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Mohamed NM, Mohamed RH, Kennedy JF, Elhefnawi MM, Hamdy NM. A comprehensive review and in silico analysis of the role of survivin (BIRC5) in hepatocellular carcinoma hallmarks: A step toward precision. Int J Biol Macromol 2025; 311:143616. [PMID: 40306500 DOI: 10.1016/j.ijbiomac.2025.143616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Revised: 04/25/2025] [Accepted: 04/27/2025] [Indexed: 05/02/2025]
Abstract
Hepatocellular carcinoma (HCC) is a complex malignancy driven by the dysregulation of multiple cellular pathways. Survivin, a key member of the inhibitor of apoptosis (IAP) family, plays a central role in HCC tumorigenesis and progression. Despite significant research, a comprehensive understanding of the contributions of survivin to the hallmarks of cancer, its molecular network, and its potential as a therapeutic target remains incomplete. In this review, we integrated bioinformatics analysis with an extensive literature review to provide deeper insights into the role of survivin in HCC. Using bioinformatics tools such as the Human Protein Atlas, GEPIA, STRING, TIMER, and Metascape, we analyzed survivin expression and its functional associations and identified the top 20 coexpressed genes in HCC. These include TK1, SPC25, SGO2, PTTG1, PRR11, PLK1, NCAPH, KPNA2, KIF2C, KIF11, HJURP, GTSE1, FOXM1, CEP55, CENPA, CDCA3, CDC45, CCNB2, CCNB1 and CTD-2510F5.4. Our findings also revealed significant protein-protein interactions among these genes, which were enriched in pathways associated with the FOXM1 oncogenic signaling cascade, and biological processes such as cell cycle regulation, mitotic checkpoints, and diseases such as liver neoplasms. We also discussed the involvement of survivin in key oncogenic pathways, including the PI3K/AKT, WNT/β-catenin, Hippo, and JAK/STAT3 pathways, and its role in modulating cell cycle checkpoints, apoptosis, and autophagy. Furthermore, we explored its interactions with the tumor microenvironment, particularly its impact on immune modulation through myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages, and natural killer cell function in HCC. Additionally, we highlighted its involvement in alkylglycerone phosphate synthase (AGPS)-mediated lipid reprogramming and identified important gaps in the survivin network that warrant further investigation. This review also examined the role of survivin in cancer stemness, inflammation, and virally mediated hepatocarcinogenesis. We evaluated its potential as a diagnostic, prognostic, predictive, and pharmacodynamic biomarker in HCC, emphasizing its relevance in precision medicine. Finally, we summarized emerging survivin-targeted therapeutics and ongoing clinical trials, underscoring the need for novel strategies to effectively target survivin in HCC.
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Affiliation(s)
- Nermin M Mohamed
- Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Abassia, 11566 Cairo, Egypt
| | - Rania Hassan Mohamed
- Department of Biochemistry, Faculty of Science, Ain Shams University, Abassia, 11566 Cairo, Egypt
| | - John F Kennedy
- Chembiotech Laboratories, Kyrewood House, Tenbury Wells, Worcestershire, United Kingdom
| | - Mahmoud M Elhefnawi
- Biomedical Informatics and Chemoinformatics Group, Informatics and Systems Department, National Research Centre, Cairo, Egypt.
| | - Nadia M Hamdy
- Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Abassia, 11566 Cairo, Egypt.
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Wang X, Yang T, Shi X. NK cell-based immunotherapy in hepatocellular carcinoma: An attractive therapeutic option for the next decade. Cell Signal 2024; 124:111405. [PMID: 39260532 DOI: 10.1016/j.cellsig.2024.111405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 08/27/2024] [Accepted: 09/08/2024] [Indexed: 09/13/2024]
Abstract
Hepatocellular carcinoma (HCC), a major subtype of liver cancer, poses significant therapeutic challenges due to its late diagnosis and rapid progression. The evolving landscape of immunotherapy offers a beacon of hope, with natural killer (NK) cells emerging as pivotal players in combating HCC. NK cells are unique cytotoxic lymphocytes that are essential in the fight against infections and malignancies. Phenotypic and functional NK cell abnormalities have been shown in HCC patients, indicating their significance as a component of the innate immune system against cancer. This review elucidates the critical role of NK cells in combating HCC, focusing on their interaction with the tumor microenvironment, the development of NK cell-based therapies, and the innovative strategies to enhance their efficacy in the immunosuppressive milieu of HCC. The review delves into the various therapeutic strategies, including autologous and allogeneic NK cell therapies, genetic engineering to improve NK cell resilience and targeting, and the integration of NK cells with other immunotherapeutic approaches like checkpoint inhibitors and oncolytic virotherapy. By highlighting recent advancements and the ongoing challenges in the field, this review sets the stage for future research directions that could unlock the full potential of NK cell-based immunotherapy for HCC, offering a beacon of hope for patients battling this formidable cancer.
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Affiliation(s)
- Xinyi Wang
- The First Clinical Medical College, Nanjing Medical University, Nanjing, Jiangsu Province 210009, China
| | - Tianye Yang
- The First Clinical Medical College, Nanjing Medical University, Nanjing, Jiangsu Province 210009, China
| | - Xiaoli Shi
- Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Transplantation, Chinese Academy of Medical Sciences, Nanjing, Jiangsu Province 210029, China; Department of General Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
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Hu X, Shui Y, Shimizu S, Sakamoto S, Kasahara M, Okada S, Guo WZ, Fujino M, Li XK. Targeted immune cell therapy for hepatocellular carcinoma using expanded liver mononuclear cell-derived natural killer cells. Neoplasia 2024; 58:101061. [PMID: 39357263 PMCID: PMC11471252 DOI: 10.1016/j.neo.2024.101061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Revised: 09/07/2024] [Accepted: 09/21/2024] [Indexed: 10/04/2024]
Abstract
Natural killer (NK) cells are a promising cellular therapy for T cell-refractory cancers but are frequently deficient or dysfunctional in patients with hepatocellular carcinoma (HCC). In the present study, we explored a novel therapy for HCC using NK cells derived from donor liver graft perfusate. These liver-derived NK cells, named LMNC-NK cells, are more abundant in liver mononuclear cells (LMNCs) than in peripheral blood mononuclear cells (PBMCs) from the same donor. We developed a method to expand LMNC-NK cells by 33.8±54.4-fold, enhancing their cytotoxic properties and cytokine production, including granzyme B, CD107a, TNF-α, and IFN-γ. These cells also showed an increased expression of cytotoxicity receptors. An RNA-seq analysis revealed considerable differences in gene expression between LMNC-NK and PBMC-NK cells, with 453 genes upregulated and 449 downregulated in LMNC-NK cells. These genes are involved in the mitogen-activated protein kinase cascade and cell differentiation, explaining the increased activity of LMNC-NK cells. Quantitative reverse transcription polymerase chain reaction confirmed the significant upregulation of TLR6, KIT, MMP14, IRF8, TCF7, FCERIG, LEF1, NLRp3, and IL16 in LMNC-NK cells. LMNC-NK cells effectively eliminated HepG-2-Luc cells in vitro, and in an orthotopic murine model of HCC, they exhibited a potent anti-tumor effect, outperforming PBMC-NK cells. The expression of the activation marker CD69+ in LMNC-NK cells was also significantly higher among tumor-infiltrating lymphocytes compared to PBMC-NK cells. Our research suggests that the adoptive transfer of LMNC-NK cells could be a promising treatment for HCC, offering a novel and effective source of NK cells with superior cytotoxic functions.
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MESH Headings
- Carcinoma, Hepatocellular/therapy
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/genetics
- Liver Neoplasms/immunology
- Liver Neoplasms/therapy
- Liver Neoplasms/pathology
- Liver Neoplasms/genetics
- Humans
- Killer Cells, Natural/immunology
- Killer Cells, Natural/metabolism
- Animals
- Mice
- Leukocytes, Mononuclear/immunology
- Leukocytes, Mononuclear/metabolism
- Xenograft Model Antitumor Assays
- Cell Line, Tumor
- Disease Models, Animal
- Cytotoxicity, Immunologic
- Cell- and Tissue-Based Therapy/methods
- Liver/immunology
- Liver/metabolism
- Liver/pathology
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Affiliation(s)
- Xin Hu
- Laboratory of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Yifang Shui
- Laboratory of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan; Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China
| | - Seiichi Shimizu
- Center for Organ Transplantation, National Center for Child Health and Development, Tokyo, Japan
| | - Seisuke Sakamoto
- Center for Organ Transplantation, National Center for Child Health and Development, Tokyo, Japan
| | - Mureo Kasahara
- Center for Organ Transplantation, National Center for Child Health and Development, Tokyo, Japan
| | - Seiji Okada
- Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan
| | - Wen-Zhi Guo
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China.
| | - Masayuki Fujino
- Laboratory of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan; Management Department of Biosafety, Laboratory Animal, and Pathogen Bank, National Institute of Infectious Diseases, Tokyo, Japan.
| | - Xiao-Kang Li
- Laboratory of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan; Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China.
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Luo T, Chen X, Pan W, Zhang S, Huang J. The sorafenib resistance-related gene signature predicts prognosis and indicates immune activity in hepatocellular carcinoma. Cell Cycle 2024; 23:150-168. [PMID: 38444181 PMCID: PMC11037289 DOI: 10.1080/15384101.2024.2309020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Revised: 12/14/2023] [Accepted: 12/15/2023] [Indexed: 03/07/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death worldwide. Most patients with advanced HCC acquire sorafenib resistance. Drug resistance reflects the heterogeneity of tumors and is the main cause of tumor recurrence and death.We identified and validated sorafenib resistance related-genes (SRGs) as prognostic biomarkers for HCC. We obtained SRGs from the Gene Expression Omnibus and selected four key SRGs using the least absolute shrinkage and selection operator, random forest, and Support Vector Machine-Recursive feature elimination machine learning algorithms. Samples from the The Cancer Genome Atlas (TCGA)-HCC were segregated into two groups by consensus clustering. Following difference analysis, 19 SRGs were obtained through univariate Cox regression analysis, and a sorafenib resistance model was constructed for risk stratification and prognosis prediction. In multivariate Cox regression analysis, the risk score was an independent predictor of overall survival (OS). Patients classified as high-risk were more sensitive to other chemotherapy drugs and showed a higher expression of the common immune checkpoints. Additionally, the expression of drug-resistance genes was verified in the International Cancer Genome Consortium cohort. A nomogram model with a risk score was established, and its prediction performance was verified by calibration chart analysis of the TCGA-HCC cohort. We conclude that there is a significant correlation between sorafenib resistance and the tumor immune microenvironment in HCC. The risk score could be used to identify a reliable prognostic biomarker to optimize the therapeutic benefits of chemotherapy and immunotherapy, which can be helpful in the clinical decision-making for HCC patients.
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Affiliation(s)
- Tianxin Luo
- School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, China
| | - Xiaomei Chen
- School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, China
| | - Wei Pan
- Prenatal Diagnosis Center, the Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Shu Zhang
- School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, China
- Center for Clinical Laboratories, the Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Jian Huang
- Center for Clinical Laboratories, the Affiliated Hospital of Guizhou Medical University, Guiyang, China
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Ahmad MF, Ahmad FA, Zeyaullah M, Alsayegh AA, Mahmood SE, AlShahrani AM, Khan MS, Shama E, Hamouda A, Elbendary EY, Attia KAHA. Ganoderma lucidum: Novel Insight into Hepatoprotective Potential with Mechanisms of Action. Nutrients 2023; 15:1874. [PMID: 37111092 PMCID: PMC10146730 DOI: 10.3390/nu15081874] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 04/03/2023] [Accepted: 04/09/2023] [Indexed: 04/29/2023] Open
Abstract
Ganoderma lucidum (G. lucidum) has been widely used for its health benefits as an edible and traditional medicinal mushroom for thousands of years in Asian countries. It is currently used as a nutraceutical and functional food owing to its major bioactive compounds, polysaccharides and triterpenoids. G. lucidum exhibits a broad range of hepatoprotective impacts in various liver disorders, such as hepatic cancer, nonalcoholic fatty liver disease (NAFLD), alcohol-induced liver disease, hepatitis B, hepatic fibrosis, and liver injury induced by carbon tetrachloride (CCl4) and α-amanitin. G. lucidum protects the liver through a broad range of mechanisms that include the modulation of liver Phase I and II enzymes, the suppression of β-glucuronidase, antifibrotic and antiviral actions, the regulation of the production of nitric oxide (NO), the maintenance of hepatocellular calcium homeostasis, immunomodulatory activity, and scavenging free radicals. G. lucidum could signify an encouraging approach for the management of various chronic hepatopathies, and its potential mechanisms make it a distinctive agent when used alone or with other drugs and applied as a functional food, nutraceutical supplement, or adjuvant to modern medicine. This review summarizes the hepatoprotective properties of G. lucidum with its various mechanisms of action on different liver ailments. Biologically active substances derived from G. lucidum are still being studied for their potential benefits in treating different liver ailments.
