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Chen J, Sun HW, Wang RZ, Zhang YF, Li WJ, Wang YK, Wang H, Jia MM, Xu QX, Zhuang H, Xue N. Glutamate promotes CCL2 expression to recruit tumor-associated macrophages by restraining EZH2-mediated histone methylation in hepatocellular carcinoma. Oncoimmunology 2025; 14:2497172. [PMID: 40271976 PMCID: PMC12026252 DOI: 10.1080/2162402x.2025.2497172] [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: 12/02/2024] [Revised: 04/02/2025] [Accepted: 04/21/2025] [Indexed: 04/25/2025] Open
Abstract
Glutamate is well-known as metabolite for maintaining the energy and redox homeostasis in cancer, moreover it is also the primary excitatory neurotransmitter in the central nervous system. However, whether glutamatergic signaling can regulate hepatocellular carcinoma (HCC) progression and the specific regulatory mechanisms are unknown. In the present study, we found that glutamate and its receptor NMDAR2B were significantly elevated in HCC patients, which predicts poor prognosis. Glutamate could upregulate CCL2 expression on hepatoma cells and further enhance the capability of tumor cells to recruit tumor-associated macrophages (TAMs). Mechanistically, glutamate could facilitate CCL2 expression through NMDAR pathway by decreasing the expression of EZH2, which regulates the H3K27me3 levels on the CCL2 promoter, rather than affecting DNA methylation. Moreover, inhibiting glutamate pathway with MK801 could significantly delay tumor growth, with reduced TAMs in implanted Hepa1-6 mouse HCC models. Our work suggested that glutamate could induce CCL2 expression to promote TAM infiltration by negatively regulating EZH2 levels in hepatoma cells, which might serve as a potential prognostic marker and a therapeutic target for HCC patients.
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Affiliation(s)
- Jing Chen
- Department of Orthopaedics, Department of Clinical Laboratory, The Affiliated Cancer Hospital of Zhengzhou University&Henan Cancer Hospital, Zhenghou, China
| | - Hong-Wei Sun
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai Clinical Medical College of Jinan University (Zhuhai People’s Hospital), Zhuhai, China
| | - Run-Zheng Wang
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yun-Fei Zhang
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Wen-Jiao Li
- Department of Orthopaedics, Department of Clinical Laboratory, The Affiliated Cancer Hospital of Zhengzhou University&Henan Cancer Hospital, Zhenghou, China
| | - Yong-Kui Wang
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Hao Wang
- Department of Orthopaedics, Department of Clinical Laboratory, The Affiliated Cancer Hospital of Zhengzhou University&Henan Cancer Hospital, Zhenghou, China
| | - Miao-Miao Jia
- Department of Orthopaedics, Department of Clinical Laboratory, The Affiliated Cancer Hospital of Zhengzhou University&Henan Cancer Hospital, Zhenghou, China
| | - Qing-Xia Xu
- Department of Orthopaedics, Department of Clinical Laboratory, The Affiliated Cancer Hospital of Zhengzhou University&Henan Cancer Hospital, Zhenghou, China
| | - Hao Zhuang
- Department of Orthopaedics, Department of Clinical Laboratory, The Affiliated Cancer Hospital of Zhengzhou University&Henan Cancer Hospital, Zhenghou, China
| | - Ning Xue
- Department of Orthopaedics, Department of Clinical Laboratory, The Affiliated Cancer Hospital of Zhengzhou University&Henan Cancer Hospital, Zhenghou, China
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2
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Xie D, Liu Y, Xu F, Dang Z, Li M, Zhang Q, Dang Z. Immune microenvironment and immunotherapy in hepatocellular carcinoma: mechanisms and advances. Front Immunol 2025; 16:1581098. [PMID: 40242773 PMCID: PMC12000014 DOI: 10.3389/fimmu.2025.1581098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2025] [Accepted: 03/17/2025] [Indexed: 04/18/2025] Open
Abstract
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality globally. The tumor microenvironment (TME) plays a pivotal role in HCC progression, characterized by dynamic interactions between stromal components, immune cells, and tumor cells. Key immune players, including tumor-associated macrophages (TAMs), tumor-infiltrating lymphocytes (TILs), cytotoxic T lymphocytes (CTLs), regulatory T cells (Tregs), MDSCs, dendritic cells (DCs), and natural killer (NK) cells, contribute to immune evasion and tumor progression. Recent advances in immunotherapy, such as immune checkpoint inhibitors (ICIs), cancer vaccines, adoptive cell therapy (ACT), and combination therapies, have shown promise in enhancing anti-tumor responses. Dual ICI combinations, ICIs with molecular targeted drugs, and integration with local treatments or radiotherapy have demonstrated improved outcomes in HCC patients. This review highlights the evolving understanding of the immune microenvironment and the therapeutic potential of immunotherapeutic strategies in HCC management.
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Affiliation(s)
- Dong Xie
- Diagnosis and Treatment Center for Digestive Diseases of Henan Province Hospital of Traditional Chinese Medicine, Zhengzhou, China
| | - Yang Liu
- College of Traditional Chinese Medicine, Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Fangbiao Xu
- Department of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhibo Dang
- Diagnosis and Treatment Center for Digestive Diseases of Henan Province Hospital of Traditional Chinese Medicine, Zhengzhou, China
| | - Mengge Li
- Diagnosis and Treatment Center for Digestive Diseases of Henan Province Hospital of Traditional Chinese Medicine, Zhengzhou, China
| | - Qinsheng Zhang
- Diagnosis and Treatment Center for Digestive Diseases of Henan Province Hospital of Traditional Chinese Medicine, Zhengzhou, China
| | - Zhongqin Dang
- Diagnosis and Treatment Center for Digestive Diseases of Henan Province Hospital of Traditional Chinese Medicine, Zhengzhou, China
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Zhang R, Dai F, Deng S, Zeng Y, Wang J, Liu G. Reprogramming of Glucose Metabolism for Revisiting Hepatocellular Carcinoma Resistance to Transcatheter Hepatic Arterial Chemoembolization. Chembiochem 2025; 26:e202400719. [PMID: 39501124 DOI: 10.1002/cbic.202400719] [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: 09/01/2024] [Revised: 11/04/2024] [Indexed: 11/24/2024]
Abstract
Hepatocellular carcinoma (HCC) is recognized globally as one of the most lethal tumors, presenting a significant menace to patients' lives owing to its exceptional aggressiveness and tendency to recur. Transcatheter hepatic arterial chemoembolization (TACE) therapy, as a first-line treatment option for patients with advanced HCC, has been proven effective. However, it is disheartening that nearly 40 % of patients exhibit resistance to this therapy. Consequently, this review delves into the metabolic aspects of glucose metabolism to explore the underlying mechanisms behind TACE treatment resistance and to propose potentially fruitful therapeutic strategies. The ultimate objective is to present novel insights for the development of personalized treatment methods targeting HCC.
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Affiliation(s)
- Ruijie Zhang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
| | - Fan Dai
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
| | - Songhan Deng
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, 361102, China
| | - Yun Zeng
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
| | - Jinyang Wang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
| | - Gang Liu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
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4
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Wang Z, Liu J, Wang X, Wu Q, Peng Q, Yang T, Sun X, Wang X, Wang Y, Wu W. Glycosyltransferase B4GALNT1 promotes immunosuppression in hepatocellular carcinoma via the HES4-SPP1-TAM/Th2 axis. MOLECULAR BIOMEDICINE 2024; 5:65. [PMID: 39616302 PMCID: PMC11608210 DOI: 10.1186/s43556-024-00231-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 11/15/2024] [Accepted: 11/19/2024] [Indexed: 12/12/2024] Open
Abstract
β-1,4-N-acetylgalactosaminyltransferase I (B4GALNT1) is a key glycosyltransferase for gangliosides. Its aberrant expression has been observed in various cancers, and its potential roles in tumor immunity were suggested recently. However, how B4GALNT1 regulate tumor progression and tumor immunity remains largely unknown. In this study, we aimed to investigate the roles of B4GALNT1 in hepatocellular carcinoma (HCC), particularly in reshaping the tumor immune microenvironment, and evaluate the potential beneficial effects of targeting B4GALNT1 in immunotherapy. Our data verified the aberrant upregulation of B4GALNT1 in HCC tumor tissues and tumor cells, which could be utilized as an independent prognostic factor and improve the predicting performance of traditional tumor node metastasis (TNM) system. We also demonstrated that B4GALNT1 increased the phosphorylation of Hes Family BHLH Transcription Factor 4 (HES4) via p38 mitogen-activated protein kinase (p38)/ c-Jun N-terminal kinase (JNK) signaling in tumor cells, thus increasing the transcriptional activity of HES4, which upregulated the synthesis and secretion of secreted phosphoprotein 1 (SPP1), modulated the composition of tumor-associated macrophages (TAMs) and T helper type 2 (Th2) cells, and eventually reshaped the immunosuppressive microenvironment. In addition, silencing B4GALNT1 was proved to enhance the tumor-killing efficiency of the programmed cell death protein 1 (PD-1)-targeting strategy in mouse model. In conclusion, this study evaluated B4GALNT1 as a prognostic predictor for HCC patients and revealed the mechanism of B4GALNT1 in microenvironmental remodeling, which extends the understanding of HCC progression and provides a novel auxiliary strategy for HCC immunotherapy.
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Affiliation(s)
- Zhifeng Wang
- Human Phenome Institute, State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wannan Medical College, Wuhu, China
- Fudan University-the People's Hospital of Rugao Joint Research Institute of Longevity and Ageing, Rugao, Jiangsu, China
| | - Jiaxin Liu
- Human Phenome Institute, State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
- Fudan University-the People's Hospital of Rugao Joint Research Institute of Longevity and Ageing, Rugao, Jiangsu, China
| | - Xiaoming Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wannan Medical College, Wuhu, China
| | - Qingyun Wu
- Human Phenome Institute, State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
- Fudan University-the People's Hospital of Rugao Joint Research Institute of Longevity and Ageing, Rugao, Jiangsu, China
| | - Qiao Peng
- Shanghai Tenth People's Hospital, School of Medicine, Tongji University Cancer Center, Tongji University, Shanghai, China
| | - Tianxiao Yang
- Human Phenome Institute, State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
| | - Xuehui Sun
- Human Phenome Institute, State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
- Fudan University-the People's Hospital of Rugao Joint Research Institute of Longevity and Ageing, Rugao, Jiangsu, China
| | - Xiaofeng Wang
- Human Phenome Institute, State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
- Fudan University-the People's Hospital of Rugao Joint Research Institute of Longevity and Ageing, Rugao, Jiangsu, China
| | - Yilin Wang
- Department of Hepatic Surgery, Department of Oncology, Shanghai Medical College, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China.
| | - Weicheng Wu
- Human Phenome Institute, State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China.
