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Wei H, Dong C, Li X. Treatment Options for Hepatocellular Carcinoma Using Immunotherapy: Present and Future. J Clin Transl Hepatol 2024; 12:389-405. [PMID: 38638377 PMCID: PMC11022065 DOI: 10.14218/jcth.2023.00462] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 01/22/2024] [Accepted: 01/25/2024] [Indexed: 04/20/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a common cancer, and the body's immune responses greatly affect its progression and the prognosis of patients. Immunological suppression and the maintenance of self-tolerance in the tumor microenvironment are essential responses, and these form part of the theoretical foundations of immunotherapy. In this review, we first discuss the tumor microenvironment of HCC, describe immunosuppression in HCC, and review the major biomarkers used to track HCC progression and response to treatment. We then examine antibody-based therapies, with a focus on immune checkpoint inhibitors (ICIs), monoclonal antibodies that target key proteins in the immune response (programmed cell death protein 1, anti-cytotoxic T-lymphocyte associated protein 4, and programmed death-ligand 1) which have transformed the treatment of HCC and other cancers. ICIs may be used alone or in conjunction with various targeted therapies for patients with advanced HCC who are receiving first-line treatments or subsequent treatments. We also discuss the use of different cellular immunotherapies, including T cell receptor (TCR) T cell therapy and chimeric antigen receptor (CAR) T cell therapy. We then review the use of HCC vaccines, adjuvant immunotherapy, and oncolytic virotherapy, and describe the goals of future research in the development of treatments for HCC.
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Affiliation(s)
- Hongbin Wei
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China
- The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Chunlu Dong
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China
- The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Xun Li
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China
- The First Hospital of Lanzhou University, Lanzhou, Gansu, China
- Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, Gansu, China
- Cancer Prevention and Treatment Center of Lanzhou University School of Medicine, Lanzhou, Gansu, China
- Hepatopancreatobiliary Surgery Institute of Gansu Province, Lanzhou, Gansu, China
- Clinical Research Center for General Surgery of Gansu Province, Lanzhou, Gansu, China
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2
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Guo Y, Hu P, Shi J. Nanomedicine Remodels Tumor Microenvironment for Solid Tumor Immunotherapy. J Am Chem Soc 2024; 146:10217-10233. [PMID: 38563421 DOI: 10.1021/jacs.3c14005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Although immunotherapy is relatively effective in treating hematological malignancies, their efficacy against solid tumors is still suboptimal or even noneffective presently. Compared to hematological cancers, solid tumors exhibit strikingly different immunosuppressive microenvironment, severely deteriorating the efficacy of immunotherapy: (1) chemical features such as hypoxia and mild acidity suppress the activity of immune cells, (2) the pro-tumorigenic domestication of immune cells in the microenvironment within the solid tumors further undermines the effectiveness of immunotherapy, and (3) the dense physical barrier of solid tumor tissues prevents the effective intratumoral infiltration and contact killing of active immune cells. Therefore, we believe that reversing the immunosuppressive microenvironment are of critical priority for the immunotherapy against solid tumors. Due to their unique morphologies, structures, and compositions, nanomedicines have become powerful tools for achieving this goal. In this Perspective, we will first briefly introduce the immunosuppressive microenvironment of solid tumors and then summarize the most recent progresses in nanomedicine-based immunotherapy for solid tumors by remodeling tumor immune-microenvironment in a comprehensive manner. It is highly expected that this Perspective will aid in advancing immunotherapy against solid tumors, and we are highly optimistic on the future development in this burgeoning field.
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Affiliation(s)
- Yuedong Guo
- Shanghai Tenth People's Hospital, Shanghai Frontiers Science Center of Nanocatalytic Medicine, School of Medicine, Tongji University, Shanghai 200331, P. R. China
| | - Ping Hu
- Shanghai Tenth People's Hospital, Shanghai Frontiers Science Center of Nanocatalytic Medicine, School of Medicine, Tongji University, Shanghai 200331, P. R. China
- Shanghai Institute of Ceramics, Chinese Academy of Sciences; Research Unit of Nanocatalytic Medicine in Specific Therapy for Serious Disease, Chinese Academy of Medical Sciences (2021RU012), Shanghai 200050, P. R. China
| | - Jianlin Shi
- Shanghai Institute of Ceramics, Chinese Academy of Sciences; Research Unit of Nanocatalytic Medicine in Specific Therapy for Serious Disease, Chinese Academy of Medical Sciences (2021RU012), Shanghai 200050, P. R. China
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Ajith A, Merimi M, Arki MK, Hossein-khannazer N, Najar M, Vosough M, Sokal EM, Najimi M. Immune regulation and therapeutic application of T regulatory cells in liver diseases. Front Immunol 2024; 15:1371089. [PMID: 38571964 PMCID: PMC10987744 DOI: 10.3389/fimmu.2024.1371089] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 02/28/2024] [Indexed: 04/05/2024] Open
Abstract
CD4+ CD25+ FOXP3+ T regulatory cells (Tregs) are a subset of the immunomodulatory cell population that can inhibit both innate and adaptive immunity by various regulatory mechanisms. In hepatic microenvironment, proliferation, plasticity, migration, and function of Tregs are interrelated to the remaining immune cells and their secreted cytokines and chemokines. In normal conditions, Tregs protect the liver from inflammatory and auto-immune responses, while disruption of this crosstalk between Tregs and other immune cells may result in the progression of chronic liver diseases and the development of hepatic malignancy. In this review, we analyze the deviance of this protective nature of Tregs in response to chronic inflammation and its involvement in inducing liver fibrosis, cirrhosis, and hepatocellular carcinoma. We will also provide a detailed emphasis on the relevance of Tregs as an effective immunotherapeutic option for autoimmune diseases, liver transplantation, and chronic liver diseases including liver cancer.
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Affiliation(s)
- Ananya Ajith
- Laboratory of Pediatric Hepatology and Cell Therapy, Institute of Experimental and Clinical Research (IREC), UCLouvain, Brussels, Belgium
| | - Makram Merimi
- Genetics and Immune Cell Therapy Unit, LBBES Laboratory, Faculty of Sciences, University Mohammed Premier, Oujda, Morocco
| | - Mandana Kazem Arki
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nikoo Hossein-khannazer
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehdi Najar
- Osteoarthritis Research Unit, Department of Medicine, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC, Canada
- Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Centre, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Huddinge, Sweden
| | - Etienne Marc Sokal
- Laboratory of Pediatric Hepatology and Cell Therapy, Institute of Experimental and Clinical Research (IREC), UCLouvain, Brussels, Belgium
| | - Mustapha Najimi
- Laboratory of Pediatric Hepatology and Cell Therapy, Institute of Experimental and Clinical Research (IREC), UCLouvain, Brussels, Belgium
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Chen Y, Meng L, Xu N, Chen H, Wei X, Lu D, Wang S, Xu X. Ten-eleven translocation-2-mediated macrophage activation promotes liver regeneration. Cell Commun Signal 2024; 22:95. [PMID: 38308318 PMCID: PMC10835877 DOI: 10.1186/s12964-023-01407-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Accepted: 11/23/2023] [Indexed: 02/04/2024] Open
Abstract
BACKGROUND The remarkable regenerative capacity of the liver enables recovery after radical Hepatocellular carcinoma (HCC) resection. After resection, macrophages secrete interleukin 6 and hepatocyte growth factors to promote liver regeneration. Ten-eleven translocation-2 (Tet2) DNA dioxygenase regulates pro-inflammatory factor secretion in macrophages. In this study, we explored the role of Tet2 in macrophages and its function independent of its enzymatic activity in liver regeneration. METHODS The model of liver regeneration after 70% partial hepatectomy (PHx) is a classic universal model for studying reparative processes in the liver. Mice were euthanized at 0, 24, and 48 h after PHx. Enzyme-linked immunosorbent assays, quantitative reverse transcription-polymerase chain reaction, western blotting, immunofluorescence analysis, and flow cytometry were performed to explore immune cell infiltration and liver regenerative capability. Molecular dynamics simulations were performed to study the interaction between Tet2 and signal transducer and activator of transcription 1 (Stat1). RESULTS Tet2 in macrophages negatively regulated liver regeneration in the partial hepatectomy mice model. Tet2 interacted with Stat1, inhibiting the expression of proinflammatory factors and suppressing liver regeneration. The Tet2 inhibitor attenuated the interaction between Stat1 and Tet2, enhanced Stat1 phosphorylation, and promoted hepatocyte proliferation. The proliferative function of the Tet2 inhibitor relied on macrophages and did not affect hepatocytes directly. CONCLUSION Our findings underscore that Tet2 in macrophages negatively regulates liver regeneration by interacting with Stat1. Targeting Tet2 in macrophages promotes liver regeneration and function after a hepatectomy, presenting a novel target to promote liver regeneration and function.
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Affiliation(s)
- Yiyuan Chen
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Lijun Meng
- Zhejiang University School of Medicine, Hangzhou, 310058, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China
| | - Nan Xu
- Zhejiang University School of Medicine, Hangzhou, 310058, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China
| | - Huan Chen
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Xuyong Wei
- Zhejiang University School of Medicine, Hangzhou, 310058, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China
| | - Di Lu
- Zhejiang University School of Medicine, Hangzhou, 310058, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China
| | - Shuai Wang
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
- Zhejiang University School of Medicine, Hangzhou, 310058, China.
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China.
| | - Xiao Xu
- Zhejiang University School of Medicine, Hangzhou, 310058, China.
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China.
- Institute of Organ Transplantation, Zhejiang University, Hangzhou, 310003, China.
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Wang M, Liu H, Huang M, Huang Y, Ming Y, Chen W, Chen Y, Tang Z, Jia B. Immunomodulatory functions of microorganisms in tissue regenerative healing. Acta Biomater 2023; 172:38-52. [PMID: 37816417 DOI: 10.1016/j.actbio.2023.10.007] [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: 04/19/2023] [Revised: 08/31/2023] [Accepted: 10/04/2023] [Indexed: 10/12/2023]
Abstract
External pathogenic microorganisms and commensal microorganisms in the body have either harmful or beneficial impacts on the regenerative repair of tissues, and the immune system plays a crucial regulatory role in this process. This review summarises our current understanding of microorganism-immune system interactions, with a focus on how these interactions impact the renewal and repair ability of tissues, including skin, bone, gut, liver, and nerves. This review concludes with a discussion of the mechanisms by which microbes act on various types of immune cells to affect tissue regeneration, offers potential strategies for using microbial therapies to enhance the regenerative repair function of tissues, and suggest novel therapeutic approaches for regenerative medicine. STATEMENT OF SIGNIFICANCE: Microbiological communities have crucial impacts on human health and illness by participating in energy collection and storage and performing various metabolic processes. External pathogenic microorganisms and commensal microorganisms in the body have either harmful or beneficial impacts on the regenerative repair of tissues, and the immune system plays a critical regulatory role in this process. This study reviews the important correlation between microorganisms and the immune system and investigates the mechanism of various microorganism that participate in the regeneration and repair of tissues and organs by modulating immune system.
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Affiliation(s)
- Min Wang
- Department of Oral Surgery, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Hongyu Liu
- Department of Oral Surgery, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Mingshu Huang
- Department of Oral Surgery, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Yisheng Huang
- Department of Oral Surgery, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Yue Ming
- Department of Oral Surgery, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Weixing Chen
- Department of Oral Surgery, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Yuanxin Chen
- Department of Oral Surgery, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Zhengming Tang
- Department of Oral Surgery, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Bo Jia
- Department of Oral Surgery, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China.
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Luo H, Chen J, Jiang Q, Yu Y, Yang M, Luo Y, Wang X. Comprehensive DNA methylation profiling of COVID-19 and hepatocellular carcinoma to identify common pathogenesis and potential therapeutic targets. Clin Epigenetics 2023; 15:100. [PMID: 37309005 DOI: 10.1186/s13148-023-01515-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Accepted: 05/31/2023] [Indexed: 06/14/2023] Open
Abstract
BACKGROUND & AIMS The effects of SARS-CoV-2 infection can be more complex and severe in patients with hepatocellular carcinoma (HCC) as compared to other cancers. This is due to several factors, including pre-existing conditions such as viral hepatitis and cirrhosis, which are commonly associated with HCC. METHODS We conducted an analysis of epigenomics in SARS-CoV-2 infection and HCC patients, and identified common pathogenic mechanisms using weighted gene co-expression network analysis (WGCNA) and other analyses. Hub genes were identified and analyzed using LASSO regression. Additionally, drug candidates and their binding modes to key macromolecular targets of COVID-19 were identified using molecular docking. RESULTS The epigenomic analysis of the relationship between SARS-CoV-2 infection and HCC patients revealed that the co-pathogenesis was closely linked to immune response, particularly T cell differentiation, regulation of T cell activation and monocyte differentiation. Further analysis indicated that CD4+ T cells and monocytes play essential roles in the immunoreaction triggered by both conditions. The expression levels of hub genes MYLK2, FAM83D, STC2, CCDC112, EPHX4 and MMP1 were strongly correlated with SARS-CoV-2 infection and the prognosis of HCC patients. In our study, mefloquine and thioridazine were identified as potential therapeutic agents for COVID-19 in combined with HCC. CONCLUSIONS In this research, we conducted an epigenomics analysis to identify common pathogenetic processes between SARS-CoV-2 infection and HCC patients, providing new insights into the pathogenesis and treatment of HCC patients infected with SARS-CoV-2.
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Affiliation(s)
- Huiyan Luo
- The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jixin Chen
- The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Qiyin Jiang
- The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yifan Yu
- The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Miaolun Yang
- The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yuehua Luo
- The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiongwen Wang
- Department of Oncology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
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El-Makarem MAERA, Sayed DM, Matta RA, Mohamed MR, El-Malak MAA, Abbas NI. Interaction of peripheral CD4+CD25+CD127− Tregs with prolactin in HCV hepatocellular carcinoma: oncogenic or immunogenic mechanisms. EGYPTIAN LIVER JOURNAL 2023. [DOI: 10.1186/s43066-023-00250-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/05/2023] Open
Abstract
Abstract
Background and objective
There is little and conflicting data about the peripheral CD4+CD25+CD127− Tregs in patients with hepatocellular carcinoma (HCC) of various etiologies. The expressed membrane-bound transforming growth factor (mTGF-β1) on these Tregs is a marker of their suppressive function. Prolactin suppresses Tregs function in healthy subjects but enhances local Tregs in breast cancer. Our study is the first to assess the frequency and function of CD4+CD25+CD127−Tregs and their association with clinicopathological features and staging in HCV-related HCC and to determine whether prolactin acts as an oncogenic growth factor or participates in the regulation of the immune response mediated by peripheral Tregs. In patients with HCV- elated HCC, HCV-cirrhotic patients, and healthy subjects, we measured the frequency of peripheral traditional CD4+ CD25+ Tregs and well-characterized CD4+CD25+CD127−Tregs and their mTGF-β1 using flow cytometric analysis and measured serum prolactin level.