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Affiliation(s)
- Md Faruque Ahmad
- Department of Clinical Nutrition, College of Applied Medical Sciences, Jazan University, Jazan 45142, Saudi Arabia
| | - Fakhruddin Ali Ahmad
- Department Forensic Science, School of Engineering and Science, G.D Goenka University, Gurugram 122103, Haryana, India;
| | - Md. Zeyaullah
- Department of Basic Medical Science, College of Applied Medical Sciences, Khamis Mushayt Campus, King Khalid University (KKU), Abha 62561, Saudi Arabia
| | - Abdulrahman A. Alsayegh
- Department of Clinical Nutrition, College of Applied Medical Sciences, Jazan University, Jazan 45142, Saudi Arabia
| | - Syed Esam Mahmood
- Department of Family and Community Medicine, College of Medicine, King Khalid University, Abha 62529, Saudi Arabia
| | - Abdullah M. AlShahrani
- Department of Basic Medical Science, College of Applied Medical Sciences, Khamis Mushayt Campus, King Khalid University (KKU), Abha 62561, Saudi Arabia
| | - Mohammad Suhail Khan
- Department of Public Health, College of Applied Medical Sciences, Khamis Mushayt Campus, King Khalid University (KKU), Abha 62561, Saudi Arabia
| | - Eman Shama
- Department of Clinical Nutrition, College of Applied Medical Sciences, Jazan University, Jazan 45142, Saudi Arabia
| | - Alshaimaa Hamouda
- Department of Clinical Nutrition, College of Applied Medical Sciences, Jazan University, Jazan 45142, Saudi Arabia
| | - Ehab Y. Elbendary
- Department of Clinical Nutrition, College of Applied Medical Sciences, Jazan University, Jazan 45142, Saudi Arabia
| | - Kandil Abdel Hai Ali Attia
- Department of Clinical Nutrition, College of Applied Medical Sciences, Jazan University, Jazan 45142, Saudi Arabia
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Feng GY, Shi ZR, Zhao YF, Chen K, Tao J, Wei XF, Cheng Y. Therapeutic effect of postoperative adjuvant transcatheter arterial chemoembolization based on the neutrophil-to-lymphocyte ratio. Front Surg 2023; 9:1072451. [PMID: 36684128 PMCID: PMC9852644 DOI: 10.3389/fsurg.2022.1072451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 11/21/2022] [Indexed: 01/09/2023] Open
Abstract
Aim To evaluate the feasibility of the preoperative neutrophil-to-lymphocyte ratio (NLR) as an index to guide postoperative adjuvant transcatheter arterial chemoembolization (PA-TACE) in patients with liver cancer. Methods We recruited a total of 166 patients with liver cancer who underwent surgery alone or surgery plus PA-TACE between January 2013 and June 2017 and compared the 1, 2, and 3-year recurrence-free survival (RFS) and overall survival (OS) between patients with high and low NLRs, surgery and surgery plus PA-TACE groups, and relevant subgroups using the Kaplan-Meier method. We also evaluated the independent factors affecting the prognosis of liver cancer after surgery using a Cox risk ratio model and correlation between NLR levels and high-risk recurrence factors of liver cancer with logistic regression analysis. Results The 1, 2, and 3-year RFS rates were all significantly higher in the low-NLR group compared to the high-NLR group (P < 0.05). However, the 1, 2, and 3-year OS rates were similar in the low- and high-NLR groups (P > 0.05). After propensity score matching, the 1, 2, and 3-year RFS and OS rates were significantly better in patients treated with surgery plus PA-TACE compared with surgery alone (P < 0.05). The 1, 2, and 3-year RFS and OS rates were also significantly better in the surgery plus PA-TACE subgroup compared with the surgery-alone subgroup in the high-NLR group (P < 0.05), but there was no significant difference in RFS or OS between the surgery plus PA-TACE and surgery-alone subgroups at 1, 2, and 3 years in the low-NLR group (P > 0.05). Multivariate analysis in the high-NLR group showed that a poorly differentiated or undifferentiated tumor was an independent risk factor for postoperative RFS. Multiple tumors were an independent risk factor for postoperative OS (P < 0.05), while PA-TACE was an independent protective factor for postoperative RFS and OS (P < 0.05). In the low-NLR group, AFP > 400 µg/L was an independent risk factor for postoperative OS (P < 0.05). Multivariate logistic regression indicated that patients with a maximum tumor diameter of >5 cm were at increased risk of having high NLR levels compared to patients with a maximum tumor diameter of <5 cm (P < 0.05). Conclusion PA-TACE can improve the prognosis of patients with a high preoperative NLR (≥2.5), but has no obvious benefit in patients with low preoperative NLR (<2.5). This may provide a reference for clinical selection of PA-TACE.
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Affiliation(s)
- Guo-Ying Feng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Department of Hepatobiliary Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Zheng-Rong Shi
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yu-Fei Zhao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Kai Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jie Tao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xu-Fu Wei
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yu Cheng
- Nursing Department, University-Town Hospital of Chongqing Medical University, Chongqing, China
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Bae WK, Lee BC, Kim HJ, Lee JJ, Chung IJ, Cho SB, Koh YS. A Phase I Study of Locoregional High-Dose Autologous Natural Killer Cell Therapy With Hepatic Arterial Infusion Chemotherapy in Patients With Locally Advanced Hepatocellular Carcinoma. Front Immunol 2022; 13:879452. [PMID: 35720374 PMCID: PMC9202498 DOI: 10.3389/fimmu.2022.879452] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Accepted: 05/09/2022] [Indexed: 11/15/2022] Open
Abstract
Background To explore the feasibility and safety of natural killer (NK) cell therapy in HCC, we performed a prospective, open-label, phase I trial to evaluate the synergistic effect of locoregional high-dose autologous NK cell therapy in combination with hepatic arterial infusion chemotherapy (HAIC). Methods Patients with locally advanced HCC who were refractory to the standard treatment were eligible for this study. Patients received expanded and activated NK cells for 5 consecutive days in a dose-escalating manner (dose 2.5×108, 5×108, 10×108 NK cells/injection) through hepatic arterial infusion following 4 cycles of HAIC with 5-fluorouracil (750 mg/m2) and cisplatin (25 mg/m2). The primary endpoint was the safety of NK cell-based immunotherapy, and the secondary endpoints were objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and immunologic responses. Results Of the 11 patients enrolled, the confirmed ORR was 63.6% (complete response [CR]: 36.4%, confirmed partial response [PR]: 27.3%). Stable disease (SD) and progressive disease (PD) were observed in two patients (18.2%) each, resulting in a disease control rate (DCR) of 81.8%. The median PFS and OS were 10.3 and 41.6 months, respectively. There were no incidences of decompensation or severe adverse events during HAIC, and no adverse events related to NK cell infusion were noted. Conclusion The combination of HAIC and locoregional high-dose NK cell therapy is a safe and effective treatment for locally advanced HCC patients who were refractory to the standard treatment. This result warrants further development of this novel treatment to establish its efficacy in HCC. Clinical Trial Registration cris.nih.go.kr, identifier KCT0003973.
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Affiliation(s)
- Woo Kyun Bae
- Department of Hematology-Oncology, Chonnam National University Medical School and Chonnam National University Hwasun Hospital, Hwasun, South Korea.,Immunotherapy Innovation Center, Chonnam National University Medical School and Chonnam National University Hwasun Hospital, Hwasun, South Korea
| | - Byung Chan Lee
- Department of Radiology, Chonnam National University Medical School and Chonnam National University Hwasun Hospital, Hwasun, South Korea
| | - Hyeon-Jong Kim
- Department of Hematology-Oncology, Chonnam National University Medical School and Chonnam National University Hwasun Hospital, Hwasun, South Korea
| | - Je-Jung Lee
- Department of Hematology-Oncology, Chonnam National University Medical School and Chonnam National University Hwasun Hospital, Hwasun, South Korea.,Vaxcell-Bio Therapeutics, Hwasun, South Korea
| | - Ik-Joo Chung
- Department of Hematology-Oncology, Chonnam National University Medical School and Chonnam National University Hwasun Hospital, Hwasun, South Korea.,Immunotherapy Innovation Center, Chonnam National University Medical School and Chonnam National University Hwasun Hospital, Hwasun, South Korea
| | - Sung Bum Cho
- Department of Gastroenterology, Chonnam National University Medical School and Chonnam National University Hwasun Hospital, Hwasun, South Korea
| | - Yang Seok Koh
- Department of General Surgery, Chonnam National University Medical School and Chonnam National University Hwasun Hospital, Hwasun, South Korea
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Dai K, Liu C, Guan G, Cai J, Wu L. Identification of immune infiltration-related genes as prognostic indicators for hepatocellular carcinoma. BMC Cancer 2022; 22:496. [PMID: 35513781 PMCID: PMC9074323 DOI: 10.1186/s12885-022-09587-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 04/18/2022] [Indexed: 12/29/2022] Open
Abstract
Hepatocellular carcinoma (HCC) has a high degree of malignancy and a poor prognosis. Immune infiltration-related genes have shown good predictive value in the prognosis of many solid tumours. In this study, we established and verified prognostic biomarkers consisting of immune infiltration-related genes in HCC. Gene expression data and clinical data were downloaded from The Cancer Genome Atlas (TCGA) database. Differential gene expression analysis, univariate Cox regression analysis and the least absolute shrinkage and selection operator (LASSO) regression algorithm were used to screen prognostic immune infiltration-related genes and to construct a risk scoring model. Kaplan-Meier (KM) survival plots and receiver operating characteristic (ROC) curve analysis were used to evaluate the prognostic performance of the risk scoring model in the TCGA-HCC cohort. In addition, a nomogram model with a risk score was established, and its predictive performance was verified by ROC analysis and calibration plot analysis in the TCGA-HCC cohort. Gene set enrichment analysis (GSEA) identified pathways and biological processes that may be enriched in the high-risk group. Finally, immune infiltration analysis was used to explore the characteristics of the tumour microenvironment related to the risk score. We identified 17 immune infiltration-related genes with prognostic value and constructed a risk scoring model. ROC analysis showed that the risk scoring model can accurately predict the 1-year, 3-year, and 5-year overall survival (OS) of HCC patients in the TCGA-HCC cohort. KM analysis showed that the OS of the high-risk group was significantly lower than that of the low-risk group (P < 0.001). The nomogram model effectively predicted the OS of HCC patients in the TCGA-HCC cohort. GSEA indicated that the immune infiltration-related genes may be involved in biological processes such as amino acid and lipid metabolism, matrisome and small molecule transportation, immune system regulation, and hepatitis virus infection. Immune infiltration analysis showed that the level of immune cell infiltration in the high-risk group was low, and the risk score was negatively correlated with infiltrating immune cells. Our prognostic model based on immune infiltration-related genes in HCC could help the prognostic assessment of HCC patients and provide potential targets for HCC inhibition.
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Affiliation(s)
- Kunfu Dai
- Liver Disease Center, The Affiliated Hospital of Qingdao University, No. 59 Haier Road, Qingdao, 266003, China
| | - Chao Liu
- Liver Disease Center, The Affiliated Hospital of Qingdao University, No. 59 Haier Road, Qingdao, 266003, China
| | - Ge Guan
- Liver Disease Center, The Affiliated Hospital of Qingdao University, No. 59 Haier Road, Qingdao, 266003, China
| | - Jinzhen Cai
- Liver Disease Center, The Affiliated Hospital of Qingdao University, No. 59 Haier Road, Qingdao, 266003, China
| | - Liqun Wu
- Liver Disease Center, The Affiliated Hospital of Qingdao University, No. 59 Haier Road, Qingdao, 266003, China.
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Tumor Microenvironment of Hepatocellular Carcinoma: Challenges and Opportunities for New Treatment Options. Int J Mol Sci 2022; 23:ijms23073778. [PMID: 35409139 PMCID: PMC8998420 DOI: 10.3390/ijms23073778] [Citation(s) in RCA: 106] [Impact Index Per Article: 35.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/25/2022] [Accepted: 03/26/2022] [Indexed: 02/06/2023] Open
Abstract
The prevalence of liver cancer is constantly rising, with increasing incidence and mortality in Europe and the USA in recent decades. Among the different subtypes of liver cancers, hepatocellular carcinoma (HCC) is the most commonly diagnosed liver cancer. Besides advances in diagnosis and promising results of pre-clinical studies, HCC remains a highly lethal disease. In many cases, HCC is an effect of chronic liver inflammation, which leads to the formation of a complex tumor microenvironment (TME) composed of immune and stromal cells. The TME of HCC patients is a challenge for therapies, as it is involved in metastasis and the development of resistance. However, given that the TME is an intricate system of immune and stromal cells interacting with cancer cells, new immune-based therapies are being developed to target the TME of HCC. Therefore, understanding the complexity of the TME in HCC will provide new possibilities to design novel and more effective immunotherapeutics and combinatorial therapies to overcome resistance to treatment. In this review, we describe the role of inflammation during the development and progression of HCC by focusing on TME. We also describe the most recent therapeutic advances for HCC and possible combinatorial treatment options.