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wannan Medical College, Wuhu, China.
- Fudan University-the People's Hospital of Rugao Joint Research Institute of Longevity and Ageing, Rugao, Jiangsu, China.
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Llamoza-Torres CJ, Fuentes-Pardo M, Ramos-Molina B. Metabolic dysfunction-associated steatotic liver disease: a key factor in hepatocellular carcinoma therapy response. METABOLISM AND TARGET ORGAN DAMAGE 2024; 4. [DOI: 10.20517/mtod.2024.64] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
The conceptual evolution of non-alcoholic fatty liver disease (NAFLD) to what, since 2023, is called metabolic dysfunction-associated steatotic liver disease (MASLD) not only represents a change in the classification and definition of the disease but also reflects a broader understanding of this heterogeneous condition, which still with many aspects to refine. Although the definition of NAFLD can be interchanged to a high percentage with the new MASLD concept in different aspects, MASLD has been proposed as a relevant factor that influences the response to new immunotherapeutic treatments in the management of MASLD-related hepatocellular carcinoma (HCC), compared to HCC of other etiologies. This indicates that the etiology of HCC plays a relevant role in the prognosis, highlighting the urgency of evaluating treatment regimens for this subgroup of patients in upcoming clinical trials. A better understanding of the pathophysiology of MASLD generates strategies that not only aid in its management but also provide strategies to directly intervene in the carcinogenesis of HCC.
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Wan F, Li Y, Zhu J, Yu D, Liu H, Hu B. Exploring the prognostic value and potential therapeutic strategies of MS4A6A in glioblastoma: A comprehensive analysis of single-cell and multi-omics data. J Cell Mol Med 2024; 28:e70177. [PMID: 39470579 PMCID: PMC11520442 DOI: 10.1111/jcmm.70177] [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: 08/26/2024] [Revised: 10/15/2024] [Accepted: 10/19/2024] [Indexed: 10/30/2024] Open
Abstract
Glioblastoma (GBM) is a highly aggressive and treatment-resistant malignancy that poses a significant challenge in modern medicine. Despite advances in surgical resection, radiotherapy and chemotherapy, complete eradication of GBM remains elusive due to its diffuse invasion into the brain parenchyma and propensity for recurrence. The tumour microenvironment (TME), particularly macrophages, has emerged as a critical player in GBM progression, invasion and metastasis. In the immune microenvironment of glioma, MS4A6A exhibits unique expression characteristics in macrophages. This study aimed to investigate the potential role of MS4A6A, a gene associated with aging and neurodegenerative diseases, in GBM and its potential as a prognostic biomarker and therapeutic target.
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Affiliation(s)
- Fangchao Wan
- Department of Neurology, Changde Hospital, Xiangya School of MedicineCentral South UniversityChangdeHunanChina
| | - Yanling Li
- Department of Neurology, Changde Hospital, Xiangya School of MedicineCentral South UniversityChangdeHunanChina
| | - Jianming Zhu
- Department of Neurology, Changde Hospital, Xiangya School of MedicineCentral South UniversityChangdeHunanChina
| | - Dandan Yu
- Department of Electrocardiogram, Changde Hospital, Xiangya School of MedicineCentral South UniversityChangdeHunanChina
| | - Hongjuan Liu
- Department of Neurology, Changde Hospital, Xiangya School of MedicineCentral South UniversityChangdeHunanChina
| | - Bohong Hu
- Department of Neurology, Changde Hospital, Xiangya School of MedicineCentral South UniversityChangdeHunanChina
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7
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Li Y, Chen Y, Wang D, Wu L, Li T, An N, Yang H. Elucidating the multifaceted role of MGAT1 in hepatocellular carcinoma: integrative single-cell and spatial transcriptomics reveal novel therapeutic insights. Front Immunol 2024; 15:1442722. [PMID: 39081317 PMCID: PMC11286416 DOI: 10.3389/fimmu.2024.1442722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Accepted: 06/28/2024] [Indexed: 08/02/2024] Open
Abstract
Background Glycosyltransferase-associated genes play a crucial role in hepatocellular carcinoma (HCC) pathogenesis. This study investigates their impact on the tumor microenvironment and molecular mechanisms, offering insights into innovative immunotherapeutic strategies for HCC. Methods We utilized cutting-edge single-cell and spatial transcriptomics to examine HCC heterogeneity. Four single-cell scoring techniques were employed to evaluate glycosyltransferase genes. Spatial transcriptomic findings were validated, and bulk RNA-seq analysis was conducted to identify prognostic glycosyltransferase-related genes and potential immunotherapeutic targets. MGAT1's role was further explored through various functional assays. Results Our analysis revealed diverse cell subpopulations in HCC with distinct glycosyltransferase gene activities, particularly in macrophages. Key glycosyltransferase genes specific to macrophages were identified. Temporal analysis illustrated macrophage evolution during tumor progression, while spatial transcriptomics highlighted reduced expression of these genes in core tumor macrophages. Integrating scRNA-seq, bulk RNA-seq, and spatial transcriptomics, MGAT1 emerged as a promising therapeutic target, showing significant potential in HCC immunotherapy. Conclusion This comprehensive study delves into glycosyltransferase-associated genes in HCC, elucidating their critical roles in cellular dynamics and immune cell interactions. Our findings open new avenues for immunotherapeutic interventions and personalized HCC management, pushing the boundaries of HCC immunotherapy.
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Affiliation(s)
- Yang Li
- Department of General Medicine, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, China
| | - Yuan Chen
- Department of General Medicine, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, China
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Danqiong Wang
- Department of General Medicine, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, China
| | - Ling Wu
- Tumor Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, China
| | - Tao Li
- Department of General Medicine, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, China
| | - Na An
- Department of General Medicine, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, China
| | - Haikun Yang
- The Gastroenterology Department, Shanxi Provincial People Hospital, Taiyuan, China
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8
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Xu K, Dong M, Wu Z, Luo L, Xie F, Li F, Huang H, Wang F, Xiong X, Wen Z. Single-Cell RNA Sequencing Identifies Crucial Genes Influencing the Polarization of Tumor-Associated Macrophages in Liver Cancer. Int J Genomics 2024; 2024:7263358. [PMID: 38938448 PMCID: PMC11208785 DOI: 10.1155/2024/7263358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Revised: 04/15/2024] [Accepted: 05/06/2024] [Indexed: 06/29/2024] Open
Abstract
Background In the context of hepatocellular carcinoma (HCC), tumor-associated macrophages (TAMs) are pivotal for the immunosuppressive nature of the tumor microenvironment (TME). This investigation delves into the functional transformations of TAMs within the TME by leveraging single-cell transcriptomics to pinpoint critical genes influencing TAM subset polarization. Methods We procured single-cell and bulk transcriptomic data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA), implementing quality assurance, dimensional reduction, clustering, and annotation on the single-cell sequencing data. To examine cellular interactions, CellChat was utilized, while single-cell regulatory network inference and clustering (SCENIC) was applied to deduce transcription factors (TFs) and their associated targets. Through gene enrichment, survival, and immune infiltration correlation analyses, we sought to pinpoint and validate influential genes. A TAM model under HCC conditions was then established to confirm the expression levels of these key genes. Results Our analysis encompassed 74,742 cells and 23,110 genes. Through postdimensional reduction and clustering, we identified seven distinct cell types and nine TAM subtypes. Analysis via CellChat highlighted a predominance of M2-phenotype-inclined TAM subsets within the tumor's core. SCENIC pinpointed the transcription factor PRDM1 and its target genes as pivotal in this region. Further analysis indicated these genes' involvement in macrophage polarization. Employing trajectory analysis, survival analysis, and immune infiltration correlation, we scrutinized and validated genes likely directing M2 polarization. Experimental validation confirmed PRDM1's heightened expression in TAMs conditioned by HCC. Conclusions Our findings suggest the PRDM1 gene is a key regulator of M2 macrophage polarization, contributing to the immunosuppressive TME in HCC.
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Affiliation(s)
- Kedong Xu
- Department of GastroenterologyThe Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Mingyi Dong
- Department of GastroenterologyThe Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Zhengqiang Wu
- Department of GastroenterologyThe Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Linfei Luo
- Department of GastroenterologyThe Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Fei Xie
- Department of GastroenterologyThe Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Fan Li
- Department of GastroenterologyThe Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Hongyan Huang
- Department of GastroenterologyThe Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Fenfen Wang
- Department of GastroenterologyThe Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Xiaofeng Xiong
- Department of GastroenterologyThe Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Zhili Wen
- Department of GastroenterologyThe Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
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Galasso L, Cerrito L, Maccauro V, Termite F, Ainora ME, Gasbarrini A, Zocco MA. Hepatocellular Carcinoma and the Multifaceted Relationship with Its Microenvironment: Attacking the Hepatocellular Carcinoma Defensive Fortress. Cancers (Basel) 2024; 16:1837. [PMID: 38791916 PMCID: PMC11119751 DOI: 10.3390/cancers16101837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 04/30/2024] [Accepted: 05/07/2024] [Indexed: 05/26/2024] Open
Abstract
Hepatocellular carcinoma is a malignant tumor that originates from hepatocytes in an inflammatory substrate due to different degrees of liver fibrosis up to cirrhosis. In recent years, there has been growing interest in the role played by the complex interrelationship between hepatocellular carcinoma and its microenvironment, capable of influencing tumourigenesis, neoplastic growth, and its progression or even inhibition. The microenvironment is made up of an intricate network of mesenchymal cells, immune system cells, extracellular matrix, and growth factors, as well as proinflammatory cytokines and translocated bacterial products coming from the intestinal microenvironment via the enterohepatic circulation. The aim of this paper is to review the role of the HCC microenvironment and describe the possible implications in the choice of the most appropriate therapeutic scheme in the prediction of tumor response or resistance to currently applied treatments and in the possible development of future therapeutic perspectives, in order to circumvent resistance and break down the tumor's defensive fort.
