2c, suggesting that Treg-directed low-dose Il-2 treatment may be considered as therapy for SC.
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Affiliation(s)
- Amy E. Taylor
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | - Alexandra N. Carey
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | - Ramesh Kudira
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | - Celine S. Lages
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | - Tiffany Shi
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | - Simon Lam
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH,Department of Pediatrics, University of Calgary, Calgary, AB
| | - Rebekah Karns
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | - Julia Simmons
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | - Kumar Shanmukhappa
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | - Maha Almanan
- Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | - Claire A. Chougnet
- Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Alexander G. Miethke
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH,Corresponding author: Alexander G Miethke, MD, Mail location 2010, 3333 Burnet Avenue, Cincinnati, Ohio, 45229-3026, Tel: 1-513-636-9078, Fax: 1-513-636-7805;
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Teymouri M, Pirro M, Fallarino F, Gargaro M, Sahebkar A. IL-35, a hallmark of immune-regulation in cancer progression, chronic infections and inflammatory diseases. Int J Cancer 2018; 143:2105-2115. [DOI: 10.1002/ijc.31382] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Affiliation(s)
- Manouchehr Teymouri
- Department of Pharmacology, School of Medicine, Biotechnology Research Center; Birjand University of Medical Sciences; Birjand Iran
| | - Matteo Pirro
- Unit of Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of Medicine; University of Perugia; Perugia Italy
| | | | - Marco Gargaro
- Department of Experimental Medicine; University of Perugia; Perugia Italy
- Department of Pathology and Immunology; School of Medicine, Washington University; St. Louis MO
| | - Amirhosein Sahebkar
- Pharmaceutical Technology Institute, Biotechnology Research Center, Mashhad University of Medical Sciences; Mashhad Iran
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences; Mashhad Iran
- School of Pharmacy; Mashhad University of Medical Sciences; Mashhad Iran
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Wang F, Zhang W, Wu T, Chu H. Reduced interleukin-38 in non-small cell lung cancer is associated with tumour progression. Open Biol 2018; 8:180132. [PMID: 30381361 PMCID: PMC6223208 DOI: 10.1098/rsob.180132] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Accepted: 09/16/2018] [Indexed: 01/05/2023] Open
Abstract
Lung cancer continues to be the leading cause of cancer-related deaths worldwide due to its high incidence, malignant behaviour and lack of major advancements in treatment strategy. The occurrence and development of lung cancer is closely related to inflammation. Thus, we conducted the present study to investigate the effects of IL-38 (interleukin-38), a newly identified anti-inflammatory factor, on non-small cell lung cancer (NSCLC), which accounts for about 85% of all lung cancers. We first evaluated the IL-38 expression in 384 pairs of NSCLC samples and their adjacent normal mucosa by real-time PCR, ELISA (enzyme-linked immunoassay) and tissue microarrays. Then the role of IL-38 on patient survival rates, cancer progression and their sensitivity to chemotherapy drugs was assessed. IL-38 was barely expressed in the NSCLC tissues but highly expressed in the adjacent normal tissues. The downregulation of IL-38 was significantly correlated with the results of the American Joint Committee on Cancer stage and degree of differentiation, and it was also shown to be an independent prognostic indicator of disease-free survival and overall survival for patients with NSCLC. Overexpression of IL-38 in NSCLC cells suppressed cell migration, invasion, proliferation and colony formation through suppressing β-catenin. IL-38 inhibited NSCLC formation in a mice model and sensitized the cancer cells to chemotherapy drugs. Our results show that IL-38 plays an inhibitory role in NSCLC development and functions as a novel prognostic indicator and a potential therapeutic target.