Results
The frequency of CD4+ CD25+ and CD4+CD25+CD127− Tregs was comparable between HCC and cirrhotic patients and healthy subjects. Serum prolactin and mTGF-β1 on traditional and CD4+CD25+CD127− Tregs were significantly higher in HCC and cirrhotic patients than healthy subjects with an insignificant difference between HCC and cirrhotic patients. Roc curve analysis revealed that cutoff value for mTGF-β1 on Tregs ≥ 13.5% is a good specific (87%) but low sensitive (54%) test in discriminating HCC patients from healthy subjects. The frequency of Tregs and mTGF-β1 were not correlated to clinicopathological characteristics or staging of HCC. Prolactin was higher in the multifocal lesions and negatively correlated to expressed mTGFβ1. The expressed mTGF-β1 was positively correlated with hemoglobin and alanine transaminase. The traditional Tregs was positively correlated with hemoglobin and albumin.
Conclusion
mTGFβ1, as a marker for suppressive function of peripheral CD4 + CD25 + CD127-Tregs, has a diagnostic role in discriminating HCV-related HCC patient from healthy subjects, unfortunately not from HCV-related cirrhotic patients. Serum prolactin has an oncogenic role as it is correlated to multiple focal lesions. It also impedes the suppressive function of peripheral Tregs as an immunogenic role. mTGF-β1 is related to hemoglobin and hepatic inflammation.
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Liu R, Liu Y, Zhang F, Wei J, Wu L. A cuproptosis random forest cox score model-based evaluation of prognosis, mutation characterization, immune infiltration, and drug sensitivity in hepatocellular carcinoma. Front Immunol 2023; 14:1146411. [PMID: 37063920 PMCID: PMC10098017 DOI: 10.3389/fimmu.2023.1146411] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 03/20/2023] [Indexed: 04/18/2023] Open
Abstract
Background Hepatocellular carcinoma is the third most deadly malignant tumor in the world with a poor prognosis. Although immunotherapy represents a promising therapeutic approach for HCC, the overall response rate of HCC patients to immunotherapy is less than 30%. Therefore, it is of great significance to explore prognostic factors and investigate the associated tumor immune microenvironment features. Methods By analyzing RNA-seq data of the TCGA-LIHC cohort, the set of cuproptosis related genes was extracted via correlation analysis as a generalization feature. Then, a random forest cox prognostic model was constructed and the cuproptosis random forest cox score was built by random forest feature filtering and univariate multivariate cox regression analysis. Subsequently, the prognosis prediction of CRFCS was evaluated via analyzing data of independent cohorts from GEO and ICGC by using KM and ROC methods. Moreover, mutation characterization, immune cell infiltration, immune evasion, and drug sensitivity of CRFCS in HCC were assessed. Results A cuproptosis random forest cox score was built based on a generalization feature of four cuproptosis related genes. Patients in the high CRFCS group exhibited a lower overall survival. Univariate multivariate Cox regression analysis validated CRFCS as an independent prognostic indicator. ROC analysis revealed that CRFCS was a good predictor of HCC (AUC =0.82). Mutation analysis manifested that microsatellite instability (MSI) was significantly increased in the high CRFCS group. Meanwhile, tumor microenvironment analysis showed that the high CRFCS group displayed much more immune cell infiltration compared with the low CRFCS group. The immune escape assessment analysis demonstrated that the high CRFCS group displayed a decreased TIDE score indicating a lower immune escape probability in the high CRFCS group compared with the low CRFCS group. Interestingly, immune checkpoints were highly expressed in the high CRFCS group. Drug sensitivity analysis revealed that HCC patients from the high CRFCS group had a lower IC50 of sorafenib than that from the low CRFCS group. Conclusions In this study, we constructed a cuproptosis random forest cox score (CRFCS) model. CRFCS was revealed to be a potential independent prognostic indicator of HCC and high CRFCS samples showed a poor prognosis. Interestingly, CRFCS were correlated with TME characteristics as well as clinical treatment efficacy. Importantly, compared with the low CRFCS group, the high CRFCS group may benefit from immunotherapy and sorafenib treatment.
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Affiliation(s)
- Ruiqi Liu
- School of Medicine, Guangxi University, Nanning, China
| | - Yingyi Liu
- School of Medicine, Guangxi University, Nanning, China
| | - Fengyue Zhang
- School of Medicine, Guangxi University, Nanning, China
| | - Jinrui Wei
- Guangxi Scientific Research Center of Traditional Chinese Medicine, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
- *Correspondence: Lichuan Wu, ; Jinrui Wei,
| | - Lichuan Wu
- School of Medicine, Guangxi University, Nanning, China
- *Correspondence: Lichuan Wu, ; Jinrui Wei,
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Potential of Compounds Originating from the Nature to Act in Hepatocellular Carcinoma Therapy by Targeting the Tumor Immunosuppressive Microenvironment: A Review. MOLECULES (BASEL, SWITZERLAND) 2022; 28:molecules28010195. [PMID: 36615387 PMCID: PMC9822070 DOI: 10.3390/molecules28010195] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 12/19/2022] [Accepted: 12/23/2022] [Indexed: 12/28/2022]
Abstract
Hepatocellular carcinoma (HCC), the most prevalent subtype of liver cancer, is the second main reason for cancer-related deaths worldwide. In recent decades, sufficient evidence supported that immunotherapy was a safe and effective treatment option for HCC. However, tolerance and frequent recurrence and metastasis occurred in patients after immunotherapy due to the complicated crosstalk in the tumor immunosuppressive microenvironment (TIME) in HCC. Therefore, elucidating the TIME in HCC and finding novel modulators to target TIME for attenuating immune suppression is critical to optimize immunotherapy. Recently, studies have shown the potentially immunoregulatory activities of natural compounds, characterized by multiple targets and pathways and low toxicity. In this review, we concluded the unique role of TIME in HCC. Moreover, we summarized evidence that supports the hypothesis of natural compounds to target TIME to improve immunotherapy. Furthermore, we discussed the comprehensive mechanisms of these natural compounds in the immunotherapy of HCC. Accordingly, we present a well-grounded review of the naturally occurring compounds in cancer immunotherapy, expecting to shed new light on discovering novel anti-HCC immunomodulatory drugs from natural sources.
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Ding Q, Li H, Xu Z, Hu K, Ye Q. Identification of CFHR4 associated with poor prognosis of hepatocellular carcinoma. Front Oncol 2022; 12:812663. [PMID: 36338737 PMCID: PMC9632743 DOI: 10.3389/fonc.2022.812663] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 09/22/2022] [Indexed: 11/13/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is one of the most leading causes of cancer death worldwide. The 5-year survival rate of HCC patients remains low due to the lack of early-stage symptoms. Human complement factor H-related protein 4 (CFHR4) is a critical gene that belongs to the factor H family of plasma glycoproteins, which has not been linked to HCC development. The correlations between CFHR4 and prognosis and tumor-infiltrating lymphocytes in HCC are yet unknown. The present study demonstrated the involvement of CFHR4 in HCC via data mining approaches. Results A total of 18 upregulated and 67 down-regulated differentially expressed genes (DEGs) were identified. Importantly, CFHR4, which was screened from DEGs, was shown to express at a lower level in HCC tumor tissue than normal tissues. Western blotting (WB), immunohistochemical (IHC) and quantitative reverse transcription PCR (qRT-PCR) experiments of clinical samples further validated CFHR4 was aberrantly expressed in HCC patients; Data from TCGA showed that CFHR4 was inversely correlated with a cancer family history, histological grade, tumor node metastasis (TNM) stage, and serum AFP level of HCC patients; Univariate and multivariate analyses revealed that low expression of CFHR4 was an independent predictive marker in patients with HCC; Kaplan-Meier analysis showed that the lower expression of CFHR4 was significantly associated with the progression of HCC and poor prognosis rates. Furthermore, TIMER analysis indicated that CFHR4 expression levels had correlations with infiltrating levels of immune cells in HCC. Conclusion CFHR4 expression was low in HCC and was significantly related to the poor prognosis of HCC and the level of immune infiltration. CFHR4 played important roles in regulating the initiation and progression of HCC and could be a potential biomarker for the diagnosis and prognosis of HCC. Methods The expression of CFHR4 was analyzed by GEO and TCGA-LIHC database and verified by WB and IHC assay. The biological function of CFHR4 was performed by GO and KEGG enrichment analysis, and the genomic alteration of CFHR4 was investigated by cBioPortal database.The correlation between CFHR4 expression and clinical relevance was evaluated through Cox proportional hazards model, and the correlation between CFHR4 expression and tumor immune infiltrates were studied by TIMER database.
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Affiliation(s)
- Qinglin Ding
- Sino-German Biomedical Center, National Center for Cellular Regulation and Molecular Pharmaceutics, Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei University of Technology, Wuhan, China
| | - Hanluo Li
- Sino-German Biomedical Center, National Center for Cellular Regulation and Molecular Pharmaceutics, Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei University of Technology, Wuhan, China
| | - Zhigao Xu
- Institute of Hepatobiliary Diseases of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Kanghong Hu
- Sino-German Biomedical Center, National Center for Cellular Regulation and Molecular Pharmaceutics, Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei University of Technology, Wuhan, China
| | - Qifa Ye
- Institute of Hepatobiliary Diseases of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Zhongnan Hospital of Wuhan University, Wuhan, China
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11
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Wang J, Jin Z, Wu G, Deng Z, Wang J, Xu B, Zhu H, Guo Y, Wen Z. Construction of a 3-mRNA hypoxia prognostic model to evaluate immune microenvironment in hepatocellular carcinoma. Medicine (Baltimore) 2022; 101:e30589. [PMID: 36181125 PMCID: PMC9524961 DOI: 10.1097/md.0000000000030589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Hypoxia is a key factor in the development of hepatocellular carcinoma (HCC), which is the most common primary liver cancer with poor prognosis. The current study aimed to identify the potential prognostic biomarkers of the hypoxia-associated gene signature in patients with HCC, and to further explore the relationship between hypoxia and immune infiltration. METHODS After the determination of differentially expressed genes (DEGs) using the HCC transcriptome data of The Cancer Genome Atlas database and hypoxia-related gene set, the prognosis-associated genes were identified using univariate Cox regression analysis. Then, the hypoxia prognosis model was established via multivariate Cox regression analysis, with functional annotation conducted using Gene Set Enrichment Analysis. CIBERSORT was utilized to analyze the degree of tumor immune invasion, and an International Cancer Genome Consortium cohort to verify the reliability of the prognosis model. Expression levels of hypoxia-associated genes were detected by real-time quantitative polymerase chain reaction in HCC samples. RESULTS 3 genes (ENO1, SAP30, and STC2) constructed the hypoxia prognosis model. The patients were subdivided into 2 groups based on median risk score, with a high hypoxic score indicating poor prognosis of HCC. The hypoxia signature could be employed as an independent prognostic factor in HCC. In addition, the proportion of macrophages was higher in the high-risk group. CONCLUSION The hypoxia-associated signature could be a potential prognostic marker of HCC and provides a different perspective for immunotherapy of HCC.
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Affiliation(s)
- Jue Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Zongrui Jin
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Guolin Wu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Zhenfeng Deng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Jilong Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Banghao Xu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Hai Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Ya Guo
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Zhang Wen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- *Correspondence: Zhang Wen, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Shuangyong Road 6#, Nanning, Guangxi 530021, China (e-mail: )
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12
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Neoantigens and their clinical applications in human gastrointestinal cancers. World J Surg Oncol 2022; 20:321. [PMID: 36171610 PMCID: PMC9520945 DOI: 10.1186/s12957-022-02776-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 09/16/2022] [Indexed: 12/24/2022] Open
Abstract
Background Tumor-specific neoantigens are ideal targets for cancer immunotherapy. As research findings have proved, neoantigen-specific T cell activity is immunotherapy’s most important determinant. Main text There is sufficient evidence showing the role of neoantigens in clinically successful immunotherapy, providing a justification for targeting. Because of the significance of the pre-existing anti-tumor immune response for the immune checkpoint inhibitor, it is believed that personalized neoantigen-based therapy may be an imperative approach for cancer therapy. Thus, intensive attention is given to strategies targeting neoantigens for the significant impact with other immunotherapies, such as the immune checkpoint inhibitor. Today, several algorithms are designed and optimized based on Next-Generation Sequencing and public databases, including dbPepNeo, TANTIGEN 2.0, Cancer Antigenic Peptide Database, NEPdb, and CEDAR databases for predicting neoantigens in silico that stimulates the development of T cell therapies, cancer vaccine, and other ongoing immunotherapy approaches. Conclusions In this review, we deliberated the current developments in understanding and recognition of the immunogenicity of newly found gastrointestinal neoantigens as well as their functions in immunotherapies and cancer detection. We also described how neoantigens are being developed and how they might be used in the treatment of GI malignancies.
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13
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Jost R, Al-Shatti N, Ghosn M, Bonnet B, Champiat S, Deschamps F, Gelli M, Boige V, Danlos FX, Susini S, Hollebecque A, Ammari S, Marabelle A, de Baere T, Tselikas L. Synergizing liver systemic treatments with interventional oncology: friend or foe? Br J Radiol 2022; 95:20220548. [PMID: 36075034 PMCID: PMC9815737 DOI: 10.1259/bjr.20220548] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 08/20/2022] [Accepted: 08/24/2022] [Indexed: 01/13/2023] Open
Abstract
Interventional radiology techniques provide excellent local tumor control for small tumors in various organs, but several limitations can hamper the oncological outcomes such as the tumor size or the number of lesions. Technical improvements, optimal patient selection and combination with systemic therapies, including immune checkpoint inhibitors, have been successfully developed to overcome these barriers.In this setting, chemotherapy and targeted therapies aim to diminish the tumor burden in addition to local treatments, while immunotherapies may have a synergistic effect in terms of mechanism of action on the tumor cell as well as the immune environment, with multiple treatment combinations being available. Finally, interventional Rrdiology treatments often increase tumor antigen exposure to the immune system, and thus stimulate a specific antitumor immune response that can act beyond the treated site. Notwithstanding their many benefits, combination treatment may also result in complications, the most feared may be auto-immune-related adverse events.In early studies, several combined therapies have shown promising levels of safety and efficacy, particularly in hepatocellular carcinoma.This review provides a comprehensive and up-to-date overview of results of combined therapies for primary and secondary liver malignancies. Recent advances and future perspectives will be discussed.