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Affiliation(s)
- Linda Galasso
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy (L.C.); (V.M.); (A.G.)
| | - Lucia Cerrito
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy (L.C.); (V.M.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Valeria Maccauro
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy (L.C.); (V.M.); (A.G.)
| | - Fabrizio Termite
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy (L.C.); (V.M.); (A.G.)
| | - Maria Elena Ainora
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy (L.C.); (V.M.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy (L.C.); (V.M.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Maria Assunta Zocco
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy (L.C.); (V.M.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
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10
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Jin D, Qian L, Chen J, Yu Z, Dong J. Prognostic impact of CD68+ tumor-associated macrophages in hepatocellular carcinoma: A meta-analysis. Medicine (Baltimore) 2024; 103:e37834. [PMID: 38640338 PMCID: PMC11029977 DOI: 10.1097/md.0000000000037834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2024] [Revised: 03/11/2024] [Accepted: 03/15/2024] [Indexed: 04/21/2024] Open
Abstract
BACKGROUND Evidence from clinical research suggests that the tumor-associated macrophages (TAMs) were associated with prognosis in hepatocellular carcinoma (HCC). The aim of the present meta-analysis was to conduct a qualitative analysis to explore the prognostic value of CD68 + TAMs in HCC. METHODS This study conducted a systematic search in Pubmed, Embase, the Cochrane Library and China National Knowledge Internet from inception of the databases to November 2023. The hazard ratio (HR) and 95% confidence interval (CI) were calculated employing fixed-effect or random-effect models depending on the heterogeneity of the included trials. The Newcastle-Ottawa Scale was used to evaluate the risk of prejudice. RESULTS We analyzed 4362 HCC patients. The present research indicated that the expression levels Of CD68 + TAMs were significantly associated with overall survival (OS) (HR = 1.55, 95% CI: 1.30-1.84) and disease-free survival (DFS) (HR = 1.44, 95% CI: 1.17-1.78). Subgroup analysis based on cutoff values showed that the "Median" subgroup showed a pooled HR of 1.66 with a 95% CI ranging from 1.32 to 2.08, which was slightly higher than the "Others" subgroup that exhibited a pooled HR of 1.40 and a 95% CI of 1.07 to 1.84. The "PT" subgroup had the highest pooled HR of 1.68 (95% CI: 1.19-2.37), indicating a worse OS compared to the "IT" (pooled HR: 1.50, 95% CI: 1.13-2.01) and "Mix" (pooled HR: 1.52, 95% CI: 1.03-2.26) subgroups. Moreover, in the sample size-based analysis, studies with more than 100 samples (>100) exhibited a higher pooled HR of 1.57 (95% CI: 1.28 to 1.93) compared to studies with fewer than 100 samples (<100), which had a pooled HR of 1.45 (95% CI: 1.00-2.10). CONCLUSIONS The analysis suggests that CD68 + TAMs were significantly associated with unfavorable OS and DFS in HCC patients, and may be served as a promising prognostic biomarker in HCC. However, more large-scale trials are needed to study the clinical value of TAMs in HCC.
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Affiliation(s)
- Danwen Jin
- Pathological Diagnosis Center, Zhoushan Hospital, Zhoushan City, Zhejiang Province, China
| | - Liyong Qian
- Pathological Diagnosis Center, Zhoushan Hospital, Zhoushan City, Zhejiang Province, China
| | - Jiayao Chen
- Department of Laboratory, Zhoushan Hospital, Zhoushan City, Zhejiang Province, China
| | - Ze Yu
- Laboratory of Cell Biology and Molecular Biology, Zhoushan Hospital, Zhoushan City, Zhejiang Province, China
| | - Jinliang Dong
- Department of Hepatobiliary Surgery, Zhoushan Hospital, Zhoushan City, Zhejiang Province, China
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11
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Ni L, Chen D, Zhao Y, Ye R, Fang P. Unveiling the flames: macrophage pyroptosis and its crucial role in liver diseases. Front Immunol 2024; 15:1338125. [PMID: 38380334 PMCID: PMC10877142 DOI: 10.3389/fimmu.2024.1338125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 01/16/2024] [Indexed: 02/22/2024] Open
Abstract
Macrophages play a critical role in innate immunity, with approximately 90% of the total macrophage population in the human body residing in the liver. This population encompasses both resident and infiltrating macrophages. Recent studies highlight the pivotal role of liver macrophages in various aspects such as liver inflammation, regeneration, and immune regulation. A novel pro-inflammatory programmed cell death, pyroptosis, initially identified in macrophages, has garnered substantial attention since its discovery. Studies investigating pyroptosis and inflammation progression have particularly centered around macrophages. In liver diseases, pyroptosis plays an important role in driving the inflammatory response, facilitating the fibrotic process, and promoting tumor progression. Notably, the role of macrophage pyroptosis cannot be understated. This review primarily focuses on the role of macrophage pyroptosis in liver diseases. Additionally, it underscores the therapeutic potential inherent in targeting macrophage pyroptosis.
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Affiliation(s)
| | | | | | | | - Peng Fang
- Department of Infectious Diseases, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China
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12
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She S, Shi J, Zhu J, Yang F, Yu J, Dai K. Impact of inflammation and the immune system on hepatocellular carcinoma recurrence after hepatectomy. Cancer Med 2024; 13:e7018. [PMID: 38457189 PMCID: PMC10922023 DOI: 10.1002/cam4.7018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 11/22/2023] [Accepted: 01/31/2024] [Indexed: 03/09/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Hepatectomy remains the first-line treatment for patients with resectable HCC. However, the reported recurrence rate of HCC at 5 years after surgery is between 50% and 70%. Tumor-related factors, including tumor size, number and differentiation, and underlying liver disease are well-known risk factors for recurrence after treatment. In addition to tumor-related factors, ever-increasing amounts of studies are finding that the tumor microenvironment also plays an important role in the recurrence of HCC, including systemic inflammatory response and immune regulation. Based on this, some inflammatory and immune markers were used in predicting postoperative cancer recurrence. These include neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, cytotoxic T cells, and regulatory T cells, among others. In this review, we summarized the inflammatory and immune markers that affect recurrence after HCC resection in order to provide direction for adjuvant therapy after HCC resection and ultimately achieve the goal of reducing recurrence.
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Affiliation(s)
- Sha She
- Department of Infectious DiseasesRenmin Hospital of Wuhan UniversityWuhanHubei ProvinceChina
| | - Jinzhi Shi
- Department of Infectious DiseasesRenmin Hospital of Wuhan UniversityWuhanHubei ProvinceChina
| | - Jiling Zhu
- Department of Infectious DiseasesRenmin Hospital of Wuhan UniversityWuhanHubei ProvinceChina
| | - Fan Yang
- Department of Infectious DiseasesRenmin Hospital of Wuhan UniversityWuhanHubei ProvinceChina
| | - Jia Yu
- Department of Hepatobiliary surgeryRenmin Hospital of Wuhan UniversityWuhanHubei ProvinceChina
| | - Kai Dai
- Department of Infectious DiseasesRenmin Hospital of Wuhan UniversityWuhanHubei ProvinceChina
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13
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Ali E, Červenková L, Pálek R, Ambrozkiewicz F, Hošek P, Daum O, Liška V, Hemminki K, Trailin A. Prognostic role of macrophages and mast cells in the microenvironment of hepatocellular carcinoma after resection. BMC Cancer 2024; 24:142. [PMID: 38287290 PMCID: PMC10823625 DOI: 10.1186/s12885-024-11904-8] [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: 12/09/2023] [Accepted: 01/20/2024] [Indexed: 01/31/2024] Open
Abstract
BACKGROUND The prognostic significance of mast cells and different phenotypes of macrophages in the microenvironment of hepatocellular carcinoma (HCC) following resection is unclear. We aimed in this study to assess the local distribution of infiltrating macrophages and mast cells of specific phenotypes in tissues of HCC and to evaluate their prognostic values for survival of post-surgical patients. METHODS The clinicopathological and follow-up data of 70 patients with HCC, who underwent curative resection of tumor from 1997 to 2019, were collected. The infiltration of CD68+ and CD163+ macrophages and CD117+ mast cells was assessed immunohistochemically in representative resected specimens of HCC and adjacent tissues. The area fraction (AF) of positively stained cells was estimated automatically using QuPath image analysis software in several regions, such as tumor center (TC), inner margin (IM), outer margin (OM), and peritumor (PT) area. The prognostic significance of immune cells, individually and in associations, for time to recurrence (TTR), disease-free survival (DFS), and overall survival (OS) was evaluated using Kaplan-Meier and Cox regression analyses. RESULTS High AF of CD68+ macrophages in TC and IM and high AF of mast cells in IM and PT area were associated with a longer DFS. High AF of CD163+ macrophages in PT area correlated with a shorter DFS. Patients from CD163TChigh & CD68TClow group had a shorter DFS compared to all the rest of the groups, and cases with CD163IMlow & CD68IMhigh demonstrated significantly longer DFS compared to low AF of both markers. Patients from CD68IMhigh & CD163PTlow group, CD117IMhigh & CD163PTlow group, and CD117PThigh & CD163PTlow group had a significantly longer DFS compared to all other combinations of respective cells. CONCLUSIONS The individual prognostic impact of CD68+ and CD163+ macrophages and mast cells in the microenvironment of HCC after resection depends on their abundance and location, whereas the cumulative impact is built upon combination of different cell phenotypes within and between regions.