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Zhao K, Zhou X, Xiao Y, Wang Y, Wen L. Research Progress in Alpha-Fetoprotein-Induced Immunosuppression of Liver Cancer. Mini Rev Med Chem 2022; 22:2237-2243. [PMID: 35184712 DOI: 10.2174/1389557522666220218124816] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 12/14/2021] [Accepted: 12/20/2021] [Indexed: 12/24/2022]
Abstract
Abstract:
Liver cancer is one of the most common malignant tumors, with limited treatment and 8.2% high mortality. Liver cancer is the fourth leading cause of cancer-related deaths, which seriously endangers human life and health. Approximately 70% of liver cancer patients show increased serum alpha-fetoprotein (AFP) levels. AFP is the main diagnostic and prognostic indicator of liver cancer. AFP, a key marker of liver cancer, plays a crucial role in regulating the proliferation of tumor cells, apoptosis, and induction of cellular immune escape. High levels of AFP during embryonic development protect the embryos from maternal immune attack. AFP also promotes immune escape of liver cancer cells by inhibiting tumor-infiltrating lymphocytes (TILs), natural killer cells (NK), dendritic cells (DC), and macrophages; thus, it is also used as a target antigen in immunotherapy for liver cancer. AFP is highly expressed in liver cancer cells. In addition to being used in the diagnosis of liver cancer, it has become a target of immunotherapy for liver cancer as a tumor-associated antigen. In immunotherapy, it was also confirmed that early AFP response was positively correlated with the efficacy of immunotherapy. Early AFP responders had longer PFS and OS than non-responders. At present, the methods of immunotherapy for liver cancer mainly include Adoptive Cell Transfer Therapy (ACT), tumor vaccine therapy, immune checkpoint inhibitors (ICIs) therapy and so on. A large number of studies have shown that AFP mainly plays a role in ACT and liver cancer vaccines. This review presents the research progress of AFP and immunosuppression of liver cancer.
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Affiliation(s)
- Kailiang Zhao
- Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Xiaoquan Zhou
- Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Yuchun Xiao
- People\'s Hospital of Shangdang District, Changzhi, 047100, China
| | - Yanni Wang
- Taizhou Institute for Drug Control, Jiangsu Taizhou, 225300, China
| | - Lu Wen
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
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Eresen A, Yang J, Scotti A, Cai K, Yaghmai V, Zhang Z. Combination of natural killer cell-based immunotherapy and irreversible electroporation for the treatment of hepatocellular carcinoma. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1089. [PMID: 34423001 PMCID: PMC8339821 DOI: 10.21037/atm-21-539] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 04/05/2021] [Indexed: 01/10/2023]
Abstract
Hepatocellular carcinoma (HCC) is among the most lethal cancer types despite great advancement in overall survival of the patients over the last decades. Surgical resection or partial hepatectomy has been approved as the curative treatment for early-stage HCC patients however only up to 30% of them are eligible for the procedures. Natural killer (NK) cells are cytotoxic lymphocytes recognized for killing virally infected cells and improving immune functions for defending the body against malignant cells. Although autologous NK cells failed to demonstrate significant clinical benefit, transfer of allogeneic adoptive NK cells arises as a promising approach for the treatment of solid tumors. The immunosuppressive tumor microenvironment and inadequate homing efficiency of NK cells to tumors can inhibit adoptive transfer immunotherapy (ATI) efficacy. However, potential of the NK cells is challenged by the transfection efficiency. The local ablation techniques that employ thermal or chemical energy have been investigated for the destruction of solid tumors for three decades and demonstrated promising benefits for individuals not eligible for surgical resection or partial hepatectomy. Irreversible electroporation (IRE) is one of the most recent minimally invasive ablation methods that destruct the cell within the targeted region through non-thermal energy. IRE destroys the tumor cell membrane by delivering high-frequency electrical energy in short pulses and overcomes tumor immunosuppression. The previous studies demonstrated that IRE can induce immune changes which can facilitate activation of specific immune responses and improve transfection efficiency. In this review paper, we have discussed the mechanism of NK cell immunotherapy and IRE ablation methods for the treatment of HCC patients and the combinatorial benefits of NK cell immunotherapy and IRE ablation.
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Affiliation(s)
- Aydin Eresen
- Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.,Department of Radiological Sciences, University of California Irvine, Irvine, CA, USA
| | - Jia Yang
- Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Alessandro Scotti
- Department of Radiology, University of Illinois at Chicago, Chicago, IL, USA.,Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, USA
| | - Kejia Cai
- Department of Radiology, University of Illinois at Chicago, Chicago, IL, USA.,Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, USA
| | - Vahid Yaghmai
- Department of Radiological Sciences, University of California Irvine, Irvine, CA, USA.,Chao Family Comprehensive Cancer Center, University of California, Irvine, CA, USA
| | - Zhuoli Zhang
- Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.,Department of Radiological Sciences, University of California Irvine, Irvine, CA, USA.,Chao Family Comprehensive Cancer Center, University of California, Irvine, CA, USA.,Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
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Natural Killer Cells and Type 1 Innate Lymphoid Cells in Hepatocellular Carcinoma: Current Knowledge and Future Perspectives. Int J Mol Sci 2021; 22:ijms22169044. [PMID: 34445750 PMCID: PMC8396475 DOI: 10.3390/ijms22169044] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 08/10/2021] [Accepted: 08/18/2021] [Indexed: 02/07/2023] Open
Abstract
Natural killer (NK) cells and type 1 innate lymphoid cells (ILC1) are specific innate lymphoid cell subsets that are key for the detection and elimination of pathogens and cancer cells. In liver, while they share a number of characteristics, they differ in many features. These include their developmental pathways, tissue distribution, phenotype and functions. NK cells and ILC1 contribute to organ homeostasis through the production of key cytokines and chemokines and the elimination of potential harmful bacteria and viruses. In addition, they are equipped with a wide range of receptors, allowing them to detect “stressed cells’ such as cancer cells. Our understanding of the role of innate lymphoid cells in hepatocellular carcinoma (HCC) is growing owing to the development of mouse models, the progress in immunotherapeutic treatment and the recent use of scRNA sequencing analyses. In this review, we summarize the current understanding of NK cells and ILC1 in hepatocellular carcinoma and discuss future strategies to take advantage of these innate immune cells in anti-tumor immunity. Immunotherapies hold great promise in HCC, and a better understanding of the role and function of NK cells and ILC1 in liver cancer could pave the way for new NK cell and/or ILC1-targeted treatment.
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Shafique Y, Qureshi MA, Khan S, Mirza T. Differential Immune Landscape of Hepatocellular Carcinoma Suggests Potential role of Macrophages in Hepatocarcinogenesis. Pak J Med Sci 2021; 37:858-862. [PMID: 34104178 PMCID: PMC8155426 DOI: 10.12669/pjms.37.3.2973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Objectives To investigate immune cell densities in tumor microenvironment of hepatocellular carcinoma. Methods This cross-sectional study was conducted during 2017-2019 at the Dow University of Health Sciences Karachi. A total of 42 subsequent patients undergoing liver biopsy/resection and diagnosed with hepatocellular carcinoma were included in the study. Moreover, a total of 10 control tissues were also included. In order to investigate immune cells densities in hepatocellular carcinoma, immunohistochemistry was performed using antibodies including α-MPO(neutrophils), α-CD-68(macrophages), α-CD-3(T-cells), α-CD-20(B-cells), α-CD-4(CD4+ T-cells) and α-CD-8(CD8+ T-cells). Quantification of immune cells/mm2 was performed as per the College of American Pathologists' guidelines. Data were analyzed using SPSS version 21. A p-value of 0.05 was considered significant at all times. Results We report significantly increased infiltration of macrophages (mean macrophages= 306.57/mm2, p-value <0.05), moderately significant infiltration of neutrophils (p-value=0.06) and B-cells (p-value=0.07) while no significant infiltration of CD4+T-cells (p- value=0.31), and CD8+T-cells (p-value=0.39) in tumour microenvironment of patients with hepatocellular carcinoma. Conclusion We provide evidence for increased macrophage infiltration in liver cancer microenvironment suggesting a potential role of these cells in hepatocarcinogenesis.
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Affiliation(s)
- Yusra Shafique
- Dr. Yusra Shafique, MBBS, M.Phil. Lecturer of Pathology, Dow International Medical College, Dow University of Health Sciences, Karachi, Pakistan
| | - Muhammad Asif Qureshi
- Prof. Dr. Muhammad Asif Qureshi, MBBS, PhD (Glasgow-UK), Professor of Pathology, MA(IR), Postdoc (Germany), CHPE, Dow International Medical College, Dow University of Health Sciences, Karachi, Pakistan
| | - Saeed Khan
- Prof. Dr. Saeed Khan, MSc, PhD, Postdoc (USA). Professor of Pathology, Dow International Medical College, Dow University of Health Sciences, Karachi, Pakistan
| | - Talat Mirza
- Prof. Dr. Talat Mirza, MBBS, M.Phil., PhD. Dean, Research Ziauddin University, Karachi, Pakistan
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Polidoro MA, Mikulak J, Cazzetta V, Lleo A, Mavilio D, Torzilli G, Donadon M. Tumor microenvironment in primary liver tumors: A challenging role of natural killer cells. World J Gastroenterol 2020; 26:4900-4918. [PMID: 32952338 PMCID: PMC7476172 DOI: 10.3748/wjg.v26.i33.4900] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 06/24/2020] [Accepted: 08/20/2020] [Indexed: 02/06/2023] Open
Abstract
In the last years, several studies have been focused on elucidate the role of tumor microenvironment (TME) in cancer development and progression. Within TME, cells from adaptive and innate immune system are one of the main abundant components. The dynamic interactions between immune and cancer cells lead to the activation of complex molecular mechanisms that sustain tumor growth. This important cross-talk has been elucidate for several kind of tumors and occurs also in patients with liver cancer, such as hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Liver is well-known to be an important immunological organ with unique microenvironment. Here, in normal conditions, the rich immune-infiltrating cells cooperate with non-parenchymal cells, such as liver sinusoidal endothelial cells and Kupffer cells, favoring self-tolerance against gut antigens. The presence of underling liver immunosuppressive microenvironment highlights the importance to dissect the interaction between HCC and iCCA cells with immune infiltrating cells, in order to understand how this cross-talk promotes tumor growth. Deeper attention is, in fact, focused on immune-based therapy for these tumors, as promising approach to counteract the intrinsic anti-tumor activity of this microenvironment. In this review, we will examine the key pathways underlying TME cell-cell communications, with deeper focus on the role of natural killer cells in primary liver tumors, such as HCC and iCCA, as new opportunities for immune-based therapeutic strategies.
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Affiliation(s)
- Michela Anna Polidoro
- Hepatobiliary Immunopathology Laboratory, Humanitas Clinical and Research Center – IRCCS, Rozzano 20089, Milan, Italy
| | - Joanna Mikulak
- Laboratory of Clinical and Experimental Immunology, Humanitas Clinical and Research Center - IRCCS, Rozzano 20089, Milan, Italy
- Department of Medical Biotechnologies and Translational Medicine (BioMeTra), University of Milan, Rozzano 20089, Milan, Italy
| | - Valentina Cazzetta
- Laboratory of Clinical and Experimental Immunology, Humanitas Clinical and Research Center - IRCCS, Rozzano 20089, Milan, Italy
| | - Ana Lleo
- Hepatobiliary Immunopathology Laboratory, Humanitas Clinical and Research Center – IRCCS, Rozzano 20089, Milan, Italy
- Department of Biomedical Science, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Department of Internal Medicine, Humanitas Clinical and Research Center – IRCCS, Rozzano 20089, Milan, Italy
| | - Domenico Mavilio
- Laboratory of Clinical and Experimental Immunology, Humanitas Clinical and Research Center - IRCCS, Rozzano 20089, Milan, Italy
- Department of Medical Biotechnologies and Translational Medicine (BioMeTra), University of Milan, Rozzano 20089, Milan, Italy
| | - Guido Torzilli
- Department of Biomedical Science, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center - IRCCS, Rozzano 20089, Milan, Italy
| | - Matteo Donadon
- Department of Biomedical Science, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center - IRCCS, Rozzano 20089, Milan, Italy
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Caputo F, Dadduzio V, Tovoli F, Bertolini G, Cabibbo G, Cerma K, Vivaldi C, Faloppi L, Rizzato MD, Piscaglia F, Celsa C, Fornaro L, Marisi G, Conti F, Silvestris N, Silletta M, Lonardi S, Granito A, Stornello C, Massa V, Astara G, Delcuratolo S, Cascinu S, Scartozzi M, Casadei-Gardini A. The role of PNI to predict survival in advanced hepatocellular carcinoma treated with Sorafenib. PLoS One 2020; 15:e0232449. [PMID: 32379785 PMCID: PMC7205300 DOI: 10.1371/journal.pone.0232449] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Accepted: 04/15/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND AND AIMS The present study aims to investigate the role of the prognostic nutritional index (PNI) on survival in patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib. METHODS This multicentric study included a training cohort of 194 HCC patients and three external validation cohorts of 129, 76 and 265 HCC patients treated with Sorafenib, respectively. The PNI was calculated as follows: 10 × serum albumin (g/dL) + 0.005 × total lymphocyte count (per mm3). Univariate and multivariate analyses were performed to investigate the association between the covariates and the overall survival (OS). RESULTS A PNI cut-off value of 31.3 was established using the ROC analysis. In the training cohort, the median OS was 14.8 months (95% CI 12-76.3) and 6.8 months (95% CI 2.7-24.6) for patients with a high (>31.3) and low (<31.3) PNI, respectively. At both the univariate and the multivariate analysis, low PNI value (p = 0.0004), a 1-unit increase of aspartate aminotransferase (p = 0.0001), and age > 70 years (p< 0.0038) were independent prognostic factors for OS. By performing the same multivariate analysis of the training cohort, the PNI <31.3 versus >31.3 was found to be an independent prognostic factor for predicting OS in all the three validation cohorts. CONCLUSIONS PNI represents a prognostic tool in advanced HCC treated with first-line Sorafenib. It is readily available and low-cost, and it could be implemented in clinical practice in patients with HCC.