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Affiliation(s)
- Raphaël Jost
- Département d’Anésthésie, Chirurgie et Imagerie Interventionnelle, Gustave Roussy, Villejuif, France
| | | | - Mario Ghosn
- Département d’Anésthésie, Chirurgie et Imagerie Interventionnelle, Gustave Roussy, Villejuif, France
| | - Baptiste Bonnet
- Département d’Anésthésie, Chirurgie et Imagerie Interventionnelle, Gustave Roussy, Villejuif, France
| | | | - Frederic Deschamps
- Département d’Anésthésie, Chirurgie et Imagerie Interventionnelle, Gustave Roussy, Villejuif, France
| | - Maximiliano Gelli
- Département d’Anésthésie, Chirurgie et Imagerie Interventionnelle, Gustave Roussy, Villejuif, France
| | - Valérie Boige
- Department of medical oncology, Gustave Roussy, Villejuif, France
| | | | | | - Antoine Hollebecque
- Département d’Innovation Thérapeutique et d’Essais Précoces (DITEP), Gustave Roussy, Villejuif, France
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14
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Zajkowska M, Mroczko B. Chemokines in Primary Liver Cancer. Int J Mol Sci 2022; 23:ijms23168846. [PMID: 36012108 PMCID: PMC9408270 DOI: 10.3390/ijms23168846] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 08/04/2022] [Accepted: 08/08/2022] [Indexed: 11/16/2022] Open
Abstract
The liver is responsible for extremely important functions in the human body. In the liver’s structure, we distinguish between connective tissue (stroma) and parenchyma, the latter of which is formed from the basic structural and functional units of the liver—hepatocytes. There are many factors, that negatively affect the liver cells, contributing to their damage. This may lead to fibrosis, liver failure and, in consequence, primary liver cancer, which is the sixth most commonly diagnosed malignancy and the fourth leading cause of cancer death worldwide. Chemokines are a large family of secreted proteins. Their main role is to direct the recruitment and migration of cells to sites of inflammation or injury. Some authors suggest that these proteins might play a potential role in the development of many malignancies, including primary liver cancer. The aim of this study was to evaluate and summarize the knowledge regarding liver diseases, especially primary liver cancer (HCC) and the participation of chemokines in the development of this malignancy. Chemokines involved in the initiation of this type of tumor belong mainly to the CC and CXC chemokines. Their significant role in the course of hepatocellular carcinoma proves their usefulness in detecting and monitoring the course and treatment in patients with this disease.
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Affiliation(s)
- Monika Zajkowska
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland
- Correspondence: ; Tel.: +48-686-5168; Fax: +48-686-5169
| | - Barbara Mroczko
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland
- Department of Biochemical Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland
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15
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He Q, Guo P, Bo Z, Yu H, Yang J, Wang Y, Chen G. Noncoding RNA-mediated molecular bases of chemotherapy resistance in hepatocellular carcinoma. Cancer Cell Int 2022; 22:249. [PMID: 35945536 PMCID: PMC9361533 DOI: 10.1186/s12935-022-02643-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 06/27/2022] [Indexed: 11/10/2022] Open
Abstract
Despite the significant progress in decreasing the occurrence and mortality of hepatocellular carcinoma (HCC), it remains a public health issue worldwide on the basis of its late presentation and tumor recurrence. To date, apart from surgical interventions, such as surgical resection, liver transplantation and locoregional ablation, current standard antitumor protocols include conventional cytotoxic chemotherapy. However, due to the high chemoresistance nature, most current therapeutic agents show dismal outcomes for this refractory malignancy, leading to disease relapse. Nevertheless, the molecular mechanisms involved in chemotherapy resistance remain systematically ambiguous. Herein, HCC is hierarchically characterized by the formation of primitive cancer stem cells (CSCs), progression of epithelial-mesenchymal transition (EMT), unbalanced autophagy, delivery of extracellular vesicles (EVs), escape of immune surveillance, disruption of ferroptosis, alteration of the tumor microenvironment and multidrug resistance-related signaling pathways that mediate the multiplicity and complexity of chemoresistance. Of note, anecdotal evidence has corroborated that noncoding RNAs (ncRNAs) extensively participate in the critical physiological processes mentioned above. Therefore, understanding the detailed regulatory bases that underlie ncRNA-mediated chemoresistance is expected to yield novel insights into HCC treatment. In the present review, a comprehensive summary of the latest progress in the investigation of chemotherapy resistance concerning ncRNAs will be elucidated to promote tailored individual treatment for HCC patients.
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Affiliation(s)
- Qikuan He
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Pengyi Guo
- Department of Cardiothoracic Surgery, Ningbo Yinzhou No. 2 Hospital, Ningbo, 315199, Zhejiang, China
| | - Zhiyuan Bo
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Haitao Yu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Jinhuan Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Yi Wang
- Department of Epidemiology and Biostatistics, School of Public Health and Management, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Gang Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
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16
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Riaz F, Wei P, Pan F. Fine-tuning of regulatory T cells is indispensable for the metabolic steatosis-related hepatocellular carcinoma: A review. Front Cell Dev Biol 2022; 10:949603. [PMID: 35912096 PMCID: PMC9337771 DOI: 10.3389/fcell.2022.949603] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Accepted: 06/28/2022] [Indexed: 12/12/2022] Open
Abstract
The majority of chronic hepatic diseases are caused by nutritional imbalance. These nutritional inequities include excessive intake of alcohol and fat, which causes alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD), respectively. The pathogenesis of hepatic diseases is mainly dependent on oxidative stress, autophagy, DNA damage, and gut microbiota and their metabolites. These factors influence the normal physiology of the liver and impact the hepatic microenvironment. The hepatic microenvironment contains several immune cells and inflammatory cytokines which interact with each other and contribute to the progression of chronic hepatic diseases. Among these immune cells, Foxp3+ CD4+ regulatory T cells (Tregs) are the crucial subset of CD4+ T cells that create an immunosuppressive environment. This review emphasizes the function of Tregs in the pathogenesis of ALD and NAFLD and their role in the progression of NAFLD-associated hepatocellular carcinoma (HCC). Briefly, Tregs establish an immunosuppressive landscape in the liver by interacting with the innate immune cells and gut microbiota and their metabolites. Meanwhile, with the advancement of steatosis, these Tregs inhibit the proliferation, activation and functions of other cytotoxic T cells and support the progression of simple steatosis to HCC. Briefly, it can be suggested that targeting Tregs can act as a favourable prognostic indicator by modulating steatosis and insulin resistance during the pathogenesis of hepatic steatosis and NAFLD-associated HCC.
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Affiliation(s)
- Farooq Riaz
- Center for Cancer Immunology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Ping Wei
- Center for Cancer Immunology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Chongqing Key Laboratory of Pediatrics, Department of otolaryngology, Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China
| | - Fan Pan
- Center for Cancer Immunology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- *Correspondence: Fan Pan,
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17
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Zhu J, Huang Q, Liu S, Peng X, Xue J, Feng T, Huang W, Chen Z, Lai K, Ji Y, Wang M, Yuan R. Construction of a Novel LncRNA Signature Related to Genomic Instability to Predict the Prognosis and Immune Activity of Patients With Hepatocellular Carcinoma. Front Immunol 2022; 13:856186. [PMID: 35479067 PMCID: PMC9037030 DOI: 10.3389/fimmu.2022.856186] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Accepted: 03/21/2022] [Indexed: 01/10/2023] Open
Abstract
Background Genomic instability (GI) plays a crucial role in the development of various cancers including hepatocellular carcinoma. Hence, it is meaningful for us to use long non-coding RNAs related to genomic instability to construct a prognostic signature for patients with HCC. Methods Combining the lncRNA expression profiles and somatic mutation profiles in The Cancer Genome Atlas database, we identified GI-related lncRNAs (GILncRNAs) and obtained the prognosis-related GILncRNAs through univariate regression analysis. These lncRNAs obtained risk coefficients through multivariate regression analysis for constructing GI-associated lncRNA signature (GILncSig). ROC curves were used to evaluate signature performance. The International Cancer Genomics Consortium (ICGC) cohort, and in vitro experiments were used for signature external validation. Immunotherapy efficacy, tumor microenvironments, the half-maximal inhibitory concentration (IC50), and immune infiltration were compared between the high- and low-risk groups with TIDE, ESTIMATE, pRRophetic, and ssGSEA program. Results Five GILncRNAs were used to construct a GILncSig. It was confirmed that the GILncSig has good prognostic evaluation performance for patients with HCC by drawing a time-dependent ROC curve. Patients were divided into high- and low-risk groups according to the GILncSig risk score. The prognosis of the low-risk group was significantly better than that of the high-risk group. Independent prognostic analysis showed that the GILncSig could independently predict the prognosis of patients with HCC. In addition, the GILncSig was correlated with the mutation rate of the HCC genome, indicating that it has the potential to measure the degree of genome instability. In GILncSig, LUCAT1 with the highest risk factor was further validated as a risk factor for HCC in vitro. The ESTIMATE analysis showed a significant difference in stromal scores and ESTIMATE scores between the two groups. Multiple immune checkpoints had higher expression levels in the high-risk group. The ssGSEA results showed higher levels of tumor-antagonizing immune cells in the low-risk group compared with the high-risk group. Finally, the GILncSig score was associated with chemotherapeutic drug sensitivity and immunotherapy efficacy of patients with HCC. Conclusion Our research indicates that GILncSig can be used for prognostic evaluation of patients with HCC and provide new insights for clinical decision-making and potential therapeutic strategies.
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Affiliation(s)
- Jinfeng Zhu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,Jiangxi Province Key Laboratory of Molecular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Qian Huang
- Department of General Practice, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Sicheng Liu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,Jiangxi Province Key Laboratory of Molecular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xingyu Peng
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,Jiangxi Province Key Laboratory of Molecular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Ju Xue
- Department of Pathology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Tangbin Feng
- Department of Surgery, II, Duchang County Hospital of Traditional Chinese Medicine, Jiujiang, China
| | - Wulang Huang
- Department of General Surgery, Affiliated Hospital of Jinggangshan University, Jian, China
| | - Zhimeng Chen
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Kuiyuan Lai
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yufei Ji
- The Second Clinical Medical College of Nanchang University, Nanchang, China
| | - Miaomiao Wang
- Queen Mary College of Nanchang University, Nanchang, China
| | - Rongfa Yuan
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
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18
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Murali M, Kumar AR, Nair B, Pavithran K, Devan AR, Pradeep GK, Nath LR. Antibody-drug conjugate as targeted therapeutics against hepatocellular carcinoma: preclinical studies and clinical relevance. Clin Transl Oncol 2022; 24:407-431. [PMID: 34595736 DOI: 10.1007/s12094-021-02707-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 08/29/2021] [Indexed: 02/05/2023]
Abstract
An antibody-drug conjugate (ADC) is an advanced chemotherapeutic option with immense promises in treating many tumor. They are designed to selectively attack and kill neoplastic cells with minimal toxicity to normal tissues. ADCs are complex engineered immunoconjugates that comprise a monoclonal antibody for site-directed delivery and cytotoxic payload for targeted destruction of malignant cells. Therefore, it enables the reduction of off-target toxicities and enhances the therapeutic index of the drug. Hepatocellular carcinoma (HCC) is a solid tumor that shows high heterogeneity of molecular phenotypes and is considered the second most common cause of cancer-related death. Studies show enormous potential for ADCs targeting GPC3 and CD24 and other tumor-associated antigens in HCC with their high, selective expression and show potential outputs in preclinical evaluations. The review mainly highlights the preclinical evaluation of different antigen-targeted ADCs such as MetFab-DOX, Anti-c-Met IgG-OXA, Anti CD 24, ANC-HN-01, G7mab-DOX, hYP7-DCand hYP7-PC, Anti-CD147 ILs-DOX and AC133-vcMMAF against hepatocellular carcinoma and its future relevance.
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Affiliation(s)
- M Murali
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P. O., Kochi, Kerala, 682041, India
| | - A R Kumar
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P. O., Kochi, Kerala, 682041, India
| | - B Nair
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P. O., Kochi, Kerala, 682041, India
| | - K Pavithran
- Department of Medical Oncology and Hematology, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, 682041, India
| | - A R Devan
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P. O., Kochi, Kerala, 682041, India
| | - G K Pradeep
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P. O., Kochi, Kerala, 682041, India
| | - L R Nath
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P. O., Kochi, Kerala, 682041, India.
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Modulation of the tumour microenvironment in hepatocellular carcinoma by tyrosine kinase inhibitors: from modulation to combination therapy targeting the microenvironment. Cancer Cell Int 2022; 22:73. [PMID: 35148789 PMCID: PMC8840552 DOI: 10.1186/s12935-021-02435-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 12/28/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide. Tyrosine kinase inhibitors (TKIs) remain the backbone of systematic therapy for advanced hepatocellular carcinoma. Sorafenib and lenvatinib are currently approved as first-line therapeutic drugs, and regorafenib and cabozantinib are applied as second-line treatments. With inhibition of angiogenesis as the main target, TKIs exert a profound effect on the tumour microenvironment (TME). The TME is a complex mixture of cellular and noncellular components surrounding the tumour mass, and is associated with tumour progression partially through the epithelial-mesenchymal transition. Specifically, the TME of HCC is characterized by profound extracellular matrix remodelling and an immunosuppressive microenvironment. The purpose of this review is to provide a summary of TME remodelling mediated by four Food and Drug Administration approved TKIs in HCC and thus summarize the rationale and potential targets for combination therapy. The modulatory effect of TKIs on the TME of HCC was reported to enhance the antitumour effect of TKIs through pyroptosis of macrophages and subsequent natural killer cell activation, T cell activation, regulatory T cell reduction in HCC. Meanwhile, TKIs also induce drug resistance via M2 polarization and accumulation, recruitment of tumour-associated neutrophils, and induction of the epithelial-mesenchymal transition. In conclusion, the effect of TKIs on TME can enhance its antitumour effect, but might also partially contribute to the drug resistance that hinders the progression of TKIs as treatment for HCC. Additionally, the effect of TKIs also provides the rationale for combination therapy, including combining TKIs with immune checkpoint inhibitors, to facilitate increased drug efficacy of TKIs.