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Affiliation(s)
- Esraa Ali
- Laboratory of Translational Cancer Genomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1655/76, Pilsen, 32300, Czech Republic
| | - Lenka Červenková
- Laboratory of Cancer Treatment and Tissue Regeneration, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1655/76, Pilsen, 32300, Czech Republic
- Department of Pathology, Third Faculty of Medicine, Charles University, Ruská 87, Prague, 10000, Czech Republic
| | - Richard Pálek
- Laboratory of Cancer Treatment and Tissue Regeneration, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1655/76, Pilsen, 32300, Czech Republic
- Department of Surgery and Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 80, Pilsen, 32300, Czech Republic
| | - Filip Ambrozkiewicz
- Laboratory of Translational Cancer Genomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1655/76, Pilsen, 32300, Czech Republic
| | - Petr Hošek
- Laboratory of Cancer Treatment and Tissue Regeneration, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1655/76, Pilsen, 32300, Czech Republic
| | - Ondrej Daum
- Sikl's Institute of Pathology, Faculty of Medicine and Teaching Hospital in Plzen, Charles University, Edvarda Beneše 13, Pilsen, 30599, Czech Republic
- Bioptická Laboratoř s.r.o, Mikulášské Nám. 4, Pilsen, 32600, Czech Republic
| | - Václav Liška
- Laboratory of Cancer Treatment and Tissue Regeneration, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1655/76, Pilsen, 32300, Czech Republic
- Department of Surgery and Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 80, Pilsen, 32300, Czech Republic
| | - Kari Hemminki
- Laboratory of Translational Cancer Genomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1655/76, Pilsen, 32300, Czech Republic
- Department of Cancer Epidemiology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
| | - Andriy Trailin
- Laboratory of Translational Cancer Genomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1655/76, Pilsen, 32300, Czech Republic.
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14
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Huang R, Ding J, Xie WF. Liver cancer. SINUSOIDAL CELLS IN LIVER DISEASES 2024:349-366. [DOI: 10.1016/b978-0-323-95262-0.00017-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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15
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Hou Q, Li H, Liang Y, Yao N, Cao X, Liu J, Sun B, Feng P, Zhang W, Cao J. Impact of the peripheral blood inflammatory indices and modified nomogram-revised risk index on survival of Extranodal Nasal-Type Natural Killer/T-Cell lymphoma. Cancer Biomark 2024; 39:27-36. [PMID: 37522199 PMCID: PMC10977361 DOI: 10.3233/cbm-230067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 06/05/2023] [Indexed: 08/01/2023]
Abstract
BACKGROUND At present, peripheral blood markers are easily accessible information and clinically valuable prognostic indicators in extranodal nasal-type natural killer/T-cell lymphoma (ENKTCL). Nevertheless, the role of its comprehensive score in ENKTCL remains to be determined. OBJECTIVE Therefore, this study aimed to investigate the prognostic effect of the peripheral inflammation score on ENKTCL. METHODS The retrospective study included 183 patients with ENKTCL. Univariate Cox regression analyses and least absolute shrinkage and selection operator (LASSO) Cox regression were used to construct the inflammation-related prognostic index named Risk. Univariate and multivariate Cox regression analyses and regression adjustment with propensity score matching (PSM) were used to evaluate the prognostic ability of risk. The performance of the modified nomogram-revised risk index (NRI) by integrating risk was evaluated with the area under the time-dependent receiver operating characteristic (ROC) curve (AUC), decision curve analysis (DCA), and integrated Brier score (IBS). RESULTS The risk cut-off value, constructed by the lymphocyte count, platelet count, albumin level, LMR, and PNI, was -1.3486. Before PSM, multivariate analysis showed that risk was significantly associated with OS (HR = 2.577, 95% CI = 1.614-4.114, P< 0.001) and PFS (HR = 2.679, 95% CI = 1.744-4.114, P< 0.001). After PSM adjustment, risk was still an independent factor for OS (HR = 2.829, 95% CI = 1.601-5.001, P< 0.001) and PFS (HR = 2.877, 95% CI = 1.735-4.770, P< 0.001). With the NRI, the modified NRI by integrating risk increased the AUC and clinical net benefit and decreased the IBS. CONCLUSIONS Risk is an easily accessible and inexpensive indicator that may be used as a prognostic marker and could improve NRI predictive power in patients with ENKTCL.
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Affiliation(s)
- Qing Hou
- Department of Radiotherapy, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China
| | - He Li
- Department of Radiotherapy, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China
- Department of Pathology, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China
| | - Yu Liang
- Department of Radiotherapy, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China
| | - Ningning Yao
- Department of Radiotherapy, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China
| | - Xin Cao
- Department of Radiotherapy, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China
| | - Jianting Liu
- Department of Radiotherapy, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China
| | - Bochen Sun
- Department of Radiotherapy, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China
| | - Peixin Feng
- Department of Radiotherapy, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China
| | - Wenjuan Zhang
- Department of Radiotherapy, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China
| | - Jianzhong Cao
- Department of Radiotherapy, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China
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16
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Wu J, Chan YT, Lu Y, Wang N, Feng Y. The tumor microenvironment in the postsurgical liver: Mechanisms and potential targets of postoperative recurrence in human hepatocellular carcinoma. Med Res Rev 2023; 43:1946-1973. [PMID: 37102365 DOI: 10.1002/med.21967] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 03/23/2023] [Accepted: 04/13/2023] [Indexed: 04/28/2023]
Abstract
Surgery remains to be the mainstay of treatment for hepatocellular carcinoma (HCC). Nonetheless, its therapeutic efficacy is significantly impaired by postoperative recurrence, which occurs in more than half of cases as a result of intrahepatic metastasis or de novo tumorigenesis. For decades, most therapeutic strategies on inhibiting postoperative HCC recurrence have been focused on the residual tumor cells but satisfying therapeutic outcomes are barely observed in the clinic. In recent years, a better understanding of tumor biology allows us to shift our focus from tumor cells toward the postoperative tumor microenvironment (TME), which is gradually identified to play a pivotal role in tumor recurrence. In this review, we describe various surgical stress and surgical perturbation on postoperative TME. Besides, we discuss how such alternations in TME give rise to postoperative recurrence of HCC. Based on its clinical significance, we additionally highlight the potential of the postoperative TME as a target for postoperative adjuvant therapeutics.
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Affiliation(s)
- Junyu Wu
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Yau-Tuen Chan
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Yuanjun Lu
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Ning Wang
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Yibin Feng
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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17
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Zhao X, Wang Y, Xia H, Liu S, Huang Z, He R, Yu L, Meng N, Wang H, You J, Li J, Yam JWP, Xu Y, Cui Y. Roles and Molecular Mechanisms of Biomarkers in Hepatocellular Carcinoma with Microvascular Invasion: A Review. J Clin Transl Hepatol 2023; 11:1170-1183. [PMID: 37577231 PMCID: PMC10412705 DOI: 10.14218/jcth.2022.00013s] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 01/18/2023] [Accepted: 03/21/2023] [Indexed: 07/03/2023] Open
Abstract
Hepatocellular carcinoma (HCC) being a leading cause of cancer-related death, has high associated mortality and recurrence rates. It has been of great necessity and urgency to find effective HCC diagnosis and treatment measures. Studies have shown that microvascular invasion (MVI) is an independent risk factor for poor prognosis after hepatectomy. The abnormal expression of biomacromolecules such as circ-RNAs, lncRNAs, STIP1, and PD-L1 in HCC patients is strongly correlated with MVI. Deregulation of several markers mentioned in this review affects the proliferation, invasion, metastasis, EMT, and anti-apoptotic processes of HCC cells through multiple complex mechanisms. Therefore, these biomarkers may have an important clinical role and serve as promising interventional targets for HCC. In this review, we provide a comprehensive overview on the functions and regulatory mechanisms of MVI-related biomarkers in HCC.
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Affiliation(s)
- Xudong Zhao
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Yudan Wang
- Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Haoming Xia
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Shuqiang Liu
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Ziyue Huang
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Risheng He
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Liang Yu
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
- Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Nanfeng Meng
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Hang Wang
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Junqi You
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Jinglin Li
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Judy Wai Ping Yam
- Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Yi Xu
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
- Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Key Laboratory of Basic Pharmacology of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, China
- Key Laboratory of Functional and Clinical Translational Medicine, Fujian Province University, Xiamen Medical College, Xiamen, Fujian, China
- Jiangsu Province Engineering Research Center of Tumor Targeted Nano Diagnostic and Therapeutic Materials, Yancheng Teachers University, Yancheng, Jiangsu, China
- Key Laboratory of Biomarkers and In Vitro Diagnosis Translation of Zhejiang province, Hangzhou, Zhejiang, China
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, China
- State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, Guangdong, China
- Key Laboratory of Intelligent Pharmacy and Individualized Therapy of Huzhou, Department of Pharmacy, Changxing People’s Hospital, Changxing, Zhejiang, China
| | - Yunfu Cui
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
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Sun C, Wang Q, Hou L, Zhang R, Chen Y, Niu L. A contrast-enhanced ultrasound-based nomogram for the prediction of therapeutic efficiency of anti-PD-1 plus anti-VEGF agents in advanced hepatocellular carcinoma patients. Front Immunol 2023; 14:1229560. [PMID: 37575236 PMCID: PMC10413126 DOI: 10.3389/fimmu.2023.1229560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 07/11/2023] [Indexed: 08/15/2023] Open
Abstract
Background There is no study focusing on noninvasive predictors for the efficacy of sintilimab (anti-PD-1) plus IBI305 (a bevacizumab biosimilar) treatment in advanced hepatocellular carcinoma (HCC). Method A total of 33 patients with advanced HCC were prospectively enrolled and received sintilimab plus IBI305 treatment from November 2018 to October 2019. Baseline characteristics including clinical data, laboratory data, and tumor features based on pretreatment CT/MR were collected. Meanwhile, pretreatment contrast-enhanced ultrasound (CEUS) for target tumor was performed and quantitative parameters were derived from time-intensity curves (TICs). A nomogram was developed based on the variables identified by the univariable and multivariable logistic regression analysis. The discrimination, calibration, and clinical utility of the nomogram were evaluated. Results Tumor embolus and grad ratio were significant variables related to the efficacy of sintilimab plus IBI305 strategy. The nomogram based on these two variables achieved an excellent predictive performance with an area under curve (AUC) of 0.909 (95% CI, 0.813-1). A bootstrapping for 500 repetitions was performed to validate this model and the AUC of the bootstrap model was 0.91 (95% CI, 0.8-0.98). The calibration curve and decision curve analysis (DCA) showed that the nomogram had a good consistency and clinical utility. Conclusions This study has established and validated a nomogram by incorporating the quantitative parameters of pretreatment CEUS and baseline clinical characteristics to predict the anti-PD-1 plus anti-VEGF treatment efficacy in advanced HCC patients.