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Affiliation(s)
- Feng Wang
- Department of Respiration, The 1st Hospital of Shangqiu, Shangqiu 476100, People's Republic of China
| | - Weihua Zhang
- Department of Respiration, The 1st Hospital of Shangqiu, Shangqiu 476100, People's Republic of China
| | - Tianfeng Wu
- Department of Cancer, The 1st Hospital of Shangqiu, Shangqiu 476100, People's Republic of China
| | - Heying Chu
- Department of Respiration, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450002, People's Republic of China
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45
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Jing CY, Fu YP, Huang JL, Zhang MX, Yi Y, Gan W, Xu X, Shen HJ, Lin JJ, Zheng SS, Zhang J, Zhou J, Fan J, Ren ZG, Qiu SJ, Zhang BH. Prognostic Nomogram Based on Histological Characteristics of Fibrotic Tumor Stroma in Patients Who Underwent Curative Resection for Intrahepatic Cholangiocarcinoma. Oncologist 2018; 23:1482-1493. [PMID: 30257891 DOI: 10.1634/theoncologist.2017-0439] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Accepted: 04/05/2018] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Fibrotic tumor stroma (FTS) has been implicated in cancer promotion in several neoplasms. The histological features of FTS are convenient and easily accessible in clinical routine in intrahepatic cholangiocarcinoma (ICC) specimens. The goal of this study was to explore prognostic impacts of the quantity and maturity of FTS on surgical ICC patients. Moreover, we aimed to propose an efficient prognostic nomogram for postoperative ICC patients. MATERIALS AND METHODS The clinical profiles of 154 consecutive postoperative ICC patients were retrospectively analyzed. Tumor-stroma ratio and morphological maturity of FTS were evaluated on hematoxylin and eosin-stained tumor sections. CD3, CD8, and α-smooth muscle actin (α-SMA) staining were performed on corresponding tissue microarrays. The nomogram was established on variables selected by multivariate analyses and was validated in 10-fold cross-validation. RESULTS Rich tumor stroma and strong α-SMA expression were associated with poor overall survival (OS). However, in multivariate analyses, these two biomarkers failed to stratify both OS and recurrence-free survival (RFS). Immature FTS was correlated with tumor multiplicity, advanced clinical stage, and sparser CD3 and CD8 positive tumor-infiltrating lymphocytes (TILs) and was identified as an independent prognostic indicator for both OS and RFS. The nomogram comprising FTS maturity, tumor number, microvascular invasion, and lymph node metastasis possessed higher predictive power relative to conventional staging systems. CONCLUSION Immature FTS was an independent risk factor for survival and was associated with sparser CD3 and CD8 positive TILs in ICC. The prognostic nomogram integrating the maturity of FTS offers a more accurate risk stratification for postoperative ICC patients. IMPLICATIONS FOR PRACTICE Accumulating evidence has suggested that fibrotic components in tumor microenvironment (TME) play a complicated and vital role in TME reprogramming and cancer progression. However, in clinical practice, the evaluation of fibrotic tumor stroma (FTS) is still neglected to some extent. This study's findings indicated that, in intrahepatic cholangiocarcinoma (ICC), the histological maturity of FTS is a robust prognostic indicator for patients who underwent curative resection. Moreover, prognostic nomogram constructed on the maturity of FTS possessed higher predictive power relative to the conventional tumor-node-metastasis staging systems. Taken together, the evaluation of FTS should be emphasized in clinical routine for more accurate prognostic prediction in postoperative ICC patients.
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Affiliation(s)
- Chu-Yu Jing
- The Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, People's Republic of China
| | - Yi-Peng Fu
- Department of Breast Surgery, The Obstetrics & Gynecology Hospital of Fudan University, Shanghai, People's Republic of China
| | - Jin-Long Huang
- The Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, People's Republic of China
| | - Mei-Xia Zhang
- The Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, People's Republic of China
| | - Yong Yi
- The Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, People's Republic of China
| | - Wei Gan
- The Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, People's Republic of China
| | - Xin Xu
- The Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, People's Republic of China
| | - Hu-Jia Shen
- The Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, People's Republic of China
| | - Jia-Jia Lin
- The Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, People's Republic of China
| | - Su-Su Zheng
- The Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, People's Republic of China
| | - Juan Zhang
- The Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, People's Republic of China
| | - Jian Zhou
- The Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, People's Republic of China
| | - Jia Fan
- The Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, People's Republic of China
| | - Zheng-Gang Ren
- The Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, People's Republic of China
| | - Shuang-Jian Qiu
- The Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, People's Republic of China