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20
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Liu JKH, Irvine AF, Jones RL, Samson A. Immunotherapies for hepatocellular carcinoma. Cancer Med 2022; 11:571-591. [PMID: 34953051 PMCID: PMC8817091 DOI: 10.1002/cam4.4468] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 10/29/2021] [Accepted: 11/02/2021] [Indexed: 12/21/2022] Open
Abstract
Cases of hepatocellular carcinoma (HCC) are rapidly rising. This is particularly the case in the Western world, as a result of increasing rates of chronic liver disease, secondary to lifestyle-associated risk factors and the lack of an established screening programme for the general population. Traditionally, radical/curative treatment options for HCC, including liver transplantation and surgical resection are reserved for the minority of patients, presenting with an early stage cancer. For patients with advanced disease, Sorafenib and Lenvatinib were, until recently, the only licensed systemic treatments, and provided only limited survival benefits at the cost of a multitude of potential side effects. Recent scientific advances in the field of cancer immunotherapy have renewed significant interest in advanced HCC, in order to fulfil this apparent area of unmet clinical need. This has led to the success and recent regulatory approval of an Atezolizumab/Bevacizumab combination for the first-line treatment of advanced HCC following results from the IMbrave150 clinical trial in 2019, with further immune checkpoint inhibitors currently undergoing testing in advanced clinical trials. Furthermore, other cancer immunotherapies, including chimeric antigen receptor T-cells, dendritic cell vaccines and oncolytic viruses are also in early stage clinical trials, for the treatment of advanced HCC. This review will summarise the major approaches that have been and are currently in development for the systemic treatment of advanced HCC, their advantages, drawbacks, and predictions of where this revolutionary treatment field will continue to travel for the foreseeable future.
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Affiliation(s)
- Justin K. H. Liu
- Leeds Institute of Medical Research at St James's (LIMR)School of MedicineFaculty of Medicine and HealthUniversity of LeedsSt James's University HospitalLeedsUK
| | - Andrew F. Irvine
- Leeds Institute of Medical Research at St James's (LIMR)School of MedicineFaculty of Medicine and HealthUniversity of LeedsSt James's University HospitalLeedsUK
| | - Rebecca L. Jones
- Leeds Liver UnitSt James's University HospitalLeeds Teaching Hospitals NHS TrustLeedsUK
| | - Adel Samson
- Leeds Institute of Medical Research at St James's (LIMR)School of MedicineFaculty of Medicine and HealthUniversity of LeedsSt James's University HospitalLeedsUK
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21
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Rai V, Mukherjee S. Targets of immunotherapy for hepatocellular carcinoma: An update. World J Hepatol 2022; 14:140-157. [PMID: 35126844 PMCID: PMC8790386 DOI: 10.4254/wjh.v14.i1.140] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 07/20/2021] [Accepted: 12/25/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma, the most common primary liver cancer, in an immunogenic tumor with a poor prognosis because these tumors are diagnosed at late stages. Although, surgical resection, ablation, liver transplant, and locoregional therapies are available for early stages; however, there are yet no effective treatment for advanced and recurrent tumors. Immune checkpoint inhibitor therapy and adoptive cell transfer therapy has gained the popularity with some positive results because these therapies overcome anergy and systemic immune suppression. However, still there is a lack of an effective treatment and thus there is an unmet need of a novel treatment. At present, the focus of the research is on oncolytic viral therapy and combination therapy where therapies including radiotherapy, immune checkpoint therapy, adoptive cell transfer therapy, and vaccines are combined to get an additive or synergistic effect enhancing the immune response of the liver with a cytotoxic effect on tumor cells. This review discusses the recent key development, the basis of drug resistance, immune evasion, immune tolerance, the available therapies based on stage of the tumor, and the ongoing clinical trials on immune checkpoint inhibitor therapy, adoptive cell transfer therapy, oncolytic viral vaccine therapy, and combination therapy.
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Affiliation(s)
- Vikrant Rai
- Department of Translational Research, Western University of Health Sciences, Pomona, CA 91766, United States
| | - Sandeep Mukherjee
- Department of Medicine, Creighton University School of Medicine, Omaha, NE 68124, United States.
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22
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Huang S, Zhang J, Lai X, Zhuang L, Wu J. Identification of Novel Tumor Microenvironment-Related Long Noncoding RNAs to Determine the Prognosis and Response to Immunotherapy of Hepatocellular Carcinoma Patients. Front Mol Biosci 2022; 8:781307. [PMID: 35004851 PMCID: PMC8739902 DOI: 10.3389/fmolb.2021.781307] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 11/25/2021] [Indexed: 12/12/2022] Open
Abstract
Introduction: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with poor prognosis. The tumor microenvironment (TME) plays a vital role in HCC progression. Thus, this research was designed to analyze the correlation between the TME and the prognosis of HCC patients and to construct a TME-related long noncoding RNA (lncRNA) signature to determine HCC patients’ prognosis and response to immunotherapy. Methods: We assessed the stromal–immune–estimate scores within the HCC microenvironment using the ESTIMATE (Estimation of Stromal and Immune Cells in Malignant Tumor Tissues Using Expression Data) algorithm based on The Cancer Genome Atlas database, and their associations with survival and clinicopathological parameters were also analyzed. Thereafter, differentially expressed lncRNAs were filtered out according to the immune and stromal scores. Cox regression analysis was performed to build a TME-related lncRNA risk signature. Kaplan–Meier analysis was used to explore the prognostic value of the risk signature. Furthermore, we explored the biological functions and immune microenvironment features in the high- and low-risk groups. Lastly, we probed the association of the risk model with treatment responses to immune checkpoint inhibitors (ICIs) in HCC. Results: The stromal, immune, and estimate scores were obtained utilizing the ESTIMATE algorithm for patients with HCC. Kaplan–Meier analysis showed that high scores were significantly correlated with better prognosis in HCC patients. Six TME-related lncRNAs were screened to construct the prognostic model. The Kaplan–Meier curves suggested that HCC patients with low risk had better prognosis than those with high risk. Receiver operating characteristic (ROC) curve and Cox regression analyses indicated that the risk model could predict HCC survival exactly and independently. Functional enrichment analysis revealed that some tumor- and immune-related pathways were activated in the high-risk group. We also revealed that some immune cells, which were important in enhancing immune responses toward cancer, were significantly increased in the low-risk group. In addition, there was a close correlation between ICIs and the risk signature, which can be used to predict the treatment responses of HCC patients. Conclusion: We analyzed the influence of the stromal, immune, and estimate scores on the prognosis of HCC patients. A novel TME-related lncRNA risk model was established, which could be effectively applied as an independent prognostic biomarker and predictor of ICIs for HCC patients.
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Affiliation(s)
- Shenglan Huang
- The Second Affiliated Hospital of Nanchang University, Nanchang, China.,Jiangxi Key Laboratory of Clinical and Translational Cancer Research, Nanchang, China
| | - Jian Zhang
- The Second Affiliated Hospital of Nanchang University, Nanchang, China.,Jiangxi Key Laboratory of Clinical and Translational Cancer Research, Nanchang, China
| | - Xiaolan Lai
- Ningde Municipal Hospital Affiliated to Ningde Normal University, Ningde, China
| | - Lingling Zhuang
- The Second Affiliated Hospital of Nanchang University, Nanchang, China.,Jiangxi Key Laboratory of Clinical and Translational Cancer Research, Nanchang, China
| | - Jianbing Wu
- The Second Affiliated Hospital of Nanchang University, Nanchang, China.,Jiangxi Key Laboratory of Clinical and Translational Cancer Research, Nanchang, China
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23
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Biondetti P, Saggiante L, Ierardi AM, Iavarone M, Sangiovanni A, Pesapane F, Fumarola EM, Lampertico P, Carrafiello G. Interventional Radiology Image-Guided Locoregional Therapies (LRTs) and Immunotherapy for the Treatment of HCC. Cancers (Basel) 2021; 13:5797. [PMID: 34830949 PMCID: PMC8616392 DOI: 10.3390/cancers13225797] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 11/16/2021] [Accepted: 11/16/2021] [Indexed: 12/12/2022] Open
Abstract
Image-guided locoregional therapies (LRTs) are a crucial asset in the treatment of hepatocellular carcinoma (HCC), which has proven to be characterized by an impaired antitumor immune status. LRTs not only directly destroy tumor cells but also have an immunomodulating role, altering the tumor microenvironment with potential systemic effects. Nevertheless, the immune activation against HCC induced by LRTs is not strong enough on its own to generate a systemic significant antitumor response, and it is incapable of preventing tumor recurrence. Currently, there is great interest in the possibility of combining LRTs with immunotherapy for HCC, as this combination may result in a mutually beneficial and synergistic relationship. On the one hand, immunotherapy could amplify and prolong the antitumoral immune response of LRTs, reducing recurrence cases and improving outcome. On the other hand, LTRs counteract the typical immunosuppressive HCC microenvironment and status and could therefore enhance the efficacy of immunotherapy. Here, after reviewing the current therapeutic options for HCC, we focus on LRTs, describing for each of them the technique and data on its effect on the immune system. Then, we describe the current status of immunotherapy and finally report the recently published and ongoing clinical studies testing this combination.
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Affiliation(s)
- Pierpaolo Biondetti
- Diagnostic and Interventional Radiology Department, IRCCS Cà Granda Fondazione Ospedale Maggiore Policlinico, Università degli Studi di Milano, 20122 Milan, Italy; (A.M.I.); (G.C.)
| | - Lorenzo Saggiante
- Postgraduate School in Radiodiagnostics, Università degli Studi di Milano, 20122 Milan, Italy;
| | - Anna Maria Ierardi
- Diagnostic and Interventional Radiology Department, IRCCS Cà Granda Fondazione Ospedale Maggiore Policlinico, Università degli Studi di Milano, 20122 Milan, Italy; (A.M.I.); (G.C.)
| | - Massimo Iavarone
- Gastroenterology Department, IRCCS Cà Granda Fondazione Ospedale Maggiore Policlinico, Università degli Studi di Milano, 20122 Milan, Italy; (M.I.); (A.S.); (P.L.)
| | - Angelo Sangiovanni
- Gastroenterology Department, IRCCS Cà Granda Fondazione Ospedale Maggiore Policlinico, Università degli Studi di Milano, 20122 Milan, Italy; (M.I.); (A.S.); (P.L.)
| | - Filippo Pesapane
- Radiology Department, IEO European Institute of Oncology IRCCS, 20122 Milan, Italy;
| | - Enrico Maria Fumarola
- Diagnostic and Interventional Radiology Department, ASST Santi Paolo e Carlo, 20122 Milan, Italy;
| | - Pietro Lampertico
- Gastroenterology Department, IRCCS Cà Granda Fondazione Ospedale Maggiore Policlinico, Università degli Studi di Milano, 20122 Milan, Italy; (M.I.); (A.S.); (P.L.)
| | - Gianpaolo Carrafiello
- Diagnostic and Interventional Radiology Department, IRCCS Cà Granda Fondazione Ospedale Maggiore Policlinico, Università degli Studi di Milano, 20122 Milan, Italy; (A.M.I.); (G.C.)
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24
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Bartolini I, Risaliti M, Tucci R, Muiesan P, Ringressi MN, Taddei A, Amedei A. Gut microbiota and immune system in liver cancer: Promising therapeutic implication from development to treatment. World J Gastrointest Oncol 2021; 13:1616-1631. [PMID: 34853639 PMCID: PMC8603449 DOI: 10.4251/wjgo.v13.i11.1616] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 04/25/2021] [Accepted: 09/02/2021] [Indexed: 02/06/2023] Open
Abstract
Liver cancer is a leading cause of death worldwide, and hepatocellular carcinoma (HCC) is the most frequent primary liver tumour, followed by cholangiocarcinoma. Notably, secondary tumours represent up to 90% of liver tumours. Chronic liver disease is a recognised risk factor for liver cancer development. Up to 90% of the patients with HCC and about 20% of those with cholangiocarcinoma have an underlying liver alteration. The gut microbiota-liver axis represents the bidirectional relationship between gut microbiota, its metabolites and the liver through the portal flow. The interplay between the immune system and gut microbiota is also well-known. Although primarily resulting from experiments in animal models and on HCC, growing evidence suggests a causal role for the gut microbiota in the development and progression of chronic liver pathologies and liver tumours. Despite the curative intent of "traditional" treatments, tumour recurrence remains high. Therefore, microbiota modulation is an appealing therapeutic target for liver cancer prevention and treatment. Furthermore, microbiota could represent a non-invasive biomarker for early liver cancer diagnosis. This review summarises the potential role of the microbiota and immune system in primary and secondary liver cancer development, focusing on the potential therapeutic implications.
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Affiliation(s)
- Ilenia Bartolini
- Department of Experimental and Clinical Medicine, University of Florence, Azienda Ospedaliero Universitaria Careggi (AOUC), Florence 50134, Italy
| | - Matteo Risaliti
- Department of Experimental and Clinical Medicine, University of Florence, Azienda Ospedaliero Universitaria Careggi (AOUC), Florence 50134, Italy
| | - Rosaria Tucci
- Department of Experimental and Clinical Medicine, University of Florence, Azienda Ospedaliero Universitaria Careggi (AOUC), Florence 50134, Italy
| | - Paolo Muiesan
- Department of Experimental and Clinical Medicine, University of Florence, Azienda Ospedaliero Universitaria Careggi (AOUC), Florence 50134, Italy
| | - Maria Novella Ringressi
- Department of Experimental and Clinical Medicine, University of Florence, Azienda Ospedaliero Universitaria Careggi (AOUC), Florence 50134, Italy
| | - Antonio Taddei
- Department of Experimental and Clinical Medicine, University of Florence, Azienda Ospedaliero Universitaria Careggi (AOUC), Florence 50134, Italy
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, SOD of Interdisciplinary Internal Medicine, Azienda Ospedaliero Universitaria Careggi (AOUC), Florence 50134, Italy
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25
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Feng X, Mu S, Ma Y, Wang W. Development and Verification of an Immune-Related Gene Pairs Prognostic Signature in Hepatocellular Carcinoma. Front Mol Biosci 2021; 8:715728. [PMID: 34660693 PMCID: PMC8517445 DOI: 10.3389/fmolb.2021.715728] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 09/21/2021] [Indexed: 12/11/2022] Open
Abstract
With the increasing prevalence of Hepatocellular carcinoma (HCC) and the poor prognosis of immunotherapy, reliable immune-related gene pairs (IRGPs) prognostic signature is required for personalized management and treatment of patients. Gene expression profiles and clinical information of HCC patients were obtained from the TCGA and ICGC databases. The IRGPs are constructed using immune-related genes (IRGs) with large variations. The least absolute shrinkage and selection operator (LASSO) regression analysis was used to construct IRGPs signature. The IRGPs signature was verified through the ICGC cohort. 1,309 IRGPs were constructed from 90 IRGs with high variability. We obtained 50 IRGPs that were significantly connected to the prognosis and constructed a signature that included 17 IRGPs. In the TCGA and ICGC cohorts, patients were divided into high and low-risk patients by the IRGPs signature. The overall survival time of low-risk patients is longer than that of high-risk patients. After adjustment for clinical and pathological factors, multivariate analysis showed that the IRGPs signature is an independent prognostic factor. The Receiver operating characteristic (ROC) curve confirmed the accuracy of the signature. Besides, gene set enrichment analysis (GSEA) revealed that the signature is related to immune biological processes, and the immune microenvironment status is distinct in different risk patients. The proposed IRGPs signature can effectively assess the overall survival of HCC, and provide the relationship between the signature and the reactivity of immune checkpoint therapy and the sensitivity of targeted drugs, thereby providing new ideas for the diagnosis and treatment of the disease.