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Affiliation(s)
- Chao Sun
- Department of Ultrasound, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qian Wang
- Department of Ultrasound, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lu Hou
- Department of Radiotherapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Rui Zhang
- Department of Ultrasound, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yu Chen
- Department of Ultrasound, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lijuan Niu
- Department of Ultrasound, 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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Kotsari M, Dimopoulou V, Koskinas J, Armakolas A. Immune System and Hepatocellular Carcinoma (HCC): New Insights into HCC Progression. Int J Mol Sci 2023; 24:11471. [PMID: 37511228 PMCID: PMC10380581 DOI: 10.3390/ijms241411471] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 07/12/2023] [Accepted: 07/13/2023] [Indexed: 07/30/2023] Open
Abstract
According to the WHO's recently released worldwide cancer data for 2020, liver cancer ranks sixth in morbidity and third in mortality among all malignancies. Hepatocellular carcinoma (HCC), the most common kind of liver cancer, accounts approximately for 80% of all primary liver malignancies and is one of the leading causes of death globally. The intractable tumor microenvironment plays an important role in the development and progression of HCC and is one of three major unresolved issues in clinical practice (cancer recurrence, fatal metastasis, and the refractory tumor microenvironment). Despite significant advances, improved molecular and cellular characterization of the tumor microenvironment is still required since it plays an important role in the genesis and progression of HCC. The purpose of this review is to present an overview of the HCC immune microenvironment, distinct cellular constituents, current therapies, and potential immunotherapy methods.
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Affiliation(s)
- Maria Kotsari
- Physiology Laboratory, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Vassiliki Dimopoulou
- Physiology Laboratory, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - John Koskinas
- B' Department of Medicine, Hippokration Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Athanasios Armakolas
- Physiology Laboratory, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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Wang MD, Xiang H, Hong TY, Mierxiati A, Yan FH, Zhang L, Wang C. Integrated analysis of intratumoral biomarker and tumor-associated macrophage to improve the prognosis prediction in cancer patients. BMC Cancer 2023; 23:593. [PMID: 37370037 DOI: 10.1186/s12885-023-11027-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Accepted: 05/30/2023] [Indexed: 06/29/2023] Open
Abstract
BACKGROUND The lack of effective and accurate predictive indicators remains a major bottleneck for the improvement of the prognosis of patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Hepatitis B virus X (HBx) has been widely suggested as a critical pathogenic protein for HBV-driven liver carcinogenesis, while tumor-associated macrophage (TAM) infiltration is also closely related to the tumorigenesis and progression of HCC. However, few studies have determined whether combining HBx expression with TAM populations could increase the accuracy of prognostic prediction for HBV-related HCC. METHODS The study cohort enrolling 251 patients with HBV-related HCC was randomly split into a training and a validation group (ratio 1:1). The expression levels of HBx and TAM marker CD68 in HCC samples were detected by immunohistochemistry. Kaplan-Meier curves, Cox regression and Harrell's concordance index (C-index) analysis were conducted to evaluate the prognostic significance of these indicators alone or in combination. RESULTS The expression level of HBx was strongly correlated with CD68+ TAM infiltration in HCC tissues. Elevated HBx or CD68 expression indicated poorer overall survival (OS) and progression-free survival (PFS) after hepatectomy, and both of them were independent risk factors for postoperative survival. Meanwhile, patients with both high HBx and CD68 levels had worst clinical outcomes. Moreover, integrating HBx and CD68 expression with clinical indicators (tumor size and micro-vascular invasion) showed the best prognostic potential with highest C-index value for survival predictivity, and this proposed model also performed better than several conventional classifications of HCC. CONCLUSION Combining the expression of intratumoral HBx, CD68+ TAM population and clinical variables could enable better prognostication for HBV-related HCC after hepatectomy, thus providing novel insights into developing more effective clinical prediction model based on both molecular phenotypes and tumor-immune microenvironment.
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Affiliation(s)
- Ming-Da Wang
- Shanghai Health Commission Key Lab of Artificial Intelligence-Based Management of Inflammation and Chronic Diseases, Gongli Hospital, Navy Medical University, 219 Miaopu Road, Shanghai, 200135, China
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Navy Medical University, Shanghai, 200433, China
| | - Hao Xiang
- The Third Affiliated Hospital of Zunyi Medical University, The First People's Hospital of Zunyi), Guizhou, 563000, China
| | - Tian-Yu Hong
- Shanghai Health Commission Key Lab of Artificial Intelligence-Based Management of Inflammation and Chronic Diseases, Gongli Hospital, Navy Medical University, 219 Miaopu Road, Shanghai, 200135, China
| | - Abudurexiti Mierxiati
- Shanghai Health Commission Key Lab of Artificial Intelligence-Based Management of Inflammation and Chronic Diseases, Gongli Hospital, Navy Medical University, 219 Miaopu Road, Shanghai, 200135, China
| | - Fei-Hu Yan
- Department of Colorectal Surgery, Shanghai Changhai Hospital, Navy Medical University, Shanghai, 200433, China.
| | - Ling Zhang
- Department of Obstetrics and Gynecology, School of Medicine, Chengdu Women's and Children's Central Hospital, University of Electronic Science and Technology of China, Sichuan, 610000, China.
| | - Chao Wang
- Shanghai Health Commission Key Lab of Artificial Intelligence-Based Management of Inflammation and Chronic Diseases, Gongli Hospital, Navy Medical University, 219 Miaopu Road, Shanghai, 200135, China.
- Department of Urinary Surgery, Gongli Hospital, Navy Medical University, Shanghai, 200135, China.
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21
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De Re V, Tornesello ML, Racanelli V, Prete M, Steffan A. Non-Classical HLA Class 1b and Hepatocellular Carcinoma. Biomedicines 2023; 11:1672. [PMID: 37371767 PMCID: PMC10296335 DOI: 10.3390/biomedicines11061672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 06/02/2023] [Accepted: 06/06/2023] [Indexed: 06/29/2023] Open
Abstract
A number of studies are underway to gain a better understanding of the role of immunity in the pathogenesis of hepatocellular carcinoma and to identify subgroups of individuals who may benefit the most from systemic therapy according to the etiology of their tumor. Human leukocyte antigens play a key role in antigen presentation to T cells. This is fundamental to the host's defense against pathogens and tumor cells. In addition, HLA-specific interactions with innate lymphoid cell receptors, such those present on natural killer cells and innate lymphoid cell type 2, have been shown to be important activators of immune function in the context of several liver diseases. More recent studies have highlighted the key role of members of the non-classical HLA-Ib and the transcript adjacent to the HLA-F locus, FAT10, in hepatocarcinoma. The present review analyzes the major contribution of these molecules to hepatic viral infection and hepatocellular prognosis. Particular attention has been paid to the association of natural killer and Vδ2 T-cell activation, mediated by specific HLA class Ib molecules, with risk assessment and novel treatment strategies to improve immunotherapy in HCC.
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Affiliation(s)
- Valli De Re
- Immunopathology and Cancer Biomarkers Unit, Centro di Riferimento Oncologico di Aviano (CRO), Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), 33081 Aviano, Italy;
| | - Maria Lina Tornesello
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, 80131 Naples, Italy;
| | - Vito Racanelli
- Department of Interdisciplinary Medicine, School of Medicine, ‘Aldo Moro’ University of Bari, 70124 Bari, Italy; (V.R.); (M.P.)
| | - Marcella Prete
- Department of Interdisciplinary Medicine, School of Medicine, ‘Aldo Moro’ University of Bari, 70124 Bari, Italy; (V.R.); (M.P.)
| | - Agostino Steffan
- Immunopathology and Cancer Biomarkers Unit, Centro di Riferimento Oncologico di Aviano (CRO), Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), 33081 Aviano, Italy;
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22
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Taufalele PV, Wang W, Simmons AJ, Southard-Smith AN, Chen B, Greenlee JD, King MR, Lau KS, Hassane DC, Bordeleau F, Reinhart-King CA. Matrix stiffness enhances cancer-macrophage interactions and M2-like macrophage accumulation in the breast tumor microenvironment. Acta Biomater 2023; 163:365-377. [PMID: 35483629 PMCID: PMC9592676 DOI: 10.1016/j.actbio.2022.04.031] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Revised: 03/17/2022] [Accepted: 04/20/2022] [Indexed: 02/07/2023]
Abstract
The role of intratumor heterogeneity is becoming increasingly apparent in part due to expansion in single cell technologies. Clinically, tumor heterogeneity poses several obstacles to effective cancer therapy dealing with biomarker variability and treatment responses. Matrix stiffening is known to occur during tumor progression and contribute to pathogenesis in several cancer hallmarks, including tumor angiogenesis and metastasis. However, the effects of matrix stiffening on intratumor heterogeneity have not been thoroughly studied. In this study, we applied single-cell RNA sequencing to investigate the differences in the transcriptional landscapes between stiff and compliant MMTV-PyMT mouse mammary tumors. We found similar compositions of cancer and stromal subpopulations in compliant and stiff tumors but differential intercellular communication and a significantly higher concentration of tumor-promoting, M2-like macrophages in the stiffer tumor microenvironments. Interestingly, we found that cancer cells seeded on stiffer substrates recruited more macrophages. Furthermore, elevated matrix stiffness increased Colony Stimulating Factor 1 (CSF-1) expression in breast cancer cells and reduction of CSF-1 expression on stiffer substrates reduced macrophage recruitment. Thus, our results demonstrate that tissue phenotypes were conserved between stiff and compliant tumors but matrix stiffening altered cell-cell interactions which may be responsible for shifting the phenotypic balance of macrophages residing in the tumor microenvironment towards a pro-tumor progression M2 phenotype. STATEMENT OF SIGNIFICANCE: Cells within tumors are highly heterogeneous, posing challenges with treatment and recurrence. While increased tissue stiffness can promote several hallmarks of cancer, its effects on tumor heterogeneity are unclear. We used single-cell RNA sequencing to investigate the differences in the transcriptional landscapes between stiff and compliant MMTV-PyMT mouse mammary tumors. We found similar compositions of cancer and stromal subpopulations in compliant and stiff tumors but differential intercellular communication and a significantly higher concentration of tumor-promoting, M2-like macrophages in the stiffer tumor microenvironments. Using a biomaterial-based platform, we found that cancer cells seeded on stiffer substrates recruited more macrophages, supporting our in vivo findings. Together, our results demonstrate a key role of matrix stiffness in affecting cell-cell communication and macrophage recruitment.