| | - Bo-Heng Zhang
- The Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, People's Republic of China
- Center for Evidence-Based Medicine, Shanghai Medical School, Fudan University, Shanghai, People's Republic of China
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Kurebayashi Y, Ojima H, Tsujikawa H, Kubota N, Maehara J, Abe Y, Kitago M, Shinoda M, Kitagawa Y, Sakamoto M. Landscape of immune microenvironment in hepatocellular carcinoma and its additional impact on histological and molecular classification. Hepatology 2018; 68:1025-1041. [PMID: 29603348 DOI: 10.1002/hep.29904] [Citation(s) in RCA: 324] [Impact Index Per Article: 46.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Revised: 03/17/2018] [Accepted: 03/25/2018] [Indexed: 12/12/2022]
Abstract
UNLABELLED Immune cells constitute an important element of tumor tissue. Accumulating evidence indicates their clinicopathological significance in predicting prognosis and therapeutic efficacy. Nonetheless, the combinations of immune cells forming the immune microenvironment and their association with histological findings remain largely unknown. Moreover, it is unclear which immune cells or immune microenvironments are the most prognostically significant. Here, we comprehensively analyzed the immune microenvironment and its intratumor heterogeneity in 919 regions of 158 hepatocellular carcinomas (HCCs), and the results were compared with the corresponding histological and prognostic data. Consequently, we classified the immune microenvironment of HCC into three distinct immunosubtypes: Immune-high, Immune-mid, and Immune-low. The Immune-high subtype was characterized by increased B-/plasma-cell and T cell infiltration, and the Immune-high subtype and B-cell infiltration were identified as independent positive prognostic factors. Varying degrees of intratumor heterogeneity of the immune microenvironment were observed, some of which reflected the multistep nature of HCC carcinogenesis. However, the predominant pattern of immunosubtype and immune cell infiltration of each tumor was prognostically important. Of note, the Immune-high subtype was associated with poorly differentiated HCC, cytokeratin 19 (CK19)+ , and/or Sal-like protein 4 (SALL4)+ high-grade HCC, and Hoshida's S1/Boyault's G2 subclasses. Furthermore, patients with high-grade HCC of the predominant Immune-high subtype had significantly better prognosis. These results provide a rationale for evaluating the immune microenvironment in addition to the usual histological/molecular classification of HCC. CONCLUSION The immune microenvironment of HCC can be classified into three immunosubtypes (Immune-high, Immune-mid, and Immune-low) with additional prognostic impact on histological and molecular classification of HCC. (Hepatology 2018).
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Affiliation(s)
- Yutaka Kurebayashi
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Hidenori Ojima
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Hanako Tsujikawa
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Naoto Kubota
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Junki Maehara
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan.,Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yuta Abe
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Minoru Kitago
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Masahiro Shinoda
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Yuko Kitagawa
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Michiie Sakamoto
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
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47
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Zhang MX, Gan W, Jing CY, Zheng SS, Zhang J, Shen HJ, Xu X, Lin JJ, Zhang BH, Qiu SJ. Overexpression of interleukin-35 in intrahepatic cholangiocarcinoma is a prognostic indicator after curative resection. Cancer Sci 2018; 109:1195-1206. [PMID: 29446854 PMCID: PMC5891208 DOI: 10.1111/cas.13535] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 02/08/2018] [Accepted: 02/10/2018] [Indexed: 02/06/2023] Open
Abstract
Interleukin‐35 (IL‐35) is implicated in tumorigenesis, but its exact impact on intrahepatic cholangiocarcinoma (ICC) is not clear. The aim of the present study was to explore the specific effect of IL‐35 on patient prognosis. Additionally, we formulated an effective prognostic nomogram for ICC patients after curative resection. Immunohistochemistry was applied to explore IL‐35 expression as well as IL‐35 receptor (IL‐35R) in 102 ICC patients. Results showed that IL‐35 was highly expressed in ICC tumor tissues and was positively associated with lymph node metastasis (LNM), TNM stage and vascular invasion and was an independent prognostic factor for patients' overall survival (OS) and recurrence‐free survival (RFS). High expression of IL‐35R (gp130 and IL‐12Rβ2) was also observed in ICC cancer tissues, but only gp130 was an independent prognostic factor for OS and RFS and was indispensable in IL‐35‐mediated ICC clinical prognosis. The nomogram comprising carcinoembryonic antigen, LNM, IL‐35 and gp130 expression achieved better predictive accuracy compared with TNM stage for OS. Our data support that high IL‐35 expression correlates with ICC aggressiveness and emerges as a valuable biomarker for evaluating ICC progression and prognosis in clinical work.