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Affiliation(s)
- Xiaofei Feng
- Department of Orthopedics, Lanzhou University First Affiliated Hospital, Lanzhou, China
| | - Shanshan Mu
- Pediatric Rheumatism Immunology Department, Lanzhou University Second Hospital, Lanzhou, China
| | - Yao Ma
- Clinical Laboratory Center, Gansu Provincial Maternity and Child-care Hospital, Lanzhou, China
| | - Wenji Wang
- Department of Orthopedics, Lanzhou University First Affiliated Hospital, Lanzhou, China
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26
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Xu L, Jian X, Liu Z, Zhao J, Zhang S, Lin Y, Xie L. Construction and Validation of an Immune Cell Signature Score to Evaluate Prognosis and Therapeutic Efficacy in Hepatocellular Carcinoma. Front Genet 2021; 12:741226. [PMID: 34646307 PMCID: PMC8503558 DOI: 10.3389/fgene.2021.741226] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 08/30/2021] [Indexed: 12/24/2022] Open
Abstract
Background: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy with high morbidity and mortality worldwide. Tumor immune microenvironment (TIME) plays a pivotal role in the outcome and treatment of HCC. However, the effect of immune cell signatures (ICSs) representing the characteristics of TIME on the prognosis and therapeutic benefit of HCC patients remains to be further studied. Materials and methods: In total, the gene expression profiles of 1,447 HCC patients from several databases, i.e., The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium, and Gene Expression Omnibus, were obtained and applied. Based on a comprehensive collection of marker genes, 182 ICSs were evaluated by single sample gene set enrichment analysis. Then, by performing univariate and multivariate Cox analysis and random forest modeling, four significant signatures were selected to fit an immune cell signature score (ICSscore). Results: In this study, an ICSscore-based prognostic model was constructed to stratify HCC patients into high-risk and low-risk groups in the TCGA-LIHC cohort, which was successfully validated in two independent cohorts. Moreover, the ICSscore values were found to positively correlate with the current American Joint Committee on Cancer staging system, indicating that ICSscore could act as a comparable biomarker for HCC risk stratification. In addition, when setting the four ICSs and ICSscores as features, the classifiers can significantly distinguish treatment-responding and non-responding samples in HCC. Also, in melanoma and breast cancer, the unified ICSscore could verify samples with therapeutic benefits. Conclusion: Overall, we simplified the tedious ICS to develop the ICSscore, which can be applied successfully for prognostic stratification and therapeutic evaluation in HCC. This study provides an insight into the therapeutic predictive efficacy of prognostic ICS, and a novel ICSscore was constructed to allow future expanded application.
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Affiliation(s)
- Linfeng Xu
- School of Medical Instrument and Food Engineering, University of Shanghai for Science and Technology, Shanghai, China.,Shanghai Center for Bioinformation Technology, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, China
| | - Xingxing Jian
- Shanghai Center for Bioinformation Technology, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, China.,Bioinformatics Center, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Zhenhao Liu
- Shanghai Center for Bioinformation Technology, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, China.,Bioinformatics Center, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Jingjing Zhao
- Shanghai Center for Bioinformation Technology, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, China.,College of Food Science and Technology, Shanghai Ocean University, Shanghai, China
| | - Siwen Zhang
- Shanghai Center for Bioinformation Technology, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, China.,College of Food Science and Technology, Shanghai Ocean University, Shanghai, China
| | - Yong Lin
- School of Medical Instrument and Food Engineering, University of Shanghai for Science and Technology, Shanghai, China
| | - Lu Xie
- Shanghai Center for Bioinformation Technology, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, China.,Bioinformatics Center, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.,College of Food Science and Technology, Shanghai Ocean University, Shanghai, China
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27
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Chen H, Jiang S, Zhang P, Ren Z, Wen J. Exosomes synergized with PIONs@E6 enhance their immunity against hepatocellular carcinoma via promoting M1 macrophages polarization. Int Immunopharmacol 2021; 99:107960. [PMID: 34284286 DOI: 10.1016/j.intimp.2021.107960] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 06/25/2021] [Accepted: 07/01/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is easy to relapse after resection for its lack of anti-tumor immunity due to pro-tumorigenesis by promoting M2 type macrophage polarization. Recent studies have shown that exosomes are closely related to the occurrence and development of HCC. Antigenic exosomes from HCC are able to polarize into alternatively activated macrophages M2, but do not stimulate M1 macrophages polarization. Iron oxide nanoparticles (IONs) have been demonstrated to be able to promote M1 macrophages polarization. This research was to explore exosomes as vehicles to synergize with pegylated IONs loaded with chlorin e6 (PIONs@E6) to enhance their immunity against HCC via promoting M1 macrophages polarization. MATERIALS AND METHODS PIONs@E6 was synthesized and then characterized by chemico-physical analysis, transmission electron microscope (TEM), respectively. After characterization of PIONs-contained exosomes by TEM, and then the exosomal surface specific molecules CD9 and CD63 were determined by Western Blotting assay. Markers of M1 macrophage polarization in vitro and in vivo were analyzed by enzyme linked immunosorbent assay (ELISA) and flow cytometry, respectively. Intracellular reactive oxygen species (ROS) in macrophages were analyzed using a Spectra Max fluorescence microplate reader. Inhibitory effect of PIONs-contained exosomes on HCC was evaluated by monitoring tumor growth in an in vivo xenograft mice model. RESULTS PIONs@E6 showed good water solubility with a core diameter around 10 nm and a hydrate diameter around 37 nm. The expression of exosome specific markers CD9 and CD63 was kept at a high level. PIONs-contained exosomes can dose-dependently promote M1 macrophages polarization in vitro and in vivo. Of note, PIONs-contained exosomes could initiate a significantly higher level of ROS in macrophages and remarkably inhibit the tumor growth in mice bearing HCC xenograft. CONCLUSION Exosomes as vehicles could be synergized with PIONs@E6 to enhance their immunity against HCC via promoting M1 macrophages polarization.
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Affiliation(s)
- Hanren Chen
- Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Shulian Jiang
- Nanjing Second Hospital, Nanjing, Jiangsu, People's Republic of China
| | - Peng Zhang
- Guilin Medical University, Guilin, Guangxi, People's Republic of China; Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Zhongyu Ren
- Guilin Medical University, Guilin, Guangxi, People's Republic of China; Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Jian Wen
- Guilin Medical University, Guilin, Guangxi, People's Republic of China; Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin, Guangxi, People's Republic of China.
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28
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Martini G, Ciardiello D, Paragliola F, Nacca V, Santaniello W, Urraro F, Stanzione M, Niosi M, Dallio M, Federico A, Selvaggi F, Della Corte CM, Napolitano S, Ciardiello F, Martinelli E. How Immunotherapy Has Changed the Continuum of Care in Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:cancers13184719. [PMID: 34572944 PMCID: PMC8466991 DOI: 10.3390/cancers13184719] [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: 08/04/2021] [Revised: 09/08/2021] [Accepted: 09/16/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of death worldwide. The use of local treatment, such as surgical resection, liver transplant, and local ablation, has improved the survival of patients with HCC detected at an early stage. Until recently, the treatment of patients with metastatic disease was limited to the use of the multikinase inhibitor (MKI) sorafenib with a marginal effect on survival outcome. New target approaches, such as the oral MKI lenvatinib in first-line treatment and regorafenib, ramucirumab, and cabozantinib in later lines of therapy, have demonstrated efficacy in patients with preserved liver function (Child-Pugh class A) and good performance status. On the other hand, the implementation of immune checkpoint inhibitors directed against PD-1 (nivolumab and pembrolizumab), PD-L1 (atezolizumab), and anti-CTLA4 (ipilimumab) in the management of advanced HCC has strongly changed the continuum of care of HCC. Future research should include the evaluation of molecular biomarkers that can help patient selection and provide new insight on potential combined approaches. In this review, we provide an overview of the clinical evidence of the use of immune checkpoint inhibitors in HCC, and discuss how immunotherapy has been implemented into the continuum of HCC care.
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Affiliation(s)
- Giulia Martini
- Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania “L. Vanvitelli”, 80100 Naples, Italy; (G.M.); (D.C.); (F.P.); (V.N.); (C.M.D.C.); (S.N.); (F.C.)
| | - Davide Ciardiello
- Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania “L. Vanvitelli”, 80100 Naples, Italy; (G.M.); (D.C.); (F.P.); (V.N.); (C.M.D.C.); (S.N.); (F.C.)
| | - Fernando Paragliola
- Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania “L. Vanvitelli”, 80100 Naples, Italy; (G.M.); (D.C.); (F.P.); (V.N.); (C.M.D.C.); (S.N.); (F.C.)
| | - Valeria Nacca
- Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania “L. Vanvitelli”, 80100 Naples, Italy; (G.M.); (D.C.); (F.P.); (V.N.); (C.M.D.C.); (S.N.); (F.C.)
| | - Walter Santaniello
- Chirurgia Epatobiliare e Trapianto di Fegato, A.O.R.N. Antonio Cardarelli, 80100 Naples, Italy;
| | - Fabrizio Urraro
- Radiologia, Dipartimento di Medicina di Precisione, Università degli Studi della Campania “L. Vanvitelli”, 80100 Naples, Italy;
| | - Maria Stanzione
- Malattie Infettive, Dipartimento di Salute Mentale e Fisica e Medicina Preventiva, Università degli Studi della Campania “L. Vanvitelli”, 80100 Naples, Italy;
| | - Marco Niosi
- Epato-Gastroenterologia, Dipartimento di Medicina di Precisione, Università degli Studi della Campania “L. Vanvitelli”, 80100 Naples, Italy; (M.N.); (M.D.); (A.F.)
| | - Marcello Dallio
- Epato-Gastroenterologia, Dipartimento di Medicina di Precisione, Università degli Studi della Campania “L. Vanvitelli”, 80100 Naples, Italy; (M.N.); (M.D.); (A.F.)
| | - Alessandro Federico
- Epato-Gastroenterologia, Dipartimento di Medicina di Precisione, Università degli Studi della Campania “L. Vanvitelli”, 80100 Naples, Italy; (M.N.); (M.D.); (A.F.)
| | - Francesco Selvaggi
- Dipartimento di Scienze Mediche e Chirurgiche Avanzate, Università degli Studi della Campania “L. Vanvitelli”, 80100 Naples, Italy;
| | - Carminia Maria Della Corte
- Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania “L. Vanvitelli”, 80100 Naples, Italy; (G.M.); (D.C.); (F.P.); (V.N.); (C.M.D.C.); (S.N.); (F.C.)
| | - Stefania Napolitano
- Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania “L. Vanvitelli”, 80100 Naples, Italy; (G.M.); (D.C.); (F.P.); (V.N.); (C.M.D.C.); (S.N.); (F.C.)
| | - Fortunato Ciardiello
- Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania “L. Vanvitelli”, 80100 Naples, Italy; (G.M.); (D.C.); (F.P.); (V.N.); (C.M.D.C.); (S.N.); (F.C.)
| | - Erika Martinelli
- Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania “L. Vanvitelli”, 80100 Naples, Italy; (G.M.); (D.C.); (F.P.); (V.N.); (C.M.D.C.); (S.N.); (F.C.)
- Correspondence:
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29
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Zhou W, Fang DL, He Y. Screening potential prognostic biomarkers for portal vein emboli in patients with hepatocellular carcinoma. J Gastrointest Oncol 2021; 12:1927-1938. [PMID: 34532139 DOI: 10.21037/jgo-21-433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 08/10/2021] [Indexed: 01/27/2023] Open
Abstract
Background The formation of portal vein tumor thrombus (PVTT) is closely related to the prognosis of patients with hepatocellular carcinoma (HCC). However, the mechanisms by which PVTTs form and the biomarkers involved are still little understood. Methods The Genome Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases were used to obtain transcriptome data from normal tissue, HCC tissue, primary tumors (PTs) of HCC, and paired PVTT tissue. Differentially expressed genes (DEGs) in PTs and PVTTs were analyzed. The differentially expressed immune genes were further investigated in terms of their prognostic significance, immune infiltration, function. Finally, we explored the relationship between risk scores and drug sensitivity based on the R package. Results In the two datasets, there were 458 DEGs identified in the PT and PVTT tissues, of which, 58 were immune-related genes. The differentially expressed immune genes may promote the progression of PVTT by participating in the regulation of non-cellular components such as the extracellular matrix, inflammatory factors, and chemokines. Furthermore, the immune genes KDR, AKT3, FCGR2B, KIAA1429, and TPT1 were correlated with the prognosis of HCC in patients with PVTT. Using this data, a model was constructed to predict the prognosis of patients, thus allowing for the identification of high- and low-risk patients. Conclusions This study demonstrated that immune-related genes may be involved in the regulation of the extracellular matrix and acellular components, and subsequently, in the formation of PVTT. These five genes KDR, AKT3, FCGR2B, KIAA1429, and TPT1 may be potential prognostic biomarkers and treatment targets for HCC patients with PVTT.