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Affiliation(s)
- Paul V Taufalele
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA
| | - Wenjun Wang
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA
| | - Alan J Simmons
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Austin N Southard-Smith
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Bob Chen
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA; Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Joshua D Greenlee
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA
| | - Michael R King
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA
| | - Ken S Lau
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA; Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Duane C Hassane
- Department of Medicine, Weill Cornell Medicine, New York, NY, USA
| | - François Bordeleau
- Cancer Research Center and Centre de Recherche du CHU de Québec, Université Laval, Canada
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23
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Donne R, Lujambio A. The liver cancer immune microenvironment: Therapeutic implications for hepatocellular carcinoma. Hepatology 2023; 77:1773-1796. [PMID: 35989535 PMCID: PMC9941399 DOI: 10.1002/hep.32740] [Citation(s) in RCA: 297] [Impact Index Per Article: 148.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 07/26/2022] [Accepted: 08/18/2022] [Indexed: 12/19/2022]
Abstract
The liver is the sixth most common site of primary cancer in humans and the fourth leading cause of cancer-related death in the world. Hepatocellular carcinoma (HCC) accounts for 90% of liver cancers. HCC is a prevalent disease with a progression that is modulated by the immune system. Half of the patients with HCC receive systemic therapies, traditionally sorafenib or lenvatinib, as a first-line therapy. In the last few years, immune-checkpoint inhibitors (ICIs) have revolutionized cancer therapy and have gained an increased interest in the treatment of HCC. In 2020, the combination of atezolizumab (anti-programmed death-ligand 1) and bevacizumab (anti-vascular endothelial growth factor) improved overall survival over sorafenib, resulting in Food and Drug Administration (FDA) approval as a first-line treatment for patients with advanced HCC. Despite these major advances, a better molecular and cellular characterization of the tumor microenvironment is still needed because it has a crucial role in the development and progression of HCC. Inflamed (hot) and noninflamed (cold) HCC tumors and genomic signatures have been associated with response to ICIs. However, there are no additional biomarkers to guide clinical decision-making. Other immune-targeting strategies, such as adoptive T-cell transfer, vaccination, and virotherapy, are currently under development. This review provides an overview on the HCC immune microenvironment, different cellular players, current available immunotherapies, and potential immunotherapy modalities.
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Affiliation(s)
- Romain Donne
- Department of Oncological Sciences , Icahn School of Medicine at Mount Sinai , New York , New York , USA
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai , Tisch Cancer Institute , New York , New York , USA
- Icahn School of Medicine at Mount Sinai , The Precision Immunology Institute , New York , New York , USA
| | - Amaia Lujambio
- Department of Oncological Sciences , Icahn School of Medicine at Mount Sinai , New York , New York , USA
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai , Tisch Cancer Institute , New York , New York , USA
- Icahn School of Medicine at Mount Sinai , The Precision Immunology Institute , New York , New York , USA
- Graduate School of Biomedical Sciences , Icahn School of Medicine at Mount Sinai , New York , New York , USA
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24
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Liu P, Kong L, Liu Y, Li G, Xie J, Lu X. A key driver to promote HCC: Cellular crosstalk in tumor microenvironment. Front Oncol 2023; 13:1135122. [PMID: 37007125 PMCID: PMC10050394 DOI: 10.3389/fonc.2023.1135122] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Accepted: 02/23/2023] [Indexed: 03/17/2023] Open
Abstract
Liver cancer is the third greatest cause of cancer-related mortality, which of the major pathological type is hepatocellular carcinoma (HCC) accounting for more than 90%. HCC is characterized by high mortality and is predisposed to metastasis and relapse, leading to a low five-year survival rate and poor clinical prognosis. Numerous crosstalk among tumor parenchymal cells, anti-tumor cells, stroma cells, and immunosuppressive cells contributes to the immunosuppressive tumor microenvironment (TME), in which the function and frequency of anti-tumor cells are reduced with that of associated pro-tumor cells increasing, accordingly resulting in tumor malignant progression. Indeed, sorting out and understanding the signaling pathways and molecular mechanisms of cellular crosstalk in TME is crucial to discover more key targets and specific biomarkers, so that develop more efficient methods for early diagnosis and individualized treatment of liver cancer. This piece of writing offers insight into the recent advances in HCC-TME and reviews various mechanisms that promote HCC malignant progression from the perspective of mutual crosstalk among different types of cells in TME, aiming to assist in identifying the possible research directions and methods in the future for discovering new targets that could prevent HCC malignant progression.
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Affiliation(s)
- Pengyue Liu
- Clinical Medical College, North China University of Science and Technology, Tangshan, China
| | - Lingyu Kong
- Department of Traditional Chinese Medicine, Affiliated Hospital of North China University of Science and Technology, Tangshan, China
| | - Ying Liu
- Department of Clinical Skills Training Center, Tangshan Gongren Hospital, Tangshan, China
| | - Gang Li
- Department of Clinical Laboratory, Tangshan Maternal and Child Health Care Hospital, Tangshan, China
| | - Jianjia Xie
- Department of Clinical Laboratory, Tangshan Maternal and Child Health Care Hospital, Tangshan, China
| | - Xin Lu
- Clinical Medical College, North China University of Science and Technology, Tangshan, China
- Department of Clinical Laboratory, Tangshan Maternal and Child Health Care Hospital, Tangshan, China
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25
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Vonderlin J, Chavakis T, Sieweke M, Tacke F. The Multifaceted Roles of Macrophages in NAFLD Pathogenesis. Cell Mol Gastroenterol Hepatol 2023; 15:1311-1324. [PMID: 36907380 PMCID: PMC10148157 DOI: 10.1016/j.jcmgh.2023.03.002] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 03/03/2023] [Accepted: 03/03/2023] [Indexed: 03/14/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the liver manifestation of the metabolic syndrome. NAFLD constitutes a spectrum of pathologies ranging from simple hepatic steatosis (nonalcoholic fatty liver) to the more progressive form of steatohepatitis and fibrosis, which can culminate in liver cirrhosis and hepatocellular carcinoma. Macrophages play multiple roles in the context of NAFLD pathogenesis by regulating inflammatory responses and metabolic homeostasis in the liver and thereby may represent an attractive therapeutic target. Advances in high-resolution methods have highlighted the extraordinary heterogeneity and plasticity of hepatic macrophage populations and activation states thereof. Harmful/disease-promoting as well as beneficial/restorative macrophage phenotypes co-exist and are dynamically regulated, thus this complexity must be taken into consideration in strategies concerning therapeutic targeting. Macrophage heterogeneity in NAFLD includes their distinct ontogeny (embryonic Kupffer cells vs bone marrow-/monocyte-derived macrophages) as well as their functional phenotype, for example, inflammatory phagocytes, lipid- and scar-associated macrophages, or restorative macrophages. Here, we discuss the multifaceted role of macrophages in the pathogenesis of NAFLD in steatosis, steatohepatitis, and transition to fibrosis and hepatocellular carcinoma, focusing on both their beneficial and maladaptive functions at different disease stages. We also highlight the systemic aspect of metabolic dysregulation and illustrate the contribution of macrophages in the reciprocal crosstalk between organs and compartments (eg, the gut-liver axis, adipose tissue, and cardiohepatic metabolic interactions). Furthermore, we discuss the current state of development of pharmacologic treatment options targeting macrophage biology.
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Affiliation(s)
- Joscha Vonderlin
- Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Triantafyllos Chavakis
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Michael Sieweke
- Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany.
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26
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Kohlhepp MS, Liu H, Tacke F, Guillot A. The contradictory roles of macrophages in non-alcoholic fatty liver disease and primary liver cancer-Challenges and opportunities. Front Mol Biosci 2023; 10:1129831. [PMID: 36845555 PMCID: PMC9950415 DOI: 10.3389/fmolb.2023.1129831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 01/31/2023] [Indexed: 02/12/2023] Open
Abstract
Chronic liver diseases from varying etiologies generally lead to liver fibrosis and cirrhosis. Among them, non-alcoholic fatty liver disease (NAFLD) affects roughly one-quarter of the world population, thus representing a major and increasing public health burden. Chronic hepatocyte injury, inflammation (non-alcoholic steatohepatitis, NASH) and liver fibrosis are recognized soils for primary liver cancer, particularly hepatocellular carcinoma (HCC), being the third most common cause for cancer-related deaths worldwide. Despite recent advances in liver disease understanding, therapeutic options on pre-malignant and malignant stages remain limited. Thus, there is an urgent need to identify targetable liver disease-driving mechanisms for the development of novel therapeutics. Monocytes and macrophages comprise a central, yet versatile component of the inflammatory response, fueling chronic liver disease initiation and progression. Recent proteomic and transcriptomic studies performed at singular cell levels revealed a previously overlooked diversity of macrophage subpopulations and functions. Indeed, liver macrophages that encompass liver resident macrophages (also named Kupffer cells) and monocyte-derived macrophages, can acquire a variety of phenotypes depending on microenvironmental cues, and thus exert manifold and sometimes contradictory functions. Those functions range from modulating and exacerbating tissue inflammation to promoting and exaggerating tissue repair mechanisms (i.e., parenchymal regeneration, cancer cell proliferation, angiogenesis, fibrosis). Due to these central functions, liver macrophages represent an attractive target for the treatment of liver diseases. In this review, we discuss the multifaceted and contrary roles of macrophages in chronic liver diseases, with a particular focus on NAFLD/NASH and HCC. Moreover, we discuss potential therapeutic approaches targeting liver macrophages.