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Affiliation(s)
- Francesco Caputo
- Division of Oncology, Department of Oncology and Hematology, University of Modena and Reggio Emilia, Modena, Italy
| | - Vincenzo Dadduzio
- Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Francesco Tovoli
- Azienda Ospedaliera Universitaria S.Orsola-Malpighi Bologna, Bologna, Italy
| | | | - Giuseppe Cabibbo
- Section of Gastroenterology & Hepatology, PROMISE, University of Palermo, Palermo, Italy
| | - Krisida Cerma
- Division of Oncology, Department of Oncology and Hematology, University of Modena and Reggio Emilia, Modena, Italy
| | | | - Luca Faloppi
- Medical Oncology Unit, Macerata General Hospital, Macerata, Italy
| | - Mario Domenico Rizzato
- Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Fabio Piscaglia
- Azienda Ospedaliera Universitaria S.Orsola-Malpighi Bologna, Bologna, Italy
| | - Ciro Celsa
- Section of Gastroenterology & Hepatology, PROMISE, University of Palermo, Palermo, Italy
| | | | - Giorgia Marisi
- Medical Oncology Unit IRCSS-IRST Meldola, Meldola, Italy
| | - Fabio Conti
- Department of Internal Medicine, Degli Infermi Hospital, Faenza, Italy
| | - Nicola Silvestris
- Medical Oncology Unit, IRCCS Giovanni Paolo II Cancer Center, Bari, Italy
| | - Marianna Silletta
- Medical Oncology Department, Campus Biomedico, University of Rome, Rome, Italy
| | - Sara Lonardi
- Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Alessandro Granito
- Azienda Ospedaliera Universitaria S.Orsola-Malpighi Bologna, Bologna, Italy
| | | | | | - Giorgio Astara
- Department of Medical Oncology, University of Cagliari, Cagliari, Italy
| | - Sabina Delcuratolo
- Medical Oncology Unit, IRCCS Giovanni Paolo II Cancer Center, Bari, Italy
| | - Stefano Cascinu
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Mario Scartozzi
- Department of Medical Oncology, University of Cagliari, Cagliari, Italy
| | - Andrea Casadei-Gardini
- Division of Oncology, Department of Oncology and Hematology, University of Modena and Reggio Emilia, Modena, Italy
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16
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Hamza A, Khan U, Khurram MS, Abraham R, Mazzara P, Hadid T, Kafri Z. Prognostic Utility of Tumor-Infiltrating Lymphocytes in Noncolorectal Gastrointestinal Malignancies. Int J Surg Pathol 2018; 27:263-267. [PMID: 30426804 DOI: 10.1177/1066896918809460] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND Tumor-infiltrating lymphocytes (TILs) and mismatch repair gene mutation (MMR) status are emerging biomarkers in immunotherapy. MMR status and TILs have significant clinical implications with regard to treatment with checkpoint inhibitors. We designed a study to determine the frequency and prognostic utility of TILs and MMR in advanced unresectable noncolorectal gastrointestinal (NCGI) malignancies. METHODS This is a retrospective cohort study of patients who were diagnosed with advanced noncolorectal gastrointestinal tumors. Biopsy specimens were tested for MMR status by immunohistochemistry along with evaluation of TILs. Kaplan-Meier analysis was performed to determine the impact of TILS and MMR on survival. RESULTS We analyzed 146 patients; the mean age at diagnosis was 66.4 ± 11.2 years. 65.8% patients were male, and 62.3% patients had stage 4 disease. All cases had proficient MMR status. The percentage of patients with TILs >5 was 50.7%. There was no statistically significant difference in median overall survival (OS) by TILs when stratified by stage of tumor. When stratified by type of tumor, median OS by TILs level was significantly different for hepatocellular cancers (⩽5 TILs, 86 days versus >5 TILs 312 days, P = .031). CONCLUSIONS Our study suggests that MMR-deficient tumors are quite rare in advanced NCGI malignancies. More than 5 TILs per high power field, evaluated simply on a routine hematoxylin and eosin-stained glass slide confer a better prognosis to most noncolorectal gastrointestinal malignancies, especially hepatocellular carcinoma. This has immense clinical utility with regard to eligibility for immunotherapy.
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Affiliation(s)
- Ameer Hamza
- 1 St John Hospital and Medical Center, Detroit, MI, USA
| | - Uqba Khan
- 1 St John Hospital and Medical Center, Detroit, MI, USA
| | | | - Renny Abraham
- 1 St John Hospital and Medical Center, Detroit, MI, USA
| | - Paul Mazzara
- 1 St John Hospital and Medical Center, Detroit, MI, USA
| | - Tarik Hadid
- 1 St John Hospital and Medical Center, Detroit, MI, USA
| | - Zyad Kafri
- 1 St John Hospital and Medical Center, Detroit, MI, USA
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Hosseinzadeh F, Verdi J, Ai J, Hajighasemlou S, Seyhoun I, Parvizpour F, Hosseinzadeh F, Iranikhah A, Shirian S. Combinational immune-cell therapy of natural killer cells and sorafenib for advanced hepatocellular carcinoma: a review. Cancer Cell Int 2018; 18:133. [PMID: 30214375 PMCID: PMC6131874 DOI: 10.1186/s12935-018-0624-x] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2018] [Accepted: 08/24/2018] [Indexed: 02/06/2023] Open
Abstract
Background High prevalence of hepatocellular carcinoma (HCC) and typically poor prognosis of this disease that lead to late stage diagnosis when potentially curative therapies are least effective; therefore, development of an effective and systematic treatment is an urgent requirement. Main body In this review, several current treatments for HCC patients and their advantages or disadvantages were summarized. Moreover, various recent preclinical and clinical studies about the performances of "two efficient agents, sorafenib or natural killer (NK) cells", against HCC cells were investigated. In addition, the focus this review was on the chemo-immunotherapy approach, correlation between sorafenib and NK cells and their effects on the performance of each other for better suppression of HCC. Conclusion It was concluded that combinational therapy with sorafenib and NK cells might improve the outcome of applied therapeutic approaches for HCC patients. Finally, it was also concluded that interaction between sorafenib and NK cells is dose and time dependent, therefore, a careful dose and time optimizing is necessary for development of a combinational immune-cell therapy.
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Affiliation(s)
- Faezeh Hosseinzadeh
- 1Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Javad Verdi
- 1Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Jafar Ai
- 1Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Saieh Hajighasemlou
- 1Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Iran Food and Drug Administration, Tehran, Iran
| | - Iman Seyhoun
- 1Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Frzad Parvizpour
- 1Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Abolfazl Iranikhah
- 4Department of Gastroenterology, Faculty of Medicine, Qom University of Medical Sciences, Qom, Iran
| | - Sadegh Shirian
- 5Department of Pathology, School of Veterinary Medicine, Shahrekord University, Shahrekord, Iran.,6Shiraz Molecular Pathology Research Center, Dr. Daneshbod Lab, Shiraz, Iran
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Hishiki T, Mise N, Harada K, Ihara F, Takami M, Saito T, Terui K, Nakata M, Komatsu S, Yoshida H, Motohashi S. Invariant natural killer T infiltration in neuroblastoma with favorable outcome. Pediatr Surg Int 2018; 34:195-201. [PMID: 29018959 DOI: 10.1007/s00383-017-4189-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/21/2017] [Indexed: 12/17/2022]
Abstract
BACKGROUND Tumor immunity has been suggested to play a key role in clinical and biological behavior of neuroblastomas. Given that CD1-restricted invariant natural killer T (iNKT) cells enhance both innate and acquired tumor immunity, we investigated the expression of the iNKT-cell-specific T-cell receptor Vα24-Jα18 in neuroblastoma tissues and its correlation with clinical and biological characteristics. METHODS Using real- time quantitative PCR, we quantified the expression of Vα24-Jα18 in untreated tumor samples from 107 neuroblastoma cases followed in our institution and analyzed the correlation between the presence of infiltrated iNKT cells and clinical characteristics or patients' outcome. RESULTS Vα24-Jα18 receptor was detected in 62 untreated cases (57.9%). The expression was significantly higher in stages 1, 2, 3, or 4S (P = 0.0099), in tumors with low or intermediate risk (P = 0.0050), with high TrkA expression (P = 0.0229), with favorable histology (P = 0.0026), with aneuploidy (P = 0.0348), and in younger patients (P = 0.0036). The overall survival rate was significantly higher in patients with iNKT-cell infiltration (log-rank; P = 0.0089). CONCLUSIONS Since tumor-infiltrating iNKT cells were predominantly observed in neuroblastomas undergoing spontaneous differentiation and/or regression, we suggest that iNKT cells might play a key role in these processes.
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Affiliation(s)
- Tomoro Hishiki
- Department of Pediatric Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.
- Division of Surgical Oncology, Children's Cancer Center, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan.
- Division of Pediatric Surgical Oncology, National Cancer Center Hospital, Tokyo, Japan.
| | - Naoko Mise
- Department of Pediatric Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
- Department of Medical Immunology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Kazuaki Harada
- Department of Pediatric Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
- Department of Medical Immunology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Fumie Ihara
- Department of Medical Immunology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Mariko Takami
- Department of Medical Immunology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Takeshi Saito
- Department of Pediatric Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Keita Terui
- Department of Pediatric Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Mitsuyuki Nakata
- Department of Pediatric Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Shugo Komatsu
- Department of Pediatric Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Hideo Yoshida
- Department of Pediatric Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Shinichiro Motohashi
- Department of Medical Immunology, Chiba University Graduate School of Medicine, Chiba, Japan
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Wang D, Yang C, Wang Z, Yang Y, Li D, Ding X, Xu W, Zheng Q. Norcantharidin combined with Coix seed oil synergistically induces apoptosis and inhibits hepatocellular carcinoma growth by downregulating regulatory T cells accumulation. Sci Rep 2017; 7:9373. [PMID: 28839202 PMCID: PMC5571147 DOI: 10.1038/s41598-017-09668-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Accepted: 07/27/2017] [Indexed: 12/30/2022] Open
Abstract
The immune system plays a critical role in exerts effects in the growth and progression of hepatocellular carcinoma (HCC), which needs interacting approaches for effective therapy. In this study, we have found that the Norcantharidin (NCTD) + Coix lacryma-jobi seed oil (CLSO) combination exhibited more potent antitumor effects in an terms of cytotoxicity and apoptotic induction in human HepG2 and HepG2/ADM cells than NCTD or CLSO alone. In vivo, administration of NCTD+CLSO combinations significantly suppressed the formation of tumor in Hepal-1 hepatoma-bearing mice. Furthermore, we found that the in vitro co-cultures of HepG2 or HepG2/ADM cells with PBMCs from healthy donors led to an increase in the number of CD4 + CD25 + T cells. This increase was down-regulated by the combination effectively. Down-regulation of FoxP3 mRNA and protein expression occurred during the combination in the co-cultures. The amount of Tregs of Hepal-1 hepatoma-bearing mice was significantly decreased in the combination treated group. The combination down-regulated the expression of FoxP3, CTLA-4 and Tregs related cytokine (TGF-β and IL-10) in the serum of tumor bearing mice. Taken together, these results suggest that the most valuable aspect of the NCTD+CLSO combined use improves the anti-tumor activity and regulates tumor infiltrating Tregs.