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Affiliation(s)
- Weijie Zhou
- Clinical Laboratory, Baise People's Hospital, Baise, China
| | - Da Lang Fang
- Department of Breast and Thyroid Surgery, the Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Yongfei He
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
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30
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Miao L, Zhang Z, Ren Z, Li Y. Application of Immunotherapy in Hepatocellular Carcinoma. Front Oncol 2021; 11:699060. [PMID: 34513678 PMCID: PMC8426571 DOI: 10.3389/fonc.2021.699060] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 08/09/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma is one of the most common malignancies globally. It not only has a hidden onset but also progresses rapidly. Most HCC patients are already in the advanced stage of cancer when they are diagnosed, and have even lost the opportunity for surgical treatment. As an inflammation-related tumor, the immunosuppressive microenvironment of HCC can promote immune tolerance through a variety of mechanisms. Immunotherapy can activate tumor-specific immune responses, which brings a new hope for the treatment of HCC. At the present time, main immunotherapy strategies of HCC include immune checkpoint inhibitors, tumor vaccines, adoptive cell therapy, and so on. This article reviews the application and research progress of immune checkpoint inhibitors, tumor vaccines, and adoptive cell therapy in the treatment of HCC.
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Affiliation(s)
- Lele Miao
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, China.,Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou, China
| | - Zhengchao Zhang
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, China.,Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou, China
| | - Zhijian Ren
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, China.,Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou, China
| | - Yumin Li
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, China.,Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou, China
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Liu J, Kuang S, Zheng Y, Liu M, Wang L. Prognostic and predictive significance of the tumor microenvironment in hepatocellular carcinoma. Cancer Biomark 2021; 32:99-110. [PMID: 34092607 DOI: 10.3233/cbm-203003] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Identification of molecular markers that reflect the characteristics of the tumor microenvironment (TME) may be beneficial to predict the prognosis of post-operative hepatocellular carcinoma (HCC) patients. OBJECTIVE AND METHODS A total of 100 tissue samples from HCC patients were separately stained by immunohistochemistry to examine the expression levels of CD56, CD8α, CD68, FoxP3, CD31 and pan-Keratin. The prognostic values were analyzed by Cox regression and the Kaplan-Meier method. RESULTS Univariate and multivariate logistic analysis showed that FoxP3 was the independent factor associated with microvascular invasion (MVI), tumor size and envelop invasion; CD68 was associated with envelope invasion and AFP. Kaplan-Meier survival curves revealed that CD68 and FoxP3 expression were significantly associated with relapse free survival (RFS) of HCC patients (P< 0.05). The ROC curve indicated that the combination of tumor number, MVI present and CD68 expression yielded a ROC curve area of 82.3% (86.36% specificity, 68.75% sensitivity) to evaluate the prognosis of HCC patients, which was higher than the classifier established by the combination of tumor number and MVI (78.8% probability, 63.64% specificity and 85.42% sensitivity). CONCLUSIONS Our study indicated that CD68 and FoxP3 are associated with prognosis of HCC patients, and CD68 can be considered as a potential prognostic and predictive biomarker.
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Affiliation(s)
- Jibing Liu
- Department of Interventional Surgical Oncology, Cancer Hospital of Shandong Province, Shandong Academy of Medical Sciences, Jinan, Shandong, China.,Department of Interventional Surgical Oncology, Cancer Hospital of Shandong Province, Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Shuwen Kuang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Department of Interventional Surgical Oncology, Cancer Hospital of Shandong Province, Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yiling Zheng
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Mei Liu
- Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Liming Wang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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32
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Nishida N. Role of Oncogenic Pathways on the Cancer Immunosuppressive Microenvironment and Its Clinical Implications in Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:3666. [PMID: 34359568 PMCID: PMC8345137 DOI: 10.3390/cancers13153666] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 07/19/2021] [Accepted: 07/19/2021] [Indexed: 12/11/2022] Open
Abstract
The tumor immune microenvironment, including hepatocellular carcinoma (HCC), is complex, consisting of crosstalk among tumor components such as the cancer cells, stromal cells and immune cells. It is conceivable that phenotypic changes in cancer cells by genetic and epigenetic alterations affect the cancer-stroma interaction and anti-cancer immunity through the expression of immune checkpoint molecules, growth factors, cytokines, chemokines and metabolites that may act on the immune system in tumors. Therefore, predicting the outcome of ICI therapy requires a thorough understanding of the oncogenic signaling pathways in cancer and how they affect tumor immune evasion. In this review, we have detailed how oncogenic signaling pathways can play a role in altering the condition of the cellular components of the tumor immune microenvironment such as tumor-associated macrophages, regulatory T cells and myeloid-derived suppressor cells. The RAS/MAPK, PI3K/Akt, Wnt/β-catenin and JAK/STAT pathways have all been implicated in anti-tumor immunity. We also found that factors that reflect the immune microenvironment of the tumor, including the status of oncogenic pathways such as the volume of tumor-infiltrating T cells, expression of the immune checkpoint protein PD-1 and its ligand PD-L1, and activation of the Wnt/β-catenin signaling pathway, predict a response to ICI therapy in HCC cases.
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Affiliation(s)
- Naoshi Nishida
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama 589-8511, Japan
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33
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Role of Oncogenic Pathways on the Cancer Immunosuppressive Microenvironment and Its Clinical Implications in Hepatocellular Carcinoma. Cancers (Basel) 2021. [PMID: 34359568 DOI: 10.3390/cancers13153666.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The tumor immune microenvironment, including hepatocellular carcinoma (HCC), is complex, consisting of crosstalk among tumor components such as the cancer cells, stromal cells and immune cells. It is conceivable that phenotypic changes in cancer cells by genetic and epigenetic alterations affect the cancer-stroma interaction and anti-cancer immunity through the expression of immune checkpoint molecules, growth factors, cytokines, chemokines and metabolites that may act on the immune system in tumors. Therefore, predicting the outcome of ICI therapy requires a thorough understanding of the oncogenic signaling pathways in cancer and how they affect tumor immune evasion. In this review, we have detailed how oncogenic signaling pathways can play a role in altering the condition of the cellular components of the tumor immune microenvironment such as tumor-associated macrophages, regulatory T cells and myeloid-derived suppressor cells. The RAS/MAPK, PI3K/Akt, Wnt/β-catenin and JAK/STAT pathways have all been implicated in anti-tumor immunity. We also found that factors that reflect the immune microenvironment of the tumor, including the status of oncogenic pathways such as the volume of tumor-infiltrating T cells, expression of the immune checkpoint protein PD-1 and its ligand PD-L1, and activation of the Wnt/β-catenin signaling pathway, predict a response to ICI therapy in HCC cases.
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34
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Liu J, Wu Z, Zhang J, Xie Y, Sun P, Wu H, Chang X, Zhang L, Liu F. Effect of partial splenic embolization on transarterial chemoembolization for hepatocellular carcinoma with hypersplenism. Medicine (Baltimore) 2021; 100:e26441. [PMID: 34190168 PMCID: PMC8257862 DOI: 10.1097/md.0000000000026441] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 06/06/2021] [Indexed: 02/07/2023] Open
Abstract
This study retrospectively studied transarterial chemoembolization (TACE) combined with partial splenic embolization (PSE) in the treatment of hepatocellular carcinoma (HCC) with severe hypersplenism.Seventy patients with HCC in Barcelona Clinic Liver Cancer (BCLC) stage B or C with hypersplenism were divided into non-partial splenic embolization group (N-PSE, n = 51) and partial splenic embolization group (PSE, n = 19). The N-PSE group was further divided into N-PSE with mild to moderate hypersplenism (N-PSE-M, 47 cases) and N-PSE with severe hypersplenism (N-PSE-S, 4 cases).In the PSE group, leukocytes, neutrophils, lymphocytes, and platelets were significantly increased (P < .05) and were significantly different from that in the N-PSE group (P < .05). In the N-PSE group, except for a slight increase in neutrophils, other blood cells were decreased, including lymphocytes that were significantly decreased (P < .05). There was no significant difference in the changes of liver function between the 2 groups before and after surgery (P > .05). The analysis showed a significant increase in ascites after 6 months of TACE in the N-PSE group (P < .05). According to the follow-up results, the median overall survival (OS) in the PSE group was 24.47 ± 3.68 (months) and progression-free survival (PFS) was 12.63 ± 4.98 (months). Regardless of OS or PFS, the PSE group was superior to the N-PSE group and its subgroups, with a statistically significant difference in PFS between the N-PSE group and PSE group (P < .05). Moreover, the time of extrahepatic progression was significantly earlier in the N-PSE group than in the PSE group (P < .05). N-PSE-S group had the worst prognosis, and PFS and OS were worse than the other 2 groups, suggesting that PSE in severe hypersplenism may improve PFS and OS.In patients with HCC and severe hypersplenism, TACE should be actively combined with PSE treatment.
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Affiliation(s)
- Jibing Liu
- Department of Interventional Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences
| | - Zhijuan Wu
- Department of Geriatrics, Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong
| | - Jianxin Zhang
- Department of Interventional Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences
| | - Yinfa Xie
- Department of Interventional Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences
| | - Peng Sun
- Department of Interventional Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences
| | - Huiyong Wu
- Department of Interventional Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences
| | - Xu Chang
- Department of Interventional Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences
| | - Lin Zhang
- Department of Interventional Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences
| | - Fengyong Liu
- Department of Intervention Therapy, General Hospital of the Chinese People's Liberation Army, Beijing, China
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35
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Wu ZJ, Xie YF, Chang X, Zhang L, Wu HY, Liu JB, Zhang JX, Sun P. Type of Necrosis Influences Prognosis in Hepatocellular Carcinoma After the First Transarterial Chemoembolization. Med Sci Monit 2021; 27:e929884. [PMID: 33967266 PMCID: PMC8120908 DOI: 10.12659/msm.929884] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common tumors. Transarterial chemoembolization (TACE) is the first choice of treatment for intermediate HCC and an important treatment option for advanced HCC. This retrospective study compared the prognosis between patients showing coagulative necrosis and patients showing liquefactive necrosis after the first TACE procedure. MATERIAL AND METHODS We divided 171 patients with Barcelona Clinic Liver Cancer (BCLC) Stage B or C HCC into 2 groups; a coagulative necrosis group (79 patients) and a liquefactive necrosis group (92 patients). The coagulative and liquefactive necroses were identified by computed tomography after the first TACE procedure. Kaplan-Meier analysis was used to identify the differences in the overall survival (OS) and progression-free survival (PFS) between the 2 groups, and the associated risk factors and safety of TACE were analyzed. RESULTS The median OS durations were 23.27±1.40 months and 8.83±2.15 months (P=0.004) and the median PFS durations were 9.33±0.96 months and 3.70±0.44 months (P=0.002) in the coagulative necrosis and liquefactive necrosis groups, respectively. Intrahepatic in situ progression, new intrahepatic metastasis, and extrahepatic progression occurred significantly earlier in the liquefactive necrosis group (P<0.05). Univariate analysis and multivariate analyses showed liquefactive necrosis was the main risk factor for OS. There was no significant difference in the hepatic function impairment or post-embolism syndrome after TACE. CONCLUSIONS After the first TACE procedure, the patients with liquefactive necrosis experienced recurrence and metastasis earlier and had a worse prognosis. Therefore, these patients should be considered for earlier administration of targeted therapies or immunotherapies after TACE.
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Affiliation(s)
- Zhi-Juan Wu
- Department of Geriatrics, Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China (mainland)
| | - Yin-Fa Xie
- Department of Interventional Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China (mainland)
| | - Xu Chang
- Department of Interventional Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China (mainland)
| | - Lin Zhang
- Department of Interventional Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China (mainland)
| | - Hui-Yong Wu
- Department of Interventional Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China (mainland)
| | - Ji-Bing Liu
- Department of Interventional Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China (mainland)
| | - Jian-Xin Zhang
- Department of Interventional Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China (mainland)
| | - Peng Sun
- Department of Interventional Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China (mainland)
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36
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Yu S, Cai L, Liu C, Gu R, Cai L, Zhuo L. Identification of prognostic alternative splicing events related to the immune microenvironment of hepatocellular carcinoma. Mol Med 2021; 27:36. [PMID: 33832428 PMCID: PMC8034091 DOI: 10.1186/s10020-021-00294-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 03/17/2021] [Indexed: 12/24/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world, and its 5-year survival rate is less than 20%, despite various treatments being available. Increasing evidence indicates that alternative splicing (AS) plays a nonnegligible role in the formation and development of the tumor microenvironment (TME). However, the comprehensive analysis of the impact on prognostic AS events on immune-related perspectives in HCC is lacking but urgently needed. Methods The transcriptional data and clinical information of HCC patients were downloaded from TCGA (The Cancer Genome Atlas) database for calculating immune and stromal scores by ESTIMATE algorithm. We then divided patients into high/low score groups and explored their prognostic significance using Kaplan–Meier curves. Based on stromal and immune scores, differentially expressed AS events (DEASs) were screened and evaluated with functional enrichment analysis. Additionally, a risk score model was established by applying univariate and multivariate Cox regression analyses. Finally, gene set variation analysis (GSVA) was adopted to explore differences in biological behaviors between the high- and low-risk subgroups. Results A total of 370 HCC patients with complete and qualified corresponding data were included in the subsequent analysis. According to the results of ESTIMATE analysis, we observed that the high immune/stromal score group had a longer survival probability, which was significantly correlated with prognosis in HCC patients. In addition, 467 stromal/immune score-related DEASs were identified, and enrichment analysis revealed that DEASs were significantly enriched in pathways related to HCC tumorigenesis and the immune microenvironment. More importantly, the final prognostic signature containing 16 DEASs showed powerful predictive ability. Finally, GSVA demonstrated that activation of carcinogenic pathways and immune-related pathways in the high-risk group may lead to poor prognosis. Conclusions Collectively, these outcomes revealed prognostic AS events related to carcinogenesis and the immune microenvironment, which may yield new directions for HCC immunotherapy. Supplementary Information The online version contains supplementary material available at 10.1186/s10020-021-00294-3.
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Affiliation(s)
- Shanshan Yu
- Department of Chemoradiation Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Luya Cai
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Chuan Liu
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Ruihong Gu
- Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Lingyi Cai
- Department of Hematology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Leying Zhuo
- Department of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical University, Southern White Elephant Town, Ouhai, Wenzhou, Zhejiang, 325000, People's Republic of China.