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27
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Feng GY, Shi ZR, Zhao YF, Chen K, Tao J, Wei XF, Cheng Y. Therapeutic effect of postoperative adjuvant transcatheter arterial chemoembolization based on the neutrophil-to-lymphocyte ratio. Front Surg 2023; 9:1072451. [PMID: 36684128 PMCID: PMC9852644 DOI: 10.3389/fsurg.2022.1072451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 11/21/2022] [Indexed: 01/09/2023] Open
Abstract
Aim To evaluate the feasibility of the preoperative neutrophil-to-lymphocyte ratio (NLR) as an index to guide postoperative adjuvant transcatheter arterial chemoembolization (PA-TACE) in patients with liver cancer. Methods We recruited a total of 166 patients with liver cancer who underwent surgery alone or surgery plus PA-TACE between January 2013 and June 2017 and compared the 1, 2, and 3-year recurrence-free survival (RFS) and overall survival (OS) between patients with high and low NLRs, surgery and surgery plus PA-TACE groups, and relevant subgroups using the Kaplan-Meier method. We also evaluated the independent factors affecting the prognosis of liver cancer after surgery using a Cox risk ratio model and correlation between NLR levels and high-risk recurrence factors of liver cancer with logistic regression analysis. Results The 1, 2, and 3-year RFS rates were all significantly higher in the low-NLR group compared to the high-NLR group (P < 0.05). However, the 1, 2, and 3-year OS rates were similar in the low- and high-NLR groups (P > 0.05). After propensity score matching, the 1, 2, and 3-year RFS and OS rates were significantly better in patients treated with surgery plus PA-TACE compared with surgery alone (P < 0.05). The 1, 2, and 3-year RFS and OS rates were also significantly better in the surgery plus PA-TACE subgroup compared with the surgery-alone subgroup in the high-NLR group (P < 0.05), but there was no significant difference in RFS or OS between the surgery plus PA-TACE and surgery-alone subgroups at 1, 2, and 3 years in the low-NLR group (P > 0.05). Multivariate analysis in the high-NLR group showed that a poorly differentiated or undifferentiated tumor was an independent risk factor for postoperative RFS. Multiple tumors were an independent risk factor for postoperative OS (P < 0.05), while PA-TACE was an independent protective factor for postoperative RFS and OS (P < 0.05). In the low-NLR group, AFP > 400 µg/L was an independent risk factor for postoperative OS (P < 0.05). Multivariate logistic regression indicated that patients with a maximum tumor diameter of >5 cm were at increased risk of having high NLR levels compared to patients with a maximum tumor diameter of <5 cm (P < 0.05). Conclusion PA-TACE can improve the prognosis of patients with a high preoperative NLR (≥2.5), but has no obvious benefit in patients with low preoperative NLR (<2.5). This may provide a reference for clinical selection of PA-TACE.
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Affiliation(s)
- Guo-Ying Feng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Department of Hepatobiliary Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Zheng-Rong Shi
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yu-Fei Zhao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Kai Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jie Tao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xu-Fu Wei
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yu Cheng
- Nursing Department, University-Town Hospital of Chongqing Medical University, Chongqing, China
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Kulle A, Thanabalasuriar A, Cohen TS, Szydlowska M. Resident macrophages of the lung and liver: The guardians of our tissues. Front Immunol 2022; 13:1029085. [PMID: 36532044 PMCID: PMC9750759 DOI: 10.3389/fimmu.2022.1029085] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 11/09/2022] [Indexed: 12/05/2022] Open
Abstract
Resident macrophages play a unique role in the maintenance of tissue function. As phagocytes, they are an essential first line defenders against pathogens and much of the initial characterization of these cells was focused on their interaction with viral and bacterial pathogens. However, these cells are increasingly recognized as contributing to more than just host defense. Through cytokine production, receptor engagement and gap junction communication resident macrophages tune tissue inflammatory tone, influence adaptive immune cell phenotype and regulate tissue structure and function. This review highlights resident macrophages in the liver and lung as they hold unique roles in the maintenance of the interface between the circulatory system and the external environment. As such, we detail the developmental origin of these cells, their contribution to host defense and the array of tools these cells use to regulate tissue homeostasis.
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Affiliation(s)
- Amelia Kulle
- Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada
| | | | - Taylor S. Cohen
- Late Stage Development, Vaccines and Immune Therapies (V&I), BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, United States
| | - Marta Szydlowska
- Bacteriology and Vaccine Discovery, Research and Early Development, Vaccines and Immune Therapies (V&I), BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, United States
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He M, Gu W, Gao Y, Liu Y, Liu J, Li Z. Molecular subtypes and a prognostic model for hepatocellular carcinoma based on immune- and immunogenic cell death-related lncRNAs. Front Immunol 2022; 13:1043827. [PMID: 36479122 PMCID: PMC9720162 DOI: 10.3389/fimmu.2022.1043827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 11/04/2022] [Indexed: 11/22/2022] Open
Abstract
Background Accumulating evidence shows that immunogenic cell death (ICD) enhances immunotherapy effectiveness. In this study, we aimed to develop a prognostic model combining ICD, immunity, and long non-coding RNA biomarkers for predicting hepatocellular carcinoma (HCC) outcomes. Methods Immune- and immunogenic cell death-related lncRNAs (IICDLs) were identified from The Cancer Genome Atlas and Ensembl databases. IICDLs were extracted based on the results of differential expression and univariate Cox analyses and used to generate molecular subtypes using ConsensusClusterPlus. We created a prognostic signature based on IICDLs and a nomogram based on risk scores. Clinical characteristics, immune landscapes, immune checkpoint blocking (ICB) responses, stemness, and chemotherapy responses were also analyzed for different molecular subtypes and risk groups. Result A total of 81 IICDLs were identified, 20 of which were significantly associated with overall survival (OS) in patients with HCC. Cluster analysis divided patients with HCC into two distinct molecular subtypes (C1 and C2), with patients in C1 having a shorter survival time than those in C2. Four IICDLs (TMEM220-AS1, LINC02362, LINC01554, and LINC02499) were selected to develop a prognostic model that was an independent prognostic factor of HCC outcomes. C1 and the high-risk group had worse OS (hazard ratio > 1.5, p < 0.01), higher T stage (p < 0.05), higher clinical stage (p < 0.05), higher pathological grade (p < 0.05), low immune cell infiltration (CD4+ T cells, B cells, macrophages, neutrophils, and myeloid dendritic cells), low immune checkpoint gene expression, poor response to ICB therapy, and high stemness. Different molecular subtypes and risk groups showed significantly different responses to several chemotherapy drugs, such as doxorubicin (p < 0.001), 5-fluorouracil (p < 0.001), gemcitabine (p < 0.001), and sorafenib (p < 0.01). Conclusion Our study identified molecular subtypes and a prognostic signature based on IICDLs that could help predict the clinical prognosis and treatment response in patients with HCC.
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Affiliation(s)
- Mingang He
- Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Wenchao Gu
- Department of Pulmonary and Critical Care Medicine, Shanghai Pudong New Area People’s Hospital, Shanghai, China
| | - Yang Gao
- Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Ying Liu
- Department of Pathology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Jie Liu
- Cancer Center, Shandong Public Health Clinical Center, Public Health Clinical Center Affiliated to Shandong University, Jinan, China,*Correspondence: Jie Liu, ; Zengjun Li,
| | - Zengjun Li
- Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China,*Correspondence: Jie Liu, ; Zengjun Li,
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Exosomal miR-452-5p Induce M2 Macrophage Polarization to Accelerate Hepatocellular Carcinoma Progression by Targeting TIMP3. J Immunol Res 2022; 2022:1032106. [PMID: 36164322 PMCID: PMC9508462 DOI: 10.1155/2022/1032106] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 06/17/2022] [Indexed: 12/04/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) cell-derived exosomes have shown effects on inducing M2 macrophage polarization and promoting HCC progression. MiR-452-5p was reported by recent studies to promote malignancy progression as an exosomal microRNA that secreted by HCC cells, of which the underlying mechanism remains unclear. Here, we further explored how miR-452-5p functions in HCC. Methods MiR-452-5p expressions in HCC cells was examined by in situ hybridization. Next, HCC cell lines were transfected with the mimics or the inhibitor of miR-452-5p. Transfected cells' biological behavior were analyzed by CCK-8, flow cytometry, and Transwell assay. Then, exosomes were purified from miR-452-5p inhibited or overexpressed HCC cells and cocultured with macrophages to examine the role of miR-452-5p in macrophage polarization. To examine the role of exosomal miR-452-5p on macrophage polarization and tumor growth. We also performed the dual-luciferase assay to explore the targeting relationship between miR-452-5p and TIMP3. Results The upregulation of miR-452-5p was identified in HCC. The effects of HCC cell-derived exosomes on accelerating HCC migration and invasion and inducing M2 macrophage polarization were confirmed, which were further enhanced after overexpressing miR-452-5p but neutralized after silencing miR-452-5p. In addition, in vivo experiments demonstrated the effect of miR-452-5p on accelerating HCC growth and metastasis. Also, we identified that TIMP3 overexpression inhibited the promoted cell invasion and migration by HCC cell-derived exosomes. Conclusion Exosomal miR-452-5p secreted from HCC cells could induce polarization of M2 macrophage and therefore stimulating HCC progression by targeting TIMP3. Thus, miR-452-5p might be a potential biomarker for HCC prognosis.
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Wang D, Ye Q, Gu H, Chen Z. The role of lipid metabolism in tumor immune microenvironment and potential therapeutic strategies. Front Oncol 2022; 12:984560. [PMID: 36172157 PMCID: PMC9510836 DOI: 10.3389/fonc.2022.984560] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Accepted: 08/01/2022] [Indexed: 11/20/2022] Open
Abstract
Aberrant lipid metabolism is nonnegligible for tumor cells to adapt to the tumor microenvironment (TME). It plays a significant role in the amount and function of immune cells, including tumor-associated macrophages, T cells, dendritic cells and marrow-derived suppressor cells. It is well-known that the immune response in TME is suppressed and lipid metabolism is closely involved in this process. Immunotherapy, containing anti-PD1/PDL1 therapy and adoptive T cell therapy, is a crucial clinical cancer therapeutic strategy nowadays, but they display a low-sensibility in certain cancers. In this review, we mainly discussed the importance of lipid metabolism in the formation of immunosuppressive TME, and explored the effectiveness and sensitivity of immunotherapy treatment by regulating the lipid metabolism.