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MESH Headings
- Animals
- Antineoplastic Agents/pharmacology
- Apoptosis/drug effects
- Biomarkers
- Bridged Bicyclo Compounds, Heterocyclic/pharmacology
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Cycle Checkpoints/drug effects
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Cell Survival/drug effects
- Coix/chemistry
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Drug Synergism
- Humans
- Immunophenotyping
- Liver Neoplasms/drug therapy
- Liver Neoplasms/immunology
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Mice
- Plant Oils/pharmacology
- Seeds/chemistry
- T-Lymphocytes, Regulatory/drug effects
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Dan Wang
- Binzhou Medical University, Yantai, 264003, China
| | - Chendong Yang
- Yantai Hospital of Traditional Chinese Medicine, Yantai, 264003, China
| | - Zhuien Wang
- Binzhou Medical University, Yantai, 264003, China
| | - Yi Yang
- Binzhou Medical University, Yantai, 264003, China
| | - Defang Li
- Binzhou Medical University, Yantai, 264003, China
| | - Xiaojie Ding
- Binzhou Medical University, Yantai, 264003, China
| | - Wenjuan Xu
- Binzhou Medical University, Yantai, 264003, China.
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20
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Geng JJ, Tang J, Yang XM, Chen R, Zhang Y, Zhang K, Miao JL, Chen ZN, Zhu P. Targeting CD147 for T to NK Lineage Reprogramming and Tumor Therapy. EBioMedicine 2017; 20:98-108. [PMID: 28571672 PMCID: PMC5478251 DOI: 10.1016/j.ebiom.2017.05.022] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Revised: 05/16/2017] [Accepted: 05/16/2017] [Indexed: 11/18/2022] Open
Abstract
CD147 is highly expressed on the surface of numerous tumor cells to promote invasion and metastasis. Targeting these cells with CD147-specific antibodies has been validated as an effective approach for lung and liver cancer therapy. In the immune system, CD147 is recognized as a co-stimulatory receptor and impacts the outcome of thymic selection. Using T cell-specific deletion, we showed here that in thymus CD147 is indispensable for the stable αβ T cell lineage commitment: loss of CD147 biases both multipotent DN (double negative) and fully committed DP (double positive) cells into innate NK-like lineages. Mechanistically, CD147 deficiency results in impaired Wnt signaling and expression of BCL11b, a master transcription factor in determining T cell identity. In addition, functional blocking of CD147 by antibody phenocopies genetic deletion to enrich NK-like cells in the periphery. Furthermore, using a melanoma model and orthotopic liver cancer transplants, we showed that the augmentation of NK-like cells strongly associates with resistance against tumor growth upon CD147 suppression. Therefore, besides its original function in tumorigenesis, CD147 is also an effective surface target for immune modulation in tumor therapy.
DN, DP cells were reprogrammed into innate NK-like cells after thymic CD147 deleted Loss of CD147 results in impaired Bcl11b expression and T-lineages development, which can be rescued by Wnt3a stimulation. CD147 is an vital target for immune modulation via NK-like cells in tumor therapy. Tumor therapy is a difficult task and many methods have been used. Among them, tumor immunotherapy is a focus in the field and has made great progress. In this study, we found CD147 is an vital target for immune modulation via NK-like cells in tumor therapy, which means CD147 antibody may be through regulating immune cells to achieve tumor therapy. Although CD147 antibody has been used for liver cancer, making clear the mechanism of CD147 antibody mediated tumor therapy may be benefit for guiding clinical treatment.
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Affiliation(s)
- Jie-Jie Geng
- Department of Clinical Immunology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shan'xi 710032, PR China; Department of Cell Biology, Fourth Military Medical University, Xi'an, Shan'xi 710032, PR China
| | - Juan Tang
- Department of Cell Biology, Fourth Military Medical University, Xi'an, Shan'xi 710032, PR China
| | - Xiang-Min Yang
- Department of Cell Biology, Fourth Military Medical University, Xi'an, Shan'xi 710032, PR China
| | - Ruo Chen
- Department of Clinical Immunology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shan'xi 710032, PR China; Department of Cell Biology, Fourth Military Medical University, Xi'an, Shan'xi 710032, PR China
| | - Yang Zhang
- Department of Cell Biology, Fourth Military Medical University, Xi'an, Shan'xi 710032, PR China
| | - Kui Zhang
- Department of Clinical Immunology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shan'xi 710032, PR China
| | - Jin-Lin Miao
- Department of Clinical Immunology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shan'xi 710032, PR China
| | - Zhi-Nan Chen
- Department of Cell Biology, Fourth Military Medical University, Xi'an, Shan'xi 710032, PR China.
| | - Ping Zhu
- Department of Clinical Immunology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shan'xi 710032, PR China.
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21
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Vujanovic L, Stahl EC, Pardee AD, Geller DA, Tsung A, Watkins SC, Gibson GA, Storkus WJ, Butterfield LH. Tumor-Derived α-Fetoprotein Directly Drives Human Natural Killer-Cell Activation and Subsequent Cell Death. Cancer Immunol Res 2017; 5:493-502. [PMID: 28468916 DOI: 10.1158/2326-6066.cir-16-0216] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Revised: 03/22/2017] [Accepted: 04/28/2017] [Indexed: 11/16/2022]
Abstract
Hepatocellular carcinoma (HCC) patients with reduced natural killer (NK)-cell numbers and function have been shown to have a poor disease outcome. Mechanisms underlying NK-cell deficiency and dysfunction in HCC patients remain largely unresolved. α-Fetoprotein (AFP) is an oncofetal antigen produced by HCC. Previous studies demonstrated that tumor-derived AFP (tAFP) can indirectly impair NK-cell activity by suppressing dendritic cell function. However, a direct tAFP effect on NK cells remains unexplored. The purpose of this study was to examine the ability of cord blood-derived AFP (nAFP) and that of tAFP to directly modulate human NK-cell activity and longevity in vitro Short-term exposure to tAFP and, especially, nAFP proteins induced a unique proinflammatory, IL2-hyperresponsive phenotype in NK cells as measured by IL1β, IL6, and TNF secretion, CD69 upregulation, and enhanced tumor cell killing. In contrast, extended coculture with tAFP, but not nAFP, negatively affected long-term NK-cell viability. NK-cell activation was directly mediated by the AFP protein itself, whereas their viability was affected by hydrophilic components within the low molecular mass cargo that copurified with tAFP. Identification of the distinct impact of circulating tAFP on NK-cell function and viability may be crucial to developing a strategy to ameliorate HCC patient NK-cell functional deficits. Cancer Immunol Res; 5(6); 493-502. ©2017 AACR.
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Affiliation(s)
- Lazar Vujanovic
- University of Pittsburgh Cancer Institute, University of Pittsburgh, Pennsylvania.,Department of Medicine, University of Pittsburgh, Pennsylvania
| | - Elizabeth C Stahl
- University of Pittsburgh Cancer Institute, University of Pittsburgh, Pennsylvania
| | - Angela D Pardee
- University of Pittsburgh Cancer Institute, University of Pittsburgh, Pennsylvania.,Department of Medicine, University of Pittsburgh, Pennsylvania
| | - David A Geller
- University of Pittsburgh School of Medicine, Department of Surgery, University of Pittsburgh, Pennsylvania
| | - Allan Tsung
- University of Pittsburgh School of Medicine, Department of Surgery, University of Pittsburgh, Pennsylvania
| | - Simon C Watkins
- Department of Cell Biology and Physiology, University of Pittsburgh, Pennsylvania
| | - Gregory A Gibson
- Department of Cell Biology and Physiology, University of Pittsburgh, Pennsylvania
| | - Walter J Storkus
- University of Pittsburgh Cancer Institute, University of Pittsburgh, Pennsylvania.,Department of Dermatology, University of Pittsburgh, Pennsylvania.,Department of Immunology, University of Pittsburgh, Pennsylvania
| | - Lisa H Butterfield
- University of Pittsburgh Cancer Institute, University of Pittsburgh, Pennsylvania. .,Department of Medicine, University of Pittsburgh, Pennsylvania.,University of Pittsburgh School of Medicine, Department of Surgery, University of Pittsburgh, Pennsylvania.,Department of Immunology, University of Pittsburgh, Pennsylvania
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22
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Sun C, Xu J, Huang Q, Huang M, Wen H, Zhang C, Wang J, Song J, Zheng M, Sun H, Wei H, Xiao W, Sun R, Tian Z. High NKG2A expression contributes to NK cell exhaustion and predicts a poor prognosis of patients with liver cancer. Oncoimmunology 2016; 6:e1264562. [PMID: 28197391 DOI: 10.1080/2162402x.2016.1264562] [Citation(s) in RCA: 205] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 11/15/2016] [Accepted: 11/17/2016] [Indexed: 02/08/2023] Open
Abstract
Background and Aims: As the predominant lymphocyte subset in the liver, natural killer (NK) cells have been shown to be highly associated with the outcomes of patients with chronic hepatitis B virus infection (CHB) and hepatocellular carcinoma (HCC). Previously, we reported that NKG2A, a checkpoint candidate, mediates human and murine NK cell dysfunction in CHB. However, NK cell exhaustion and, particularly, the level of NKG2A expression within liver tumors have not been reported. Methods: In this study, we analyzed NKG2A expression and the related dysfunction of NK cells located in intra- or peritumor regions of liver tissue samples from 207 HCC patients, in addition to analyzing disease outcomes. Results: The expression of NKG2A in NK cells and the NKG2A ligand, HLA-E, in intratumor HCC tissues was observed to be increased. These NK cells, and particularly CD56dim NK cells, with higher NKG2A expression showed features of functional exhaustion and were associated with a poor prognosis. The increase in NKG2A expression might be induced by IL-10, which was present at a high level in the plasma of HCC patients. Blocking IL-10 could specifically inhibit NKG2A expression in NK cells. Conclusions: These findings indicate that NKG2A expression is influenced by factors from cancer nests and contributes to NK cell exhaustion, suggesting that NKG2A blockade has the potential to restore immunity against liver tumors by reversing NK cell exhaustion.
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Affiliation(s)
- Cheng Sun
- Institute of Immunology, The Key Laboratory of Innate Immunity and Chronic Disease (Chinese Academy of Medical Science), School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jing Xu
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China , Guangzhou, China
| | - Qiang Huang
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Anhui Provincial Hospital Affiliated to Anhui Medical University , Hefei, China
| | - Mei Huang
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Anhui Provincial Hospital Affiliated to Anhui Medical University , Hefei, China
| | - Hao Wen
- Xinjiang Key Laboratory of Echinococcosis, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University , Urumqi, China
| | - Chuanshan Zhang
- Xinjiang Key Laboratory of Echinococcosis, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University , Urumqi, China
| | - Jinyu Wang
- Institute of Immunology, The Key Laboratory of Innate Immunity and Chronic Disease (Chinese Academy of Medical Science), School of Life Sciences and Medical Center, University of Science & Technology of China , Hefei, Anhui, China
| | - Jiaxi Song
- Institute of Immunology, The Key Laboratory of Innate Immunity and Chronic Disease (Chinese Academy of Medical Science), School of Life Sciences and Medical Center, University of Science & Technology of China , Hefei, Anhui, China
| | - Meijuan Zheng
- Department of Clinical Laboratory, First Affiliated Hospital of Anhui Medical University , Hefei, China
| | - Haoyu Sun
- Institute of Immunology, The Key Laboratory of Innate Immunity and Chronic Disease (Chinese Academy of Medical Science), School of Life Sciences and Medical Center, University of Science & Technology of China , Hefei, Anhui, China
| | - Haiming Wei
- Institute of Immunology, The Key Laboratory of Innate Immunity and Chronic Disease (Chinese Academy of Medical Science), School of Life Sciences and Medical Center, University of Science & Technology of China , Hefei, Anhui, China
| | - Weihua Xiao
- Institute of Immunology, The Key Laboratory of Innate Immunity and Chronic Disease (Chinese Academy of Medical Science), School of Life Sciences and Medical Center, University of Science & Technology of China , Hefei, Anhui, China
| | - Rui Sun
- Institute of Immunology, The Key Laboratory of Innate Immunity and Chronic Disease (Chinese Academy of Medical Science), School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Zhigang Tian
- Institute of Immunology, The Key Laboratory of Innate Immunity and Chronic Disease (Chinese Academy of Medical Science), School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
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23
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Regulatory T-cells promote hepatitis B virus infection and hepatocellular carcinoma progression. Chronic Dis Transl Med 2016; 2:67-80. [PMID: 29063027 PMCID: PMC5643754 DOI: 10.1016/j.cdtm.2016.09.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2016] [Indexed: 02/08/2023] Open
Abstract
Regulatory T-cells (Tregs), known for their immune suppressive function, have been reported in higher numbers, with activated phenotypes and greater potency, in hepatitis B virus (HBV)-related liver diseases than in normal conditions. The numbers, phenotypes, and function of intrahepatic and/or tumor-infiltrating Tregs in HBV-related liver diseases also differ from those of Tregs in the peripheral blood. By inhibiting the function of effector T-cells (Teffs), Tregs play a substantial role in the formation and maintenance of the liver's suppressive microenvironment, which might account for the progression of HBV-related hepatitis and hepatocellular carcinoma (HCC). In acute hepatitis B virus infection, Tregs can safeguard the liver from damage at the cost of prolonged antiviral processes, which results in chronic HBV infection in the liver. Furthermore, Tregs play a role in the development of cirrhosis, the transformation of cirrhosis to HCC, and the progression and metastasis of HCC. Higher levels of Tregs in the peripheral blood and/or tumor sites signify a poorer prognosis in HBV-related liver conditions, and observational data from mouse models and human patients support the theory that depleting Tregs may be therapeutic in HBV-related liver diseases by inducing antiviral and antitumor immunity.