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Affiliation(s)
- Mei-Xia Zhang
- Liver Cancer Institute and Zhongshan Hospital of Fudan University, Shanghai, China
| | - Wei Gan
- Liver Cancer Institute and Zhongshan Hospital of Fudan University, Shanghai, China
| | - Chu-Yu Jing
- Liver Cancer Institute and Zhongshan Hospital of Fudan University, Shanghai, China
| | - Su-Su Zheng
- Liver Cancer Institute and Zhongshan Hospital of Fudan University, Shanghai, China
| | - Juan Zhang
- Liver Cancer Institute and Zhongshan Hospital of Fudan University, Shanghai, China
| | - Hu-Jia Shen
- Liver Cancer Institute and Zhongshan Hospital of Fudan University, Shanghai, China
| | - Xin Xu
- Liver Cancer Institute and Zhongshan Hospital of Fudan University, Shanghai, China
| | - Jia-Jia Lin
- Liver Cancer Institute and Zhongshan Hospital of Fudan University, Shanghai, China
| | - Bo-Heng Zhang
- Liver Cancer Institute and Zhongshan Hospital of Fudan University, Shanghai, China.,Center for Evidence-Based Medicine, Fudan University, Shanghai, China
| | - Shuang-Jian Qiu
- Liver Cancer Institute and Zhongshan Hospital of Fudan University, Shanghai, China
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48
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Song Q, Chen X, Hu W, Mei G, Yang X, Wu H. Downregulation of Epstein-Barr virus-induced gene 3 is associated with poor prognosis of hepatocellular carcinoma after curative resection. Oncol Lett 2018; 15:7751-7759. [PMID: 29740492 PMCID: PMC5934722 DOI: 10.3892/ol.2018.8272] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Accepted: 01/19/2018] [Indexed: 01/13/2023] Open
Abstract
Epstein-Barr virus-induced gene 3 (EBI3) encodes a secretory glycoprotein, and has previously been identified as upregulated in various types of tumors. The presnet study examined the clinical significance of EBI3 expression for predicting tumor recurrence and survival after resection in hepatocellular carcinoma (HCC). EBI3 expression in various HCC cell lines and in 20 pairs of tumor and peritumor tissue samples were detected using western blot analysis. Immunohistochemical staining using tissue microarray with 312 samples from randomly selected patients with HCC who underwent surgery. Survival analysis was performed using univariate and multivariate analyses. EBI3 protein level was higher in L-02 cells and in peri-tumor tissues compared with tumor tissues. Immunohistochemical staining of EBI3 was reduced in HCC tissues in comparison with adjacent normal tissues and significantly associated with tumor invasive characteristics, including tumor thrombus, poor differentiation and large size. Notably, the results suggested that EBI3 was a predictor for tumor recurrence and patient survival, and multivariate analysis indicated EBI3 to be an independent prognostic factor. Even in early-stage disease, low EBI3 expression was also independently associated with increased tumor recurrence and shortened survival. Downregulation of EBI3 in HCC indicated aggressive tumor behaviors and predicted a more severe clinical outcome, which suggests that EBI2 may be a useful biomarker to identify patients at high risk of post-operative recurrence.
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Affiliation(s)
- Qingjie Song
- Department of General Surgery, The Qidong People's Hospital and Qidong Liver Cancer Institute, Nantong, Jiangsu 226200, P.R. China
| | - Xi Chen
- Department of General Surgery, The Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Weidong Hu
- Department of General Surgery, The Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Guanglin Mei
- Department of General Surgery, The Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Xiaobing Yang
- Department of General Surgery, The Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Han Wu
- Department of General Surgery, The Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
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Cheng ST, Yuan D, Liu Y, Huang Y, Chen X, Yu HB, He L, Jiang H, Ren JH, Chen J. Interleukin-35 Level Is Elevated in Patients with Chronic Hepatitis B Virus Infection. Int J Med Sci 2018; 15:188-194. [PMID: 29333103 PMCID: PMC5765732 DOI: 10.7150/ijms.21957] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Accepted: 11/13/2017] [Indexed: 02/07/2023] Open
Abstract
Backgrounds: As one of the major public health problems, the hepatitis B virus (HBV) infection would activate the immune system. The outcome of HBV infection was affect significantly by the interactions between HBV and host immune response. Interleukins play important role in anti-viral immunity. Here we investigated the role of interleukin-35 (IL-35) in chronic HBV infection patients. Methods/Results: Serum IL-35 in 72 chronic hepatitis B virus infection patients and 41 healthy control subjects were analyzed by ELISA assay. The mRNA level of IL-35 in PBMCs was determined by RT-qPCR. In this study, we found that both protein and mRNA levels of IL-35 were significantly decreased in chronic HBV patients compared to the healthy controls. Furthermore, the statistical analysis found that serum IL-35 was significantly associated with HBV DNA (P =0.0158), ALT (P =0.0003), AST (P =0.0216), TB (P =0.0270) and AFP (P =0.0369). Importantly, correlation analysis also found that serum IL-35 level was negatively correlated with HBV DNA copies, ALT, AST, TB and AFP. Meanwhile, IL-35 treatment inhibited the level of HBV DNA, HBsAg and HBeAg in HepAD38 cells. Conclusion: Our study identified that IL-35 may be a novel marker associated with HBV infection and hepatocytes injury. These data suggested the potential use of IL-35 in the HBV treatment.