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Affiliation(s)
- Danting Wang
- Department of Breast Surgery (Surgical Oncology), Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qizhen Ye
- Department of Breast Surgery (Surgical Oncology), Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Haochen Gu
- Department of Breast Surgery (Surgical Oncology), Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhigang Chen
- Department of Breast Surgery (Surgical Oncology), Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Second Affiliated Hospital, Zhejiang University, Hangzhou, China
- Cancer Centre, Zhejiang University, Hangzhou, China
- Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Integration of OV6 expression and CD68 + tumor-associated macrophages with clinical features better predicts the prognosis of patients with hepatocellular carcinoma. Transl Oncol 2022; 25:101509. [PMID: 36030750 PMCID: PMC9428913 DOI: 10.1016/j.tranon.2022.101509] [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: 05/06/2022] [Revised: 07/31/2022] [Accepted: 08/01/2022] [Indexed: 11/20/2022] Open
Abstract
BACKGROUND Reliable prognostic indicators for accurately predicting postoperative outcomes in Hepatocellular carcinoma (HCC) patients are lacking. Although cancer stem-like cells (CSCs) and tumor-associated macrophages (TAMs) in tumor microenvironment are implicated in the occurrence and development of HCC, whether the combination of CSC biomarkers and TAM populations could achieve better performance in predicting the prognosis of patients with HCC has been rarely reported. METHODS A total of 306 HCC patients were randomly divided into the training and validation cohorts at a 1:1 ratio, and the expression of OV6 and CD68 was assessed using immunohistochemistry in HCC samples. The prognostic value of these biomarkers for post-surgical survival and recurrence were evaluated by the curve of receiver operating characteristic and multivariate Cox regression analyses. RESULTS The density of OV6+ CSCs was positively correlated with the infiltration of CD68+ TAMs in HCC. Both high OV6 expression and CD68+ TAM infiltration was closely associated with poor overall survival (OS) and progression-free survival (PFS) of HCC patients. Moreover, overexpression of OV6 and infiltration of CD68+ TAMs were identified as independent prognostic factors for OS and PFS after liver resection. The integration of OV6 and CD68 with tumor size and microvascular invasion exhibited highest C-index value for survival predictivity in HCC patients than any other biomarkers or clinical indicators alone. CONCLUSION Incorporating intratumoral OV6 expression and CD68+ TAMs infiltration with established clinical indicators may serve as a promising prognostic signature for HCC, and could more accurately predict the clinical outcomes for HCC patients after liver resection.
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Sun W, Shen J, Liu J, Han K, Liang L, Gao Y. Gene Signature and Prognostic Value of Ubiquitin-Specific Proteases Members in Hepatocellular Carcinoma and Explored the Immunological Role of USP36. FRONT BIOSCI-LANDMRK 2022; 27:190. [PMID: 35748266 DOI: 10.31083/j.fbl2706190] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/06/2022] [Accepted: 05/26/2022] [Indexed: 11/06/2022]
Abstract
BACKGROUND Ubiquitination is one of the most common post-translational modifications in cells and dysregulation is closely associated with the development of cancer. However, a comprehensive analysis of the role of ubiquitination in hepatocellular carcinoma (HCC) is still lacking. In this study we analyzed expression and prognostic value of Ubiquitin-Specific Proteases (USPs) in HCC, and the immunological role of USP36 in HCC. METHODS Expression data, prognostic data, and DNA methylation data in cases of HCC were obtained from the cancer genome atlas (TCGA). Overexpression of USP36 in HCC was confirmed in the gene expression omnibus (GEO) database and verified by quantitative PCR in 10 pairs of HCC samples. ULCAN was used to analyze the correlation between USP36 and clinicopathological features. TIMER2.0 and DriverDBv3 were used to analyze the USP36 mutational profile. GSEA analysis explored the potential signaling pathways of USP36 affecting HCC. The immune and stromal scores of HCC samples were calculated using the ESTIMATE algorithm. TIMER1.0 was used to explore the correlation between USP36 and immune cell infiltration. Finally, we analyzed the correlation of USP36 expression with immune checkpoint molecules and determined the IC50 values of 6 chemotherapeutic drugs using the pRRophetic software package. RESULTS Most USPs are abnormally expressed in HCC, among which USP36 and USP39 are most closely associated with HCC prognosis. We also found that USP36 is associated with TP53 mutational status. GSEA analysis indicated that USP36 may affect HCC progression through the dysregulation of various pathways such as ubiquitin-mediated proteolysis. USP36 expression positively correlated with both macrophage infiltration levels and multiple immune checkpoint molecules. Finally, chemosensitivity analysis indicated that chemosensitivity was lower in cells within the USP36 high expression group. CONCLUSIONS Most USPs are abnormally expressed in HCC. Overexpression of USP36 in HCC is closely related to poor prognosis. In particular, the unique immunological role of USP36 may have potential clinical application value.
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Affiliation(s)
- Weijie Sun
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, 230022 Hefei, Anhui, China
| | - Jiapei Shen
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, 230022 Hefei, Anhui, China
| | - Jiaying Liu
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, 230022 Hefei, Anhui, China
| | - Kexing Han
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, 230022 Hefei, Anhui, China
| | - Leilei Liang
- Department of Gynecologic Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021 Beijing, China
| | - Yufeng Gao
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, 230022 Hefei, Anhui, China
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Downregulation of miR-122-5p Activates Glycolysis via PKM2 in Kupffer Cells of Rat and Mouse Models of Non-Alcoholic Steatohepatitis. Int J Mol Sci 2022; 23:ijms23095230. [PMID: 35563621 PMCID: PMC9101520 DOI: 10.3390/ijms23095230] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 04/29/2022] [Accepted: 05/05/2022] [Indexed: 02/05/2023] Open
Abstract
Non-alcoholic steatohepatitis (NASH) has pathological characteristics similar to those of alcoholic hepatitis, despite the absence of a drinking history. The greatest threat associated with NASH is its progression to cirrhosis and hepatocellular carcinoma. The pathophysiology of NASH is not fully understood to date. In this study, we investigated the pathophysiology of NASH from the perspective of glycolysis and the Warburg effect, with a particular focus on microRNA regulation in liver-specific macrophages, also known as Kupffer cells. We established NASH rat and mouse models and evaluated various parameters including the liver-to-body weight ratio, blood indexes, and histopathology. A quantitative phosphoproteomic analysis of the NASH rat model livers revealed the activation of glycolysis. Western blotting and immunohistochemistry results indicated that the expression of pyruvate kinase muscle 2 (PKM2), a rate-limiting enzyme of glycolysis, was upregulated in the liver tissues of both NASH models. Moreover, increases in PKM2 and p-PKM2 were observed in the early phase of NASH. These observations were partially induced by the downregulation of microRNA122-5p (miR-122-5p) and occurred particularly in the Kupffer cells. Our results suggest that the activation of glycolysis in Kupffer cells during NASH was partially induced by the upregulation of PKM2 via miR-122-5p suppression.
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Li S, Yu J, Huber A, Kryczek I, Wang Z, Jiang L, Li X, Du W, Li G, Wei S, Vatan L, Szeliga W, Chinnaiyan AM, Green MD, Cieslik M, Zou W. Metabolism drives macrophage heterogeneity in the tumor microenvironment. Cell Rep 2022; 39:110609. [PMID: 35385733 PMCID: PMC9052943 DOI: 10.1016/j.celrep.2022.110609] [Citation(s) in RCA: 74] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 01/04/2022] [Accepted: 03/11/2022] [Indexed: 12/18/2022] Open
Abstract
Tumor-associated macrophages (TAMs) are a major cellular component in the tumor microenvironment (TME). However, the relationship between the phenotype and metabolic pattern of TAMs remains poorly understood. We performed single-cell transcriptome profiling on hepatic TAMs from mice bearing liver metastatic tumors. We find that TAMs manifest high heterogeneity at the levels of transcription, development, metabolism, and function. Integrative analyses and validation experiments indicate that increased purine metabolism is a feature of TAMs with pro-tumor and terminal differentiation phenotypes. Like mouse TAMs, human TAMs are highly heterogeneous. Human TAMs with increased purine metabolism exhibit a pro-tumor phenotype and correlate with poor therapeutic efficacy to immune checkpoint blockade. Altogether, our work demonstrates that TAMs are developmentally, metabolically, and functionally heterogeneous and purine metabolism may be a key metabolic feature of a pro-tumor macrophage population.
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Affiliation(s)
- Shasha Li
- Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA; Department of Computational Medicine and Bioinformatics, University of Michigan School of Medicine, Ann Arbor, MI, USA
| | - Jiali Yu
- Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA
| | - Amanda Huber
- Department of Radiation Oncology, University of Michigan School of Medicine, Ann Arbor, MI, USA
| | - Ilona Kryczek
- Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA
| | - Zhuwen Wang
- Department of Radiation Oncology, University of Michigan School of Medicine, Ann Arbor, MI, USA
| | - Long Jiang
- Department of Radiation Oncology, University of Michigan School of Medicine, Ann Arbor, MI, USA
| | - Xiong Li
- Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA
| | - Wan Du
- Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA
| | - Gaopeng Li
- Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA
| | - Shuang Wei
- Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA
| | - Linda Vatan
- Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA
| | - Wojciech Szeliga
- Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA
| | - Arul M Chinnaiyan
- Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA; Howard Hughes Medical Institute, University of Michigan School of Medicine, Ann Arbor, MI, USA
| | - Michael D Green
- Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA; Department of Radiation Oncology, University of Michigan School of Medicine, Ann Arbor, MI, USA; Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI, USA
| | - Marcin Cieslik
- Department of Computational Medicine and Bioinformatics, University of Michigan School of Medicine, Ann Arbor, MI, USA; Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA.
| | - Weiping Zou
- Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA; Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA; Graduate Program in Immunology, University of Michigan School of Medicine, Ann Arbor, MI, USA; Graduate Program in Cancer Biology, University of Michigan School of Medicine, Ann Arbor, MI, USA.
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Hu Z, Yin Y, Jiang J, Yan