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24
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Jin J, Zhu P, Liao Y, Li J, Liao W, He S. Elevated preoperative aspartate aminotransferase to lymphocyte ratio index as an independent prognostic factor for patients with hepatocellular carcinoma after hepatic resection. Oncotarget 2016; 6:19217-27. [PMID: 26057470 PMCID: PMC4662486 DOI: 10.18632/oncotarget.4265] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Accepted: 05/13/2015] [Indexed: 12/15/2022] Open
Abstract
Few studies have elucidated the relationship between preoperative aspartate aminotransferase (AST) to lymphocyte ratio and high incidence of hepatocellular carcinoma (HCC). In search of a simple non-invasive prognostic marker, we investigated the prognostic significance of AST to lymphocyte ratio index (ALRI) in HCC. We reviewed retrospectively clinical parameters of 371 HCC patients who were treated with hepatectomy. Receiver operating characteristic (ROC) curve analysis was performed to determine the cut-off value of preoperative ALRI. The predictive value of preoperative ALRI in HCC was evaluated by univariate and multivariate analyses using Cox proportional hazards regression modeling, and the survival probability of HCC patients was acquired by the Kaplan-Meier plots. In addition, stratified analysis was used to investigate the impact of preoperative ALRI on survival in different HCC subgroups. The results showed that preoperative ALRI was closely correlated with age (p = 0.007), median size (p = 0.004), clinical tumor-node-metastasis (TNM) stage (p < 0.001), and portal vein tumor thrombosis (PVTT) (p < 0.001). Survival analysis indicated that HCC patients with preoperative ALRI > 25.2 have a poorer disease-free survival (DFS) and overall survival (OS) after tumor resection. Multivariate analysis further identified preoperative ALRI > 25.2 (p = 0.002), III-IV of TNM stage (p = 0.011), PVTT (p = 0.035), size of tumor > 5 cm (p < 0.001) as independent risk factors of DFS; and preoperative ALRI > 25.2 (p = 0.001), III-IV of TNM stage (p = 0.005), PVTT (p = 0.012), size of tumor > 5 cm (p < 0.001), recurrence (p < 0.001) as independent prognostic factors for OS in HCC patients. Additionally, preoperative ALRI also showed different prognostic value in various subgroups of HCC. Elevated preoperative ALRI as a noninvasive, simple, and easily assessable parameter is an independent effective predictor of prognosis for patients with HCC.
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Affiliation(s)
- Junfei Jin
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, People's Republic of China.,Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Pengpeng Zhu
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Yan Liao
- Disease Prevention and Control Center of Guilin, Guilin, Guangxi, People's Republic of China
| | - Jun Li
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Weijia Liao
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, People's Republic of China.,Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Songqing He
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, People's Republic of China.,Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, Guilin Medical University, Guilin, Guangxi, People's Republic of China
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25
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Chen H, Zhidan W, Xia R, Zhaoxia W, Qing J, Qiang G, Haipeng Y, Hengxiao W. Scorpion venom activates natural killer cells in hepatocellular carcinoma via the NKG2D-MICA pathway. Int Immunopharmacol 2016; 35:307-314. [PMID: 27089390 DOI: 10.1016/j.intimp.2016.03.045] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Revised: 03/25/2016] [Accepted: 03/25/2016] [Indexed: 12/23/2022]
Abstract
Previous studies have demonstrated that polypeptides extracted from scorpion venom (PESV) inhibited cell proliferation in several tumors, however, the effect on dysfunctional and exhausted natural killer cells which contribute to tumor escape from immune surveillance remain to be elucidated. In this study, we determined the effect of PESV on NK infiltration into H22 cells orthotopic transplantation tumors and on the expression of MHC class I chain-related proteins A (MICA) in HepG2 cells. We found that tumor growth in mice was significantly inhibited by PESV and the survival time of tumor-bearing mice treated with PESV was significantly prolonged. Moreover, levels of tumor-infiltrating NK cells, NKG2D protein, perforin and granzyme B mRNA were significantly increased in the group treated with PESV compared with the tumor-bearing control group. In addition, In addition, up-regulation of MICA by PESV enhances the susceptibility of HepG2 cells to NK lysis in vitro. These results indicate that the inhibitory effects of PESV on hepatic carcinoma are likely mediated by up-regulation of NK cell activity via the MICA-NKG2D pathway.
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Affiliation(s)
- Han Chen
- Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan 250062, China; School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan 250062, China
| | - Wang Zhidan
- Department of Frontier Health Sciences, Tokyo Metropolitan University, 7-2-10 Higashiogu, Arakawa-ku, Tokyo, Japan
| | - Ren Xia
- Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan 250062, China
| | - Wang Zhaoxia
- Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan 250062, China
| | - Jia Qing
- Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan 250062, China
| | - Guo Qiang
- Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan 250062, China
| | - Yin Haipeng
- Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan 250062, China
| | - Wang Hengxiao
- Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan 250062, China.
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26
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Ramzan M, Sturm N, Decaens T, Bioulac-Sage P, Bancel B, Merle P, Tran Van Nhieu J, Slama R, Letoublon C, Zarski JP, Jouvin-Marche E, Marche PN, Leroy V. Liver-infiltrating CD8(+) lymphocytes as prognostic factor for tumour recurrence in hepatitis C virus-related hepatocellular carcinoma. Liver Int 2016. [PMID: 26215124 DOI: 10.1111/liv.12927] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Chronic liver inflammation and immune/inflammatory response promote hepatocellular carcinoma. The aim of this study was to characterize the immune status of HCV-related cirrhosis in patients with hepatocellular carcinoma (HCV-HCC) as compared to HCV patients without hepatocellular carcinoma. METHOD Immune markers (CD3, CD4, CD8, CD20, CD56, TCRγδ, FoxP3) and gene expression profiles (CD8α, CD8β, FoxP3, IL-6, IFN-γ, perforin, RANTES) were analysed in a test cohort by immunohistochemistry and quantitative RT-PCR analysis on serial non-tumorous and tumorous tissues. RESULTS Immune micro-environment was more inflammatory in HCV-HCC than HCV cirrhotic livers. The number of CD3(+) , CD4(+) , CD8(+) and CD20(+) liver-infiltrating lymphocytes was significantly higher, whereas the number of CD56(+) cells was significantly lower in HCV-HCC compared to HCV cirrhotic parenchyma. These differences were restricted to fibrous septa for CD4(+) and CD20(+) cells and to nodular parenchyma for CD8(+) cells. Gene expressions of CD8α, FoxP3 and RANTES were also significantly higher in HCV-HCC than in HCV cirrhosis. Interestingly, in a large cohort of 63 HCV-HCC patients. The number of CD8(+) cells ≥100/field was associated with significant higher tumour recurrence (P = 0.003) and lower overall survival (P = 0.05) at 5 years. CONCLUSION High densities of liver-infiltrating lymphocytes in HCV-HCC cirrhotic parenchyma prevail inflammatory conditions and could contribute to tumorigenesis and tumour recurrence. These results could contribute towards better clinical evaluation of patients susceptible for HCC recurrence after curative surgery.
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Affiliation(s)
- Muhammad Ramzan
- INSERM, Unité 823, Grenoble, France.,Université Grenoble-Alpes, Faculté de Médecine, UMR-S823, Grenoble, France
| | - Nathalie Sturm
- INSERM, Unité 823, Grenoble, France.,Université Grenoble-Alpes, Faculté de Médecine, UMR-S823, Grenoble, France.,Département d'Anatomie et de Cytologie Pathologiques, CHU de Grenoble, Grenoble, France
| | - Thomas Decaens
- INSERM, Unité 823, Grenoble, France.,Université Grenoble-Alpes, Faculté de Médecine, UMR-S823, Grenoble, France.,Clinique d' Hépatogastroentérologie, pôle DigiDune, CHU de Grenoble, Grenoble, France
| | - Paulette Bioulac-Sage
- Service d'Anatomie et de Cytologie Pathologiques, Hôpital Pellegrin, Bordeaux, France
| | - Brigitte Bancel
- Service de Pathologie, Hôpital de la Croix Rousse, Lyon, France.,Université Claude Bernard Lyon 1, INSERM UMR-S1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.,Hospices Civils de Lyon, Lyon, France
| | - Philippe Merle
- Université Claude Bernard Lyon 1, INSERM UMR-S1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.,Hospices Civils de Lyon, Lyon, France.,Service d'Hépatologie, Hôpital de la Croix-Rousse, Lyon, France
| | - Jeanne Tran Van Nhieu
- Département de Pathologie, APHP, Groupe Hospitalier Henri Mondor, Val de Marne, Université Paris Est-Créteil, Créteil, France
| | - Rémy Slama
- INSERM, Unité 823, Grenoble, France.,Université Grenoble-Alpes, Faculté de Médecine, UMR-S823, Grenoble, France
| | - Christian Letoublon
- INSERM, Unité 823, Grenoble, France.,Université Grenoble-Alpes, Faculté de Médecine, UMR-S823, Grenoble, France.,Clinique de Chirurgie Digestive, pôle DIGIDUNE, CHU de Grenoble, Grenoble, France
| | - Jean-Pierre Zarski
- INSERM, Unité 823, Grenoble, France.,Université Grenoble-Alpes, Faculté de Médecine, UMR-S823, Grenoble, France.,Clinique d' Hépatogastroentérologie, pôle DigiDune, CHU de Grenoble, Grenoble, France
| | - Evelyne Jouvin-Marche
- INSERM, Unité 823, Grenoble, France.,Université Grenoble-Alpes, Faculté de Médecine, UMR-S823, Grenoble, France
| | - Patrice N Marche
- INSERM, Unité 823, Grenoble, France.,Université Grenoble-Alpes, Faculté de Médecine, UMR-S823, Grenoble, France.,Clinique d' Hépatogastroentérologie, pôle DigiDune, CHU de Grenoble, Grenoble, France
| | - Vincent Leroy
- INSERM, Unité 823, Grenoble, France.,Université Grenoble-Alpes, Faculté de Médecine, UMR-S823, Grenoble, France.,Clinique d' Hépatogastroentérologie, pôle DigiDune, CHU de Grenoble, Grenoble, France
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27
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Gasparri ML, Attar R, Palaia I, Perniola G, Marchetti C, Di Donato V, Farooqi AA, Papadia A, Panici PB. Tumor infiltrating lymphocytes in ovarian cancer. Asian Pac J Cancer Prev 2016; 16:3635-8. [PMID: 25987014 DOI: 10.7314/apjcp.2015.16.9.3635] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Several improvements in ovarian cancer treatment have been achieved in recent years, both in surgery and in combination chemotherapy with targeting. However, ovarian tumors remain the women's cancers with highest mortality rates. In this scenario, a pivotal role has been endorsed to the immunological environment and to the immunological mechanisms involved in ovarian cancer behavior. Recent evidence suggests a loss of the critical balance between immune-activating and immune-suppressing mechanisms when oncogenesis and cancer progression occur. Ovarian cancer generates a mechanism to escape the immune system by producing a highly suppressive environment. Immune-activated tumor infiltrating lymphocytes (TILs) in ovarian tumor tissue testify that the immune system is the trigger in this neoplasm. The TIL mileau has been demonstrated to be associated with better prognosis, more chemosensitivity, and more cases of optimal residual tumor achieved during primary cytoreduction. Nowadays, scientists are focusing attention on new immunologically effective tumor biomarkers in order to optimize selection of patients for recruitment in clinical trials and to identify relationships of these biomarkers with responses to immunotherapeutics. Assessing this point of view, TILs might be considered as a potent predictive immunotherapy biomarker.
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Affiliation(s)
- Maria Luisa Gasparri
- Department of Gynecologic-Obstetrical and Urologic Sciences, "Sapienza" University of Rome, Italy E-mail :
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28
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Yang Z, Zhang J, Lu Y, Xu Q, Tang B, Wang Q, Zhang W, Chen S, Lu L, Chen X. Aspartate aminotransferase-lymphocyte ratio index and systemic immune-inflammation index predict overall survival in HBV-related hepatocellular carcinoma patients after transcatheter arterial chemoembolization. Oncotarget 2015; 6:43090-43098. [PMID: 26506519 PMCID: PMC4767493 DOI: 10.18632/oncotarget.5719] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Accepted: 09/16/2015] [Indexed: 02/05/2023] Open
Abstract
It has been suggested that lymphocytes play central roles in host antitumor immune responses and control cancer outcome. We reviewed the clinical parameters of 189 hepatocellular carcinoma (HCC) patients and investigated the prognostic significance of lymphocyte-related scores in HCC patients following transcatheter arterial chemoembolization (TACE). Survival analysis revealed that an elevated aspartate aminotransferase-lymphocyte ratio index (ALRI) > 57 and a systemic immune-inflammation index (SII) > 300 were negatively associated with overall survival in HBV-related HCC (HR = 2.181, P = 0.003 and HR = 2.453, P = 0.003; respectively). Spearman chi-square analysis showed that ALRI had a specificity of 82.4% and that SII index had a sensitivity of 71.9% for HCC overall survival. ALRI and SII had negative predictive values of 74.6% and 80%, respectively for HCC overall survival. Additionally, Barcelona Clinic Liver Cancer (BCLC) stage C patients had significantly higher ALRI and SII scores (both P < 0.0001) and poorer overall survival (HR = 3.618, P < 0.001). Additionally, HCC patients with portal vein tumor thrombosis (PVTT) had higher ALRI and SII scores (P < 0.0001 and P = 0.0059, respectively). In conclusion, as noninvasive, low cost, easily assessable and reproducible parameters, elevated ALRI and SII should be used as negative predictive factors for overall survival in HBV-related HCC in clinical practice.
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Affiliation(s)
- Zongguo Yang
- Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Jianliang Zhang
- Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Yunfei Lu
- Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Qingnian Xu
- Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Bozong Tang
- Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Qiang Wang
- Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Wensi Zhang
- Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Shishi Chen
- Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Lingqing Lu
- Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Xiaorong Chen
- Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
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Li X, Peng J, Pang Y, Yu S, Yu X, Chen P, Wang W, Han W, Zhang J, Yin Y, Zhang Y. Identification of a FOXP3(+)CD3(+)CD56(+) population with immunosuppressive function in cancer tissues of human hepatocellular carcinoma. Sci Rep 2015; 5:14757. [PMID: 26437631 PMCID: PMC4594002 DOI: 10.1038/srep14757] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Accepted: 08/28/2015] [Indexed: 12/29/2022] Open
Abstract
The liver resident lymphoid population is featured by the presence of a large number of CD3+CD56+ cells referred as natural T cells. In human hepatocellular carcinoma (HCC) patients, the natural T cells were found to be sharply decreased in tumor (5.871 ± 3.553%) versus non-tumor (14.02 ± 6.151%) tissues. More intriguingly, a substantial fraction of the natural T cells (22.76 ± 18.61%) assumed FOXP3 expression. These FOXP3-expressing CD3+CD56+ cells lost the expression of IFN-γ and perforin, which are critical for the effector function of natural T cells. On the other hand, they acquired surface expression of CD25 and CTLA-4 typically found in regulatory T (Treg) cells. Consistent with the phenotypic conversion, they imposed an inhibitory effect on anti-CD3-induced proliferation of naive T cells. Further studies demonstrated that transforming growth factor β1 (TGF-β1) could effectively induce FOXP3 expression in CD3+CD56+ cells and the cells were thus endowed with a potent immunosuppressive capacity. Finally, Kaplan-Meier analysis revealed that the relative abundance of FOXP3-expressing CD3+CD56+ cells in tumor tissues was significantly correlated with the survival of HCC patients. In conclusion, the present study identified a new type of regulatory immune cells whose emergence in liver cancer tissues may contribute to tumor progression.
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Affiliation(s)
- Xiaofeng Li
- Department of Immunology, Peking University Health Science Center, Beijing 100191, China.,Department of Molecular Imaging and Nuclear Medicine, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
| | - Jirun Peng
- Center of Hepatobiliary Surgery, Peking University People's Hospital, Beijing 100044, China
| | - Yanli Pang
- Department of Immunology, Peking University Health Science Center, Beijing 100191, China
| | - Sen Yu
- Department of Immunology, Peking University Health Science Center, Beijing 100191, China
| | - Xin Yu
- Center of Hepatobiliary Surgery, Peking University People's Hospital, Beijing 100044, China
| | - Pengcheng Chen
- Center of Hepatobiliary Surgery, Peking University People's Hospital, Beijing 100044, China
| | - Wenzhen Wang
- Center of Hepatobiliary Surgery, Peking University People's Hospital, Beijing 100044, China
| | - Wenling Han
- Department of Immunology, Peking University Health Science Center, Beijing 100191, China
| | - Jun Zhang
- Department of Immunology, Peking University Health Science Center, Beijing 100191, China
| | - Yanhui Yin
- Department of Immunology, Peking University Health Science Center, Beijing 100191, China
| | - Yu Zhang
- Department of Immunology, Peking University Health Science Center, Beijing 100191, China
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30
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Sun C, Sun HY, Xiao WH, Zhang C, Tian ZG. Natural killer cell dysfunction in hepatocellular carcinoma and NK cell-based immunotherapy. Acta Pharmacol Sin 2015; 36:1191-9. [PMID: 26073325 PMCID: PMC4648180 DOI: 10.1038/aps.2015.41] [Citation(s) in RCA: 148] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Accepted: 04/16/2015] [Indexed: 02/06/2023]
Abstract
The mechanisms linking hepatitis B virus (HBV) and hepatitis C virus (HCV) infection to hepatocellular carcinoma (HCC) remain largely unknown. Natural killer (NK) cells account for 25%–50% of the total number of liver lymphocytes, suggesting that NK cells play an important role in liver immunity. The number of NK cells in the blood and tumor tissues of HCC patients is positively correlated with their survival and prognosis. Furthermore, a group of NK cell-associated genes in HCC tissues is positively associated with the prolonged survival. These facts suggest that NK cells and HCC progression are strongly associated. In this review, we describe the abnormal NK cells and their functional impairment in patients with chronic HBV and HCV infection, which contribute to the progression of HCC. Then, we summarize the association of NK cells with HCC based on the abnormalities in the numbers and phenotypes of blood and liver NK cells in HCC patients. In particular, the exhaustion of NK cells that represents lower cytotoxicity and impaired cytokine production may serve as a predictor for the occurrence of HCC. Finally, we present the current achievements in NK cell immunotherapy conducted in mouse models of liver cancer and in clinical trials, highlighting how chemoimmunotherapy, NK cell transfer, gene therapy, cytokine therapy and mAb therapy improve NK cell function in HCC treatment. It is conceivable that NK cell-based anti-HCC therapeutic strategies alone or in combination with other therapies will be great promise for HCC treatment.
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31
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Sun C, Sun H, Zhang C, Tian Z. NK cell receptor imbalance and NK cell dysfunction in HBV infection and hepatocellular carcinoma. Cell Mol Immunol 2015; 12:292-302. [PMID: 25308752 PMCID: PMC4654321 DOI: 10.1038/cmi.2014.91] [Citation(s) in RCA: 145] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Revised: 08/25/2014] [Accepted: 08/26/2014] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is currently the third leading cause of cancer mortality and a common poor-prognosis malignancy due to postoperative recurrence and metastasis. There is a significant correlation between chronic hepatitis B virus (HBV) infection and hepatocarcinogenesis. As the first line of host defense against viral infections and tumors, natural killer (NK) cells express a large number of immune recognition receptors (NK receptors (NKRs)) to recognize ligands on hepatocytes, liver sinusoidal endothelial cells, stellate cells and Kupffer cells, which maintain the balance between immune response and immune tolerance of NK cells. Unfortunately, the percentage and absolute number of liver NK cells decrease significantly during the development and progression of HCC. The abnormal expression of NK cell receptors and dysfunction of liver NK cells contribute to the progression of chronic HBV infection and HCC and are significantly associated with poor prognosis for liver cancer. In this review, we focus on the role of NK cell receptors in anti-tumor immune responses in HCC, particularly HBV-related HCC. We discuss specifically how tumor cells evade attack from NK cells and how emerging understanding of NKRs may aid the development of novel treatments for HCC. Novel mono- and combination therapeutic strategies that target the NK cell receptor-ligand system may potentially lead to successful and effective immunotherapy in HCC.Cellular & Molecular Immunology advance online publication, 6 October 2014; doi:10.1038/cmi.2014.91.
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Affiliation(s)
- Cheng Sun
- Institute of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, China
| | - Haoyu Sun
- Institute of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, China
| | - Cai Zhang
- Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Zhigang Tian
- Institute of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, China
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Cheung PF, Yip CW, Ng LW, Wong CK, Cheung TT, Lo CM, Fan ST, Cheung ST. Restoration of natural killer activity in hepatocellular carcinoma by treatment with antibody against granulin-epithelin precursor. Oncoimmunology 2015; 4:e1016706. [PMID: 26140244 PMCID: PMC4485783 DOI: 10.1080/2162402x.2015.1016706] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Revised: 02/03/2015] [Accepted: 02/03/2015] [Indexed: 02/04/2023] Open
Abstract
Impairment of natural killer (NK) cell activity is an important mechanism of tumor immunoevasion. We have previously shown that expression of granulin-epithelin precursor (GEP) in hepatocellular carcinoma (HCC) cells rendered the cells resistant to NK cell immunosurveillance. Here, we examined whether targeting GEP could rescue NK activity in HCC patients. The current study demonstrated that quantities and activities of NK cells were significantly lower in HCC patients compared with healthy individuals, and were negatively correlated with GEP levels in HCC cells. NK cells demonstrated enhanced expression of the stimulatory receptors natural-killer group 2, member D (NKG2D) and CD69, increased secretion of IFN-γ and perforin, and cytotoxicity against HCC cells upon GEP suppression. Opposite phenotypes of NK cells were observed when GEP was overexpressed in HCC cells. Importantly, GEP blockage by monoclonal antibody A23 restored NK activity in HCC patients and sensitized HCC cells to NK cytotoxicity. Furthermore, A23 induced NK-mediated antibody-dependent cell-mediated cytotoxicity against HCC. In summary, the activity of NK cells in HCC was impaired by GEP expression, which could be rescued by GEP antibody. This study provides new insight for treatments targeting GEP to boost NK activity in HCC patients.
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Affiliation(s)
- Phyllis Fy Cheung
- Department of Surgery ; Center for Cancer Research; The University of Hong Kong ; Hong Kong, China
| | - Chi Wai Yip
- Department of Surgery ; Center for Cancer Research; The University of Hong Kong ; Hong Kong, China
| | | | - Chun Kwok Wong
- Department of Chemical Pathology; The Chinese University of Hong Kong; Prince of Wales Hospital ; Hong Kong, China
| | - Tan To Cheung
- Department of Surgery ; Department of Surgery; Queen Mary Hospital ; Hong Kong, China
| | - Chung Mau Lo
- Department of Surgery ; Department of Surgery; Queen Mary Hospital ; Hong Kong, China
| | - Sheung Tat Fan
- Department of Surgery ; Department of Surgery; Queen Mary Hospital ; Hong Kong, China
| | - Siu Tim Cheung
- Department of Surgery ; Center for Cancer Research; The University of Hong Kong ; Hong Kong, China
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Li A, Shuai X, Jia Z, Li H, Liang X, Su D, Guo W. Ganoderma lucidum polysaccharide extract inhibits hepatocellular carcinoma growth by downregulating regulatory T cells accumulation and function by inducing microRNA-125b. J Transl Med 2015; 13:100. [PMID: 25889022 PMCID: PMC4379953 DOI: 10.1186/s12967-015-0465-5] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2014] [Accepted: 03/16/2015] [Indexed: 02/21/2023] Open
Abstract
Background Ganoderma lucidum polysaccharides (GLPS) have been used as traditional Chinese medicine for their properties of cancer prevention and immunomodulation. However, it is unclear whether GLPS has therapeutic effect on anti-hepatocellular carcinoma (HCC) in vivo. In this study, the effect of GLPS and their impact on the balance of regulatory T cell (Treg) and effector T cell (Teff) was measured in a model of hepatoma-bearing mice. Methods The effect of GLPS and their impact on the balance of regulatory T cell (Treg) and effector T cell (Teff) were measured in a model of hepatoma-bearing mice. Real-time PCR detected the levels of MicroRNAs (miRNAs) and mRNA. The effects of Tregs on Teff proliferation were determined via suppression assay. The mircroRNA-125b (miR-125b) inhibitor was used to down-regulate miR-125b expression. Results GLPS significantly suppressed tumor growth in hepatoma-bearing mice associated with an increase of the ratio of Teffs to Tregs. Moreover, GLPS eliminate Treg suppression of Teff proliferation with an increase in IL-2 secretion. Addition of GLPS to treat T cells inhibited Notch1 and FoxP3 expression through increase of miR-125b expression. In hepatoma-bearing mice, miR-125b inhibitor obviously abolished the effect of GLPS on tumor growth. Conclusions This finding provides the novel evidence for GLPS on inhibition of HCC through miR-125b inhibiting Tregs accumulation and function.