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Affiliation(s)
- Sheng-Tao Cheng
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), The Second Affiliated Hospital, Chongqing Medical University, Chongqing Medical University, Chongqing, China
| | - Ding Yuan
- Department of Neurosurgery, The Fifth People's Hospital of Chongqing, Chongqing, China
| | - Yi Liu
- Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Ying Huang
- Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Xiang Chen
- Department of Clinical Laboratory, Zhuzhou Central Hospital, Zhuzhou, China
| | - Hai-Bo Yu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), The Second Affiliated Hospital, Chongqing Medical University, Chongqing Medical University, Chongqing, China
| | - Lin He
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), The Second Affiliated Hospital, Chongqing Medical University, Chongqing Medical University, Chongqing, China
| | - Hui Jiang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), The Second Affiliated Hospital, Chongqing Medical University, Chongqing Medical University, Chongqing, China
| | - Ji-Hua Ren
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), The Second Affiliated Hospital, Chongqing Medical University, Chongqing Medical University, Chongqing, China
| | - Juan Chen
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), The Second Affiliated Hospital, Chongqing Medical University, Chongqing Medical University, Chongqing, China
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Huang JL, Fu YP, Jing CY, Yi Y, Sun J, Gan W, Lu ZF, Zhou J, Fan J, Qiu SJ. A novel and validated prognostic nomogram based on liver fibrosis and tumor burden for patients with hepatocellular carcinoma after curative resection. J Surg Oncol 2017; 117:625-633. [PMID: 29165812 DOI: 10.1002/jso.24895] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Accepted: 10/02/2017] [Indexed: 12/21/2022]
Abstract
BACKGROUND AND OBJECTIVES Most conventional staging systems were formulated concerning the tumor burden rather than the severity of liver fibrosis, which plays a central role in tumor promotion. The aim of this study was to formulate a prognostic nomogram comprehensively considering these two aspects for HCC after hepatectomy. METHODS The prognostic significances of the four indicators namely laminin, hyaluronic acid, human procollagen type-III, and collagen type-IV that reflect liver fibrosis were explored in two independent cohorts. A nomogram was established based on the results of multivariate analysis. The predictive accuracy of the nomogram was measured by concordance index (C-index) and calibration. The decision curve analysis (DCA) was used to evaluate the clinical benefit of the nomogram. RESULTS Preoperative serum laminin level is an independent prognostic factor for overall survival in HCC patients after resection. The C-indices of the nomogram in the training and validation cohorts were 0.779 and 0.719, respectively. The calibration showed optimal agreement between the prediction by nomogram and actual observation. Moreover, the C-indices and DCA revealed that the nomogram provided better clinical benefit compared with the BCLC stage, CLIP score, and AJCC 7th edition. CONCLUSIONS The prognostic nomogram constructed on laminin represents a superior predictive model.
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Affiliation(s)
- Jin-Long Huang
- Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis & Cancer Invasion, The Chinese Ministry of Education, Shanghai, People's Republic of China
| | - Yi-Peng Fu
- Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis & Cancer Invasion, The Chinese Ministry of Education, Shanghai, People's Republic of China
| | - Chu-Yu Jing
- Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis & Cancer Invasion, The Chinese Ministry of Education, Shanghai, People's Republic of China
| | - Yong Yi
- Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis & Cancer Invasion, The Chinese Ministry of Education, Shanghai, People's Republic of China
| | - Jian Sun
- Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis & Cancer Invasion, The Chinese Ministry of Education, Shanghai, People's Republic of China
| | - Wei Gan
- Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis & Cancer Invasion, The Chinese Ministry of Education, Shanghai, People's Republic of China
| | - Zhu-Feng Lu
- Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis & Cancer Invasion, The Chinese Ministry of Education, Shanghai, People's Republic of China
| | - Jian Zhou
- Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis & Cancer Invasion, The Chinese Ministry of Education, Shanghai, People's Republic of China
| | - Jia Fan
- Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis & Cancer Invasion, The Chinese Ministry of Education, Shanghai, People's Republic of China
| | - Shuang-Jian Qiu
- Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis & Cancer Invasion, The Chinese Ministry of Education, Shanghai, People's Republic of China.,Biomedical Research Center, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
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