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Xu Q, Xu H, Deng R, Li N, Mu R, Qi Z, Shen Y, Wang Z, Wen J, Zhao J, Weng D, Huang W. Immunological significance of prognostic alternative splicing signature in hepatocellular carcinoma. Cancer Cell Int 2021; 21:190. [PMID: 33794886 PMCID: PMC8017877 DOI: 10.1186/s12935-021-01894-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 03/23/2021] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) ranks the sixth prevalent tumors with high mortality globally. Alternative splicing (AS) drives protein diversity, the imbalance of which might act an important factor in tumorigenesis. This study aimed to construct of AS-based prognostic signature and elucidate the role in tumor immune microenvironment (TIME) and immunotherapy in HCC. METHODS Univariate Cox regression analysis was performed to determine the prognosis-related AS events and gene set enrichment analysis (GSEA) was employed for functional annotation, followed by the development of prognostic signatures using univariate Cox, LASSO and multivariate Cox regression. K-M survival analysis, proportional hazards model, and ROC curves were conducted to validate prognostic value. ESTIMATE R package, ssGSEA algorithm and CIBERSORT method and TIMER database exploration were performed to uncover the context of TIME in HCC. Quantitative real-time polymerase chain reaction was implemented to detect ZDHHC16 mRNA expression. Cytoscape software 3.8.0 were employed to visualize AS-splicing factors (SFs) regulatory networks. RESULTS A total of 3294 AS events associated with survival of HCC patients were screened. Based on splicing subtypes, eight AS prognostic signature with robust prognostic predictive accuracy were constructed. Furthermore, quantitative prognostic nomogram was developed and exhibited robust validity in prognostic prediction. Besides, the consolidated signature was significantly correlated with TIME diversity and ICB-related genes. ZDHHC16 presented promising prospect as prognostic factor in HCC. Finally, the splicing regulatory network uncovered the potential functions of splicing factors (SFs). CONCLUSION Herein, exploration of AS patterns may provide novel and robust indicators (i.e., risk signature, prognostic nomogram, etc.,) for prognostic prediction of HCC. The AS-SF networks could open up new approach for investigation of potential regulatory mechanisms. And pivotal players of AS events in context of TIME and immunotherapy efficiency were revealed, contributing to clinical decision-making and personalized prognosis monitoring of HCC.
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Affiliation(s)
- Qianhui Xu
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, No 109. Xueyuan West Road, Wenzhou, 325000, Zhejiang, China
| | - Hao Xu
- Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China
| | - Rongshan Deng
- Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China
| | - Nanjun Li
- Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China
| | - Ruiqi Mu
- Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China
| | - Zhixuan Qi
- Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China
| | - Yunuo Shen
- Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China
| | - Zijie Wang
- Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China
| | - Jingchao Wen
- Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China
| | - Jiaxin Zhao
- Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China
| | - Di Weng
- Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China
| | - Wen Huang
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, No 109. Xueyuan West Road, Wenzhou, 325000, Zhejiang, China.
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Wang Y, Wang X, Huang X, Zhang J, Hu J, Qi Y, Xiang B, Wang Q. Integrated Genomic and Transcriptomic Analysis reveals key genes for predicting dual-phenotype Hepatocellular Carcinoma Prognosis. J Cancer 2021; 12:2993-3010. [PMID: 33854600 PMCID: PMC8040886 DOI: 10.7150/jca.56005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 02/20/2021] [Indexed: 12/24/2022] Open
Abstract
Dual-phenotype hepatocellular carcinoma (DPHCC) expresses both hepatocyte and cholangiocyte markers, and is characterized by high recurrence and low survival rates. The underlying molecular mechanisms of DPHCC pathogenesis are unclear. We performed whole exome sequencing and RNA sequencing of three subtypes of HCC (10 DPHCC, 10 CK19-positive HCC, and 14 CK19-negative HCC), followed by integrated bioinformatics analysis, including somatic mutation analysis, mutation signal analysis, differential gene expression analysis, and pathway enrichment analysis. Cox proportional hazard regression analyses were applied for exploring survival related characteristics. We found that mutated genes in DPHCC patients were associated with carcinogenesis and immunity, and the up-regulated genes were mainly enriched in transcription-related and cancer-related pathways, and the down-regulated genes were mainly enriched in immune-related pathways. CXCL9 was selected as the hub gene, which is associated with immune cells and survival prognosis. Our results showed that low CXCL9 expression was significantly associated with poor prognosis, and its expression was significantly reduced in DPHCC samples. In conclusion, we explored the molecular mechanisms governing DPHCC development and progression and identified CXCL9, which influences the immune microenvironment and prognosis of DPHCC and might be new clinically significant biomarkers for predicting prognosis.
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Affiliation(s)
- Yaobang Wang
- Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China.,Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China.,Department of Clinical Laboratory. First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Xi Wang
- Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China.,Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Xiaoliang Huang
- Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China.,Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Jie Zhang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Guangxi Zhuang Autonomous Region, China
| | - Junwen Hu
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Guangxi Zhuang Autonomous Region, China
| | - Yapeng Qi
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Guangxi Zhuang Autonomous Region, China
| | - Bangde Xiang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Guangxi Zhuang Autonomous Region, China
| | - Qiuyan Wang
- Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China.,Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China
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Lin X, Wang X, Gu Q, Lei D, Liu X, Yao C. Emerging nanotechnological strategies to reshape tumor microenvironment for enhanced therapeutic outcomes of cancer immunotherapy. Biomed Mater 2021; 16:042001. [PMID: 33601351 DOI: 10.1088/1748-605x/abe7b3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 02/18/2021] [Indexed: 12/12/2022]
Abstract
Immunotherapy has emerged as a novel cancer treatment over the last decade, however, efficacious responses to mono-immunotherapy have only been achieved in a relatively small portion of patients whereas combinational immunotherapies often lead to concurrent side effects. It has been proved that the tumor microenvironment (TME) is responsible for tumor immune escape and the ultimate treatment failure. Recently, there has been remarkable progress in both the understanding of the TME and the applications of nanotechnological strategies, and reviewing the emerging immune-regulatory nanosystems may provide valuable information for specifically modulating the TME at different immune stages. In this review, we focus on comprehending the recently-proposed T-cell-based tumor classification and identifying the most promising targets for different tumor phenotypes, and then summarizing the nanotechnological strategies to best target corresponding immune-related factors. For future precise personalized immunotherapy, tailor-made TME modulation strategies conducted by well-designed nanosystems to alleviate the suppressive TME and then promote anti-tumor immune responses will significantly benefit the clinical outcomes of cancer patients.
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Affiliation(s)
- Xinyi Lin
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, Institute of Biomedical Photonics and sensing, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, People's Republic of China
- Contributed equally to this review
| | - Xiaoyan Wang
- School of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, People's Republic of China
- Contributed equally to this review
| | - Qing Gu
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, Institute of Biomedical Photonics and sensing, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, People's Republic of China
| | - Dongqin Lei
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, Institute of Biomedical Photonics and sensing, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, People's Republic of China
| | - Xiaolong Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, People's Republic of China
- Mengchao Med-X Center, Fuzhou University, Fuzhou 350116, People's Republic of China
- Author to whom any corresponding should be addressed
| | - Cuiping Yao
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, Institute of Biomedical Photonics and sensing, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, People's Republic of China
- Author to whom any corresponding should be addressed
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40
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Liu X, Lu Y, Qin S. Atezolizumab and bevacizumab for hepatocellular carcinoma: mechanism, pharmacokinetics and future treatment strategies. Future Oncol 2021; 17:2243-2256. [PMID: 33663220 DOI: 10.2217/fon-2020-1290] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a common cancer globally and a leading cause of cancer-related deaths. Although early-stage disease may be curable by resection, liver transplantation or ablation, many patients present with unresectable disease and have a poor prognosis. Combination treatment with atezolizumab (targeting PD-L1) and bevacizumab (targeting VEGF) in the recent IMbrave150 study was shown to be effective with an acceptable safety profile in patients with unresectable HCC. Herein, we discuss this novel combination in the context of the liver immune environment, summarize the mechanism and pharmacokinetics of atezolizumab and bevacizumab, and examine recent data on other immune checkpoint inhibitor combination strategies as well as future directions in the treatment of patients with advanced HCC.
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Affiliation(s)
- Xiufeng Liu
- Department of Medical Oncology, Bayi Hospital Affiliated to Nanjing Chinese Medical University, Nanjing, 210002, China
| | - Yi Lu
- Shanghai Roche Pharmaceuticals Ltd, Shanghai, 201203, China
| | - Shukui Qin
- Department of Medical Oncology, Bayi Hospital Affiliated to Nanjing Chinese Medical University, Nanjing, 210002, China
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41
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Shi X, Li Q, Wang Y. Impact of regulatory T cells on the prognosis of hepatocellular carcinoma: A protocol for systematic review and meta analysis. Medicine (Baltimore) 2021; 100:e23957. [PMID: 33545975 PMCID: PMC7837976 DOI: 10.1097/md.0000000000023957] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 12/01/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND This meta-analysis aimed to systematically review current available literature to assess the impact of regulatory T cells (Tregs) on the prognosis of hepatocellular carcinoma (HCC). METHODS We will browse the online databases of PubMed and Cochrane Library. The summary hazard ratio (HR) and their 95% confidence intervals (CIs) will be combined to present the value reported in the study. CONCLUSION Our meta-analysis will provide useful guidance in treatment of HCC based on the reported evidences regarding the impact of Tregs on the prognosis of HCC. OSF REGISTRATION NUMBER 10.17605/OSF.IO/3Q8PW.
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Affiliation(s)
- Xinhui Shi
- Department of Medical Laboratory, Yancheng No.1 People's Hospital & Yancheng First Hospital Affiliated Hospital of Nanjing University Medical School
| | - Qisong Li
- College of Medical Technology, Jiangsu Vocational College of Medicine, Yancheng, P.R. China
| | - Yungang Wang
- Department of Medical Laboratory, Yancheng No.1 People's Hospital & Yancheng First Hospital Affiliated Hospital of Nanjing University Medical School
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Dai X, Guo Y, Hu Y, Bao X, Zhu X, Fu Q, Zhang H, Tong Z, Liu L, Zheng Y, Zhao P, Fang W. Immunotherapy for targeting cancer stem cells in hepatocellular carcinoma. Theranostics 2021; 11:3489-3501. [PMID: 33537099 PMCID: PMC7847682 DOI: 10.7150/thno.54648] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Accepted: 12/21/2020] [Indexed: 02/06/2023] Open
Abstract
The rapid development and remarkable success of checkpoint inhibitors have provided significant breakthroughs in cancer treatment, including hepatocellular carcinoma (HCC). However, only 15-20% of HCC patients can benefit from checkpoint inhibitors. Cancer stem cells (CSCs) are responsible for recurrence, metastasis, and local and systemic therapy resistance in HCC. Accumulating evidence has suggested that HCC CSCs can create an immunosuppressive microenvironment through certain intrinsic and extrinsic mechanisms, resulting in immune evasion. Intrinsic evasion mechanisms mainly include activation of immune-related CSC signaling pathways, low-level expression of antigen presenting molecules, and high-level expression of immunosuppressive molecules. External evasion mechanisms are mainly related to HBV/HCV infection, alcoholic/nonalcoholic steatohepatitis, hypoxia stimulation, abnormal angiogenesis, and crosstalk between CSCs and immune cells. A better understanding of the complex mechanisms of CSCs involved in immune evasion will contribute to therapies for HCC. Here we will outline the detailed mechanisms of immune evasion for CSCs, and provide an overview of the current immunotherapies targeting CSCs in HCC.
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MESH Headings
- Antigen Presentation/drug effects
- Antineoplastic Agents, Immunological/therapeutic use
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/therapy
- Fatty Liver/genetics
- Fatty Liver/immunology
- Fatty Liver/pathology
- Fatty Liver/therapy
- Gene Expression Regulation, Neoplastic
- Hepatitis B/genetics
- Hepatitis B/immunology
- Hepatitis B/pathology
- Hepatitis B/therapy
- Hepatitis C/genetics
- Hepatitis C/immunology
- Hepatitis C/pathology
- Hepatitis C/therapy
- Humans
- Immunologic Factors/therapeutic use
- Immunotherapy/methods
- Liver Neoplasms/genetics
- Liver Neoplasms/immunology
- Liver Neoplasms/pathology
- Liver Neoplasms/therapy
- Neoplasm Proteins/antagonists & inhibitors
- Neoplasm Proteins/genetics
- Neoplasm Proteins/immunology
- Neoplasm Recurrence, Local/genetics
- Neoplasm Recurrence, Local/immunology
- Neoplasm Recurrence, Local/pathology
- Neoplasm Recurrence, Local/therapy
- Neoplastic Stem Cells/drug effects
- Neoplastic Stem Cells/immunology
- Neoplastic Stem Cells/pathology
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/immunology
- Neovascularization, Pathologic/pathology
- Neovascularization, Pathologic/prevention & control
- Signal Transduction
- Tumor Escape/drug effects
- Tumor Microenvironment/drug effects
- Tumor Microenvironment/genetics
- Tumor Microenvironment/immunology
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Peng Zhao
- Department of Medical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Weijia Fang
- Department of Medical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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Gu X, Guan J, Xu J, Zheng Q, Chen C, Yang Q, Huang C, Wang G, Zhou H, Chen Z, Zhu H. Model based on five tumour immune microenvironment-related genes for predicting hepatocellular carcinoma immunotherapy outcomes. J Transl Med 2021; 19:26. [PMID: 33407546 PMCID: PMC7788940 DOI: 10.1186/s12967-020-02691-4] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Accepted: 12/22/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Although the tumour immune microenvironment is known to significantly influence immunotherapy outcomes, its association with changes in gene expression patterns in hepatocellular carcinoma (HCC) during immunotherapy and its effect on prognosis have not been clarified. METHODS A total of 365 HCC samples from The Cancer Genome Atlas liver hepatocellular carcinoma (TCGA-LIHC) dataset were stratified into training datasets and verification datasets. In the training datasets, immune-related genes were analysed through univariate Cox regression analyses and least absolute shrinkage and selection operator (LASSO)-Cox analyses to build a prognostic model. The TCGA-LIHC, GSE14520, and Imvigor210 cohorts were subjected to time-dependent receiver operating characteristic (ROC) and Kaplan-Meier survival curve analyses to verify the reliability of the developed model. Finally, single-sample gene set enrichment analysis (ssGSEA) was used to study the underlying molecular mechanisms. RESULTS Five immune-related genes (LDHA, PPAT, BFSP1, NR0B1, and PFKFB4) were identified and used to establish the prognostic model for patient response to HCC treatment. ROC curve analysis of the TCGA (training and validation sets) and GSE14520 cohorts confirmed the predictive ability of the five-gene-based model (AUC > 0.6). In addition, ROC and Kaplan-Meier analyses indicated that the model could stratify patients into a low-risk and a high-risk group, wherein the high-risk group exhibited worse prognosis and was less sensitive to immunotherapy than the low-risk group. Functional enrichment analysis predicted potential associations of the five genes with several metabolic processes and oncological signatures. CONCLUSIONS We established a novel five-gene-based prognostic model based on the tumour immune microenvironment that can predict immunotherapy efficacy in HCC patients.