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Affiliation(s)
- Aimei Li
- Department of Pathology, Nanjing Medical University, Nanjing, China. .,Department of Nuclear Medicine, The Affiliated Drum Tower Hospital of NanJing University, Zhongshan Road, Nanjing, 210008, China.
| | - Xuanyu Shuai
- Department of Pathology, Nanjing Medical University, Nanjing, China.
| | - Zhijun Jia
- Department of Nuclear Medicine, The Affiliated Drum Tower Hospital of NanJing University, Zhongshan Road, Nanjing, 210008, China.
| | - Hangyu Li
- Department of General Surgery, Shengjing Hospital Affiliated to China Medical University, Shenyang, China.
| | - Xiubin Liang
- Center of Metabolic Disease Research, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, China.
| | - Dongming Su
- Department of Pathology, Nanjing Medical University, Nanjing, China. .,Center of Cellular Therapy, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China. .,Center of Metabolic Disease Research, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, China.
| | - Wanhua Guo
- Department of Nuclear Medicine, The Affiliated Drum Tower Hospital of NanJing University, Zhongshan Road, Nanjing, 210008, China.
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34
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Jeng KS, Chang CF, Jeng WJ, Sheen IS, Jeng CJ. Heterogeneity of hepatocellular carcinoma contributes to cancer progression. Crit Rev Oncol Hematol 2015; 94:337-47. [PMID: 25680939 DOI: 10.1016/j.critrevonc.2015.01.009] [Citation(s) in RCA: 72] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2014] [Revised: 10/24/2014] [Accepted: 01/21/2015] [Indexed: 01/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly heterogeneous disease displaying differences in angiogenesis, extracellular matrix proteins, the immune microenvironment and tumor cell populations. Additionally, genetic variations and epigenetic changes of HCC cells could lead to aberrant signaling pathways, induce cancer stem cells and enhance tumor progression. Thus, the heterogeneity in HCC contributes to disease progression and a better understanding of its heterogeneity will greatly aid in the development of strategies for the HCC treatment.
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Affiliation(s)
- Kuo-Shyang Jeng
- Department of Surgery, Far Eastern Memorial Hospital, New Taipei City, Taiwan; Department of Medical Research, Far Eastern Memorial Hospital, New Taipei City, Taiwan.
| | - Chiung-Fang Chang
- Department of Medical Research, Far Eastern Memorial Hospital, New Taipei City, Taiwan
| | - Wen-Juei Jeng
- Department of Hepato-Gastroenterology, Chang-Gung Memorial Hospital, LinKou Medical Center, Chang Gung University, Taiwan
| | - I-Shyan Sheen
- Department of Hepato-Gastroenterology, Chang-Gung Memorial Hospital, LinKou Medical Center, Chang Gung University, Taiwan
| | - Chi-Juei Jeng
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
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35
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Sun YX, Cheng W, Han X, Liu Z, Wang QC, Shao H. In Vivo Experimental Study on the Effects of Fluid in Increasing the Efficiency of Radiofrequency Ablation. Asian Pac J Cancer Prev 2014; 15:5799-804. [DOI: 10.7314/apjcp.2014.15.14.5799] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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36
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Zhao JJ, Pan QZ, Pan K, Weng DS, Wang QJ, Li JJ, Lv L, Wang DD, Zheng HX, Jiang SS, Zhang XF, Xia JC. Interleukin-37 mediates the antitumor activity in hepatocellular carcinoma: role for CD57+ NK cells. Sci Rep 2014; 4:5177. [PMID: 24898887 PMCID: PMC4046124 DOI: 10.1038/srep05177] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2014] [Accepted: 05/02/2014] [Indexed: 12/19/2022] Open
Abstract
The biological role of interleukin-37 (IL-37) in cancer is large unknown. Through immunohistochemical detection using 163 primary hepatocellular carcinoma (HCC) clinical specimens, we found the expression of IL-37 was decreased in tumor tissues, and the expression level was negatively correlated with tumor size. High expression of IL-37 in HCC tumor tissues was associated with better overall survival (OS) and disease-free survival (DFS). IL-37 expression in tumor tissues was positively associated with the density of tumor-infiltrating CD57+ natural killer (NK) cells, but not with the CD3+ and CD8+ T cells. Consistently, in vitro chemotaxis analysis showed that IL-37- overexpressing HCC cells could recruit more NK cells. The in vivo mouse model experiments also revealed that overexpression IL-37 in HCC cells significantly delayed tumor growth and recruited more NK cells into tumors tissues. Our finding suggested that IL-37 might play an important role for the prognosis of HCC patients via regulating innate immune-action.
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Affiliation(s)
- Jing-Jing Zhao
- 1] State Key Laboratory of Oncology in Southern China; Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China [2] Department of Biotherapy, Sun Yat-Sen University Cancer Center, Guangzhou 510060, People's Republic of China [3]
| | - Qiu-Zhong Pan
- 1] State Key Laboratory of Oncology in Southern China; Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China [2]
| | - Ke Pan
- 1] State Key Laboratory of Oncology in Southern China; Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China [2] Department of Biotherapy, Sun Yat-Sen University Cancer Center, Guangzhou 510060, People's Republic of China [3]
| | - De-Sheng Weng
- 1] State Key Laboratory of Oncology in Southern China; Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China [2] Department of Biotherapy, Sun Yat-Sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Qi-Jing Wang
- 1] State Key Laboratory of Oncology in Southern China; Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China [2] Department of Biotherapy, Sun Yat-Sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Jian-Jun Li
- State Key Laboratory of Oncology in Southern China; Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Lin Lv
- State Key Laboratory of Oncology in Southern China; Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Dan-Dan Wang
- State Key Laboratory of Oncology in Southern China; Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Hai-Xia Zheng
- 1] State Key Laboratory of Oncology in Southern China; Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China [2] Department of Biotherapy, Sun Yat-Sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Shan-Shan Jiang
- State Key Laboratory of Oncology in Southern China; Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Xiao-Fei Zhang
- State Key Laboratory of Oncology in Southern China; Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Jian-Chuan Xia
- 1] State Key Laboratory of Oncology in Southern China; Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China [2] Department of Biotherapy, Sun Yat-Sen University Cancer Center, Guangzhou 510060, People's Republic of China
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Ma WL, Lai HC, Yeh S, Cai X, Chang C. Androgen receptor roles in hepatocellular carcinoma, fatty liver, cirrhosis and hepatitis. Endocr Relat Cancer 2014; 21:R165-82. [PMID: 24424503 PMCID: PMC4165608 DOI: 10.1530/erc-13-0283] [Citation(s) in RCA: 125] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Androgen/androgen receptor (AR) signaling plays important roles in normal liver function and in progression of liver diseases. In studies of noncancerous liver diseases, AR knockout mouse models of liver disease have revealed that androgen/AR signaling suppresses the development of steatosis, virus-related hepatitis, and cirrhosis. In addition, studies have shown that targeting AR in bone marrow-derived mesenchymal stem cells (BM-MSCs) improves their self-renewal and migration potentials, thereby increasing the efficacy of BM-MSC transplantation as a way to control the progression of cirrhosis. Androgen/AR signaling is known to be involved in the initiation of carcinogen- or hepatitis B virus-related hepatocellular carcinoma (HCC). However, studies have demonstrated that AR, rather than androgen, plays the dominant role in cancer initiation. Therefore, targeting AR might be an appropriate therapy for patients with early-stage HCC. In contrast, androgen/AR signaling has been shown to suppress metastasis of HCC in patients with late-stage disease. In addition, there is evidence that therapy comprising Sorafenib and agents that enhance the functional expression of AR may suppress the progression of late-stage HCC.
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Affiliation(s)
- Wen-Lung Ma
- Sex Hormone Research Center, Department of
Gastroenterology, and Graduate Institute of Clinical Medical Science, China Medical
University/Hospital, Taichung 404, Taiwan
- George Whipple Lab for Cancer Research, Departments of
Pathology and Urology and The Wilmot Cancer Center, University of Rochester Medical
Center, Rochester, NY 14642, USA
| | - Hsueh-Chou Lai
- Sex Hormone Research Center, Department of
Gastroenterology, and Graduate Institute of Clinical Medical Science, China Medical
University/Hospital, Taichung 404, Taiwan
| | - Shuyuan Yeh
- George Whipple Lab for Cancer Research, Departments of
Pathology and Urology and The Wilmot Cancer Center, University of Rochester Medical
Center, Rochester, NY 14642, USA
| | - Xiujun Cai
- Department of General Surgery, Chawnshang Chang Liver
Cancer Center, Sir Run-run Shaw Hospital, Zhejiang University, Hangzhou, China
- Corresponding author: Chawnshang
Chang () and Xiujun Cai
()
| | - Chawnshang Chang
- Sex Hormone Research Center, Department of
Gastroenterology, and Graduate Institute of Clinical Medical Science, China Medical
University/Hospital, Taichung 404, Taiwan
- George Whipple Lab for Cancer Research, Departments of
Pathology and Urology and The Wilmot Cancer Center, University of Rochester Medical
Center, Rochester, NY 14642, USA
- Corresponding author: Chawnshang
Chang () and Xiujun Cai
()
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Xue TC, Zhang L, Xie XY, Ge NL, Li LX, Zhang BH, Ye SL, Ren ZG. Prognostic significance of the neutrophil-to-lymphocyte ratio in primary liver cancer: a meta-analysis. PLoS One 2014; 9:e96072. [PMID: 24788770 PMCID: PMC4008563 DOI: 10.1371/journal.pone.0096072] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2013] [Accepted: 04/02/2014] [Indexed: 02/07/2023] Open
Abstract
The neutrophil-to-lymphocyte ratio (NLR) is a useful biomarker that reflects systemic inflammation responses. However, the prognostic value of the NLR in patients with primary liver cancer (PLC) remains controversial. We performed a meta-analysis of 26 studies (comprising 4,461 patients) to evaluate the association between the pre-treatment NLR and clinical outcomes of overall survival (OS) and disease-free survival (DFS) in patients with PLC. The correlation between NLR and tumor characteristics or other inflammation-related parameters was also assessed. Data were synthesized using the random-effects model of DerSimonian and Laird, and the hazard ratio (HR) or odds ratio (OR) with 95% confidence interval (CI) was used to estimate effect size. Our analysis indicated that a high NLR predicted poor OS (HR, 2.102; 95% CI: 1.741-2.538) and DFS (HR, 2.474; 95% CI: 1.855-3.300) for PLC. A high NLR was associated with the presence of tumor vascular invasion (OR: 1.889, 95% CI: 1.487-2.400; p<0.001) and an elevated alpha-fetoprotein level (OR: 1.536; 95% CI: 1.152-2.048; p = 0.003). Thus, we conclude that a high NLR indicates a poor prognosis for patients with PLC and may also be predictive for PLC invasion and metastasis. Subgroup analysis suggested that the predictive role of NLR in cholangiocarcinoma is limited, and a further large study to confirm these findings is warranted.
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Affiliation(s)
- Tong-Chun Xue
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China
| | - Lan Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China
| | - Xiao-Yin Xie
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China
| | - Ning-Ling Ge
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China
| | - Li-Xin Li
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China
| | - Bo-Heng Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China
- Department of Medical Statistics, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
| | - Sheng-Long Ye
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China
| | - Zheng-Gang Ren
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China
- * E-mail:
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Schiavoni G, Gabriele L, Mattei F. The tumor microenvironment: a pitch for multiple players. Front Oncol 2013; 3:90. [PMID: 23616948 PMCID: PMC3628362 DOI: 10.3389/fonc.2013.00090] [Citation(s) in RCA: 119] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2013] [Accepted: 04/03/2013] [Indexed: 12/13/2022] Open
Abstract
The cancer microenvironment may be conceptually regarded as a pitch where the main players are resident and non-resident cellular components, each covering a defined role and interconnected by a complex network of soluble mediators. The crosstalk between these cells and the tumor cells within this environment crucially determines the fate of tumor progression. Immune cells that infiltrate the tumor bed are transported there by blood circulation and exert a variety of effects, either counteracting or favoring tumor outgrowth. Here, we review and discuss the multiple populations composing the tumor bed, with special focus on immune cells subsets that positively or negatively dictate neoplastic progression. In this scenario, the contribution of cancer stem cells within the tumor microenvironment will also be discussed. Finally, we illustrate recent advances on new integrated approaches to investigate the tumor microenvironment in vitro.
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Affiliation(s)
- Giovanna Schiavoni
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità Rome, Italy
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