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Affiliation(s)
- Xinyu Gu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Jun Guan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Jia Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Qiuxian Zheng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Chao Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Qin Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Chunhong Huang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Gang Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Haibo Zhou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Zhi Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Haihong Zhu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China.
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Kabashima A, Shimada S, Shimokawa M, Akiyama Y, Tanabe M, Tanaka S. Molecular and immunological paradigms of hepatocellular carcinoma: Special reference to therapeutic approaches. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2021; 28:62-75. [PMID: 33259135 DOI: 10.1002/jhbp.874] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 10/09/2020] [Accepted: 10/11/2020] [Indexed: 12/14/2022]
Abstract
The development of hepatocellular carcinoma (HCC) is a multistep process with a complex interaction of various genetic backgrounds and the tumor microenvironment. In addition to the development of rational approaches to epidemiologic research, early detection, and diagnosis, considerable progress has been made in systemic treatment with molecular-targeted agents for patients with advanced HCC. Moreover, encouraging reports of recent clinical trials of combination therapy with immune-checkpoint inhibitors (ICIs) has raised high hopes. Each HCC is the result of a unique combination of somatic alterations, including genetic, epigenetic, transcriptomic, and metabolic events, leading to conclusive tumoral heterogeneity. Recent advances in comprehensive genetic analysis have accelerated molecular classification and defined subtypes with specific characteristics, including immune-associated molecular profiles reflecting the immune reactivity in the tumor. In considering the development of therapeutic strategies in combination with immunotherapy, proper interpretation of molecular pathological characterization could lead to effective therapeutic deployment and enable individualization of the management of HCC. Here, we review distinctive molecular alterations in the subtype classification of HCC, current therapies, and representative clinical trials with alternative immune-combination approaches from a molecular pathological point.
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Affiliation(s)
- Ayano Kabashima
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shu Shimada
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Masahiro Shimokawa
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yoshimitsu Akiyama
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Minoru Tanabe
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shinji Tanaka
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
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Zhu J, Wang L, Zhou Y, Hao J, Wang S, Liu L, Li J. Comprehensive analysis of the relationship between competitive endogenous RNA (ceRNA) networks and tumor infiltrating-cells in hepatocellular carcinoma. J Gastrointest Oncol 2020; 11:1381-1398. [PMID: 33457008 DOI: 10.21037/jgo-20-555] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Background The innovation of immune checkpoint blockade (ICB) represents a promising shift in the treatment of advanced hepatocellular carcinoma (HCC). However, response to ICB has varied largely due to the high tumor heterogeneity and complex tumor microenvironment (TME). The competitive endogenous RNA (ceRNA) network also plays an important role in tumor occurrence and progression, but its relation with tumor-infiltrating immune cells (TICs) remains largely unexplored in HCC. The overriding objective of our study was thus to construct a prognosis-related risk model and to further evaluate the relationship between ceRNA networks and TICs. Methods Differentially expressed gene (DEG) analysis was performed to identify the differentially expressed RNAs. Lasso and multivariable Cox regression analyses were used to construct risk models, which were assessed by the area under the receiver operating characteristic curve (AUC of ROC) and Kaplan-Meier (K-M) curves. Then, a single-sample gene set enrichment analysis (ssGSEA) algorithm was adopted to dissect the TICs in HCC samples. Nomograms were constructed and calibration curves were used to verify the discrimination and accuracy of the nomograms. Finally, integration analysis was performed to validate the correlation of ceRNA and TICs. Results In the study, 7 differentially expressed RNAs [5 messenger RNA s (mRNAs) and 2 micro RNAs (miRNAs)] were incorporated to construct a ceRNA risk model. The AUC of the 1-, 3-, and 5-year overall survival (OS) were 0.784, 0.685, and 0.691 respectively. Likewise, 7 types TICs were in the TICs signature model and the AUC of the 1-, 3-, and 5-year OS were 0.706, 0.731, and 0.721 respectively. The integration analysis showed that 7 pairs of mRNA-TICs and 1 pair of miRNA-TICs had a close relation (all correlation coefficients >0.2, P<0.001). Conclusions Through constructing two risk models based on ceRNA network and TICs, we identified the hub RNAs and key TICs in the progression and prognosis of HCC, and further explored the relationship between ceRNA and TME. Importantly, targeting these hub RNAs may facilitate the remodeling of the TME and be a potential therapeutic alternative to enhancing the response to ICB, thus improving the prognosis of HCC patients.
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Affiliation(s)
- Jun Zhu
- State Key Laboratory of Cancer Biology, Institute of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Liang Wang
- Department of Ophthalmology, Eye Institute of Chinese PLA, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Yifan Zhou
- Department of Basic Medicine, The Fourth Military Medical University, Xi'an, China
| | - Jun Hao
- Department of Experiment Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Shuai Wang
- State Key Laboratory of Cancer Biology, Institute of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Lei Liu
- Department of Gastroenterology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Jipeng Li
- State Key Laboratory of Cancer Biology, Institute of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
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Wang K, Chen X, Jin C, Mo J, Jiang H, Yi B, Chen X. A novel immune-related genes prognosis biomarker for hepatocellular carcinoma. Aging (Albany NY) 2020; 13:675-693. [PMID: 33260154 PMCID: PMC7834986 DOI: 10.18632/aging.202173] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 10/05/2020] [Indexed: 04/16/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is closely associated with the immune microenvironment. To identify the effective population before administering treatment, the establishment of prognostic immune biomarkers is crucial for early HCC diagnosis and treatment. RESULTS A total of 335 IRGs identified from 788 overlapping IRGs were associated with the survival of HCC. A prognostic immunoscore model was identified. The Kaplan-Meier survival curves and time-dependent ROC analysis revealed a powerful prognostic performance of immunoscore signature via multi validation. Besides, the immunoscore signature exhibited a better predictive power compared to other prognostic signatures. Gene set enrichment analysis showed multiple signaling differences between the high and low immunoscore group. Furthermore, immunoscore was significantly associated with multiple immune cells and immune infiltration in the tumor microenvironment. CONCLUSIONS We identified the immunoscore as a robust marker for predicting HCC patient survival. METHODS Three sets of immune-related genes (IRGs) were integrated to identify the overlapping IRGs. Weighted gene co-expression network analysis was performed to obtain the survival-related IRGs. Further, the prognostic immunoscore model was constructed via LASSO-penalized Cox regression analysis. Then the prognostic performance of immunoscore was evaluated. In addition, ESTIMATE and CIBERSORT algorithms were applied to explore the relationship between immunoscore and tumor immune microenvironment.
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Affiliation(s)
- Kunpeng Wang
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou 318000, China
| | - Xinyi Chen
- Department of Anesthesia Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou 318000, China
| | - Chong Jin
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou 318000, China
| | - Jinggang Mo
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou 318000, China
| | - Hao Jiang
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou 318000, China
| | - Bin Yi
- Department of Cardio-Vascular Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Xiang Chen
- Department of Anesthesia, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510655, China
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The novel glycyrrhetinic acid–tetramethylpyrazine conjugate TOGA induces anti-hepatocarcinogenesis by inhibiting the effects of tumor-associated macrophages on tumor cells. Pharmacol Res 2020; 161:105233. [DOI: 10.1016/j.phrs.2020.105233] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 09/29/2020] [Accepted: 09/30/2020] [Indexed: 02/06/2023]
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Fan J, Han J, Li J, Gu A, Yin D, Song F, Wang L, Yi Y. The expression and function of immunoglobulin-like transcript 4 in dendritic cells from patients with hepatocellular carcinoma. Hum Immunol 2020; 81:714-725. [PMID: 33228921 DOI: 10.1016/j.humimm.2020.10.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 09/23/2020] [Accepted: 10/09/2020] [Indexed: 12/18/2022]
Abstract
Due to their easy availability and expansion in vitro, monocyte-derived dendritic cells (moDCs) are most frequently used for tumor vaccination. Immunoglobulin-like transcript 4 (ILT4), as inhibitory receptor, has been reported to be related to DC tolerance. However, the influence of ILT4 for DC tolerance in hepatocellular carcinoma (HCC) patients has not been illustrated. In this research, we explored the expression of ILT4 on moDCs from HCC patients and its effect on moDC function. We demonstrated that the expression of ILT4 on mature DCs (mDCs) was higher in the peripheral blood from HCC patients than in that from healthy donors. The levels of cytokines IL-1β and IL-6 secreted by mDCs from both HCC patients and healthy controls, stimulated by anti-ILT4 agonistic mAb, were decreased. In contrast, the levels of IL-10 and IL-23 were upregulated. In addition, ILT4, triggered by anti-ILT4 agonistic mAb, could reduce allogeneic T cell proliferation stimulated by the mDCs. Moreover, ILT4 triggered by anti-ILT4 agonistic mAb could also reduce the ability of the mDCs to stimulate tumor cell antigen-specific autologous CD4+ T cells (production of IFN-γ) and CD8+ T cells (production of IFN-γ and IL-2). Furthermore, ILT4 expression impaired the cytotoxicity of autologous T cells induced by the mDCs against the HCC tumor cell line SMMC-7721. Our data revealed that the high expression of ILT4 promoted the immune tolerance of DCs, resulting in an inefficiency of the T cell response, a process that is exacerbated in HCC patients.
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Affiliation(s)
- Jing Fan
- Clinical Research Center, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine. Zhong Fu Road, Gulou District, Nanjing, Jiangsu 210003, PR China
| | - Jianbo Han
- Department of Hepatobiliary Surgery, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine. Zhong Fu Road, Gulou District, Nanjing, Jiangsu 210003, PR China
| | - Jiayan Li
- Clinical Research Center, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine. Zhong Fu Road, Gulou District, Nanjing, Jiangsu 210003, PR China
| | - Aidong Gu
- Department of Hepatobiliary Surgery, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine. Zhong Fu Road, Gulou District, Nanjing, Jiangsu 210003, PR China
| | - Dandan Yin
- Clinical Research Center, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine. Zhong Fu Road, Gulou District, Nanjing, Jiangsu 210003, PR China
| | - Fangnan Song
- Department of Hepatobiliary Surgery, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine. Zhong Fu Road, Gulou District, Nanjing, Jiangsu 210003, PR China
| | - Lili Wang
- Clinical Research Center, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine. Zhong Fu Road, Gulou District, Nanjing, Jiangsu 210003, PR China.
| | - Yongxiang Yi
- Clinical Research Center, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine. Zhong Fu Road, Gulou District, Nanjing, Jiangsu 210003, PR China; Department of Hepatobiliary Surgery, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine. Zhong Fu Road, Gulou District, Nanjing, Jiangsu 210003, PR China.
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Zeng Z, Yang B, Liao ZY. Current progress and prospect of immune checkpoint inhibitors in hepatocellular carcinoma. Oncol Lett 2020; 20:45. [PMID: 32802167 PMCID: PMC7412709 DOI: 10.3892/ol.2020.11909] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 06/19/2020] [Indexed: 02/06/2023] Open
Abstract
In recent years, the incidence of liver cancer has increased and is currently the sixth most common tumor and the second leading cause of cancer-associated mortality worldwide. Most cases of liver cancer are hepatocellular carcinoma (HCC). Surgery, including liver transplantation or resection, and radiofrequency ablation therapies are all considered to be the curative treatment options for early-stage HCC. However, most patients have advanced HCC at the time of diagnosis, contributing to a poor prognosis. Therefore, improved treatment for late-stage HCC is needed. Immune checkpoint inhibitors (ICIs), among which programmed death receptor 1 (PD-1)/PD-ligand 1 and cytotoxic T lymphocyte-associated protein 4 are the representative immunological checkpoints, have shown great promise and progress for HCC treatment. The present review summarizes recent studies that have focused on ICIs and discusses the present limitations affecting the development of new therapeutic strategies.
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Affiliation(s)
- Zhu Zeng
- Department of Abdominal Oncology, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Biao Yang
- Department of Gastroenterology, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Zheng-Yin Liao
- Department of Abdominal Oncology, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, P.R. China
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Chen W, Zhang X, Bi K, Zhou H, Xu J, Dai Y, Diao H. Comprehensive Study of Tumor Immune Microenvironment and Relevant Genes in Hepatocellular Carcinoma Identifies Potential Prognostic Significance. Front Oncol 2020; 10:554165. [PMID: 33072579 PMCID: PMC7541903 DOI: 10.3389/fonc.2020.554165] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 08/13/2020] [Indexed: 12/11/2022] Open
Abstract
Background: The tumor immune microenvironment (TIME) is an external immune system that regulates tumorigenesis. However, cellular interactions involving the TIME in hepatocellular carcinoma (HCC) are poorly characterized. Methods: In this study, we used multidimensional bioinformatic methods to comprehensively analyze cellular TIME characteristics in 735 HCC patients. Additionally, we explored associations involving TIME molecular subtypes and gene types and clinicopathological features to construct a prognostic signature. Results: Based on their characteristics, we classified TIME and gene signatures into three phenotypes (TIME T1–3) and two gene clusters (Gene G1–2), respectively. Further analysis revealed that Gene G1 was associated with immune activation and surveillance and included CD8+ T cells, natural killer cell activation, and activated CD4+ memory T cells. In contrast, Gene G2 was characterized by increased M0 macrophage and regulatory T cell levels. After calculation of principal component algorithms, a TIME score (TS) model, including 78 differentially expressed genes, was constructed based on TIME phenotypes and gene clusters. Furthermore, we observed that the Gene G2 cluster was characterized by high TS, and Gene G1 was characterized by low TS, which correlated with poor and favorable prognosis of HCC, respectively. Correlation analysis showed that TS had a positive association with several clinicopathologic signatures [such as grade, stage, tumor (T), and node (N)] and known somatic gene mutations (such as TP53 and CTNNB1). The prognostic value of the TS model was verified using external data sets. Conclusion: We constructed a TS model based on differentially expressed genes and involving immune phenotypes and demonstrated that the TS model is an effective prognostic biomarker and predictor for HCC patients.
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Affiliation(s)
- Wenbiao Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Disease, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Xujun Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Disease, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Kefan Bi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Disease, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Hetong Zhou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Disease, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Jia Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Disease, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Yong Dai
- Department of Clinical Medical Research Center, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital Southern University of Science and Technology, Shenzhen People's Hospital, Shenzhen, China
| | - Hongyan Diao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Disease, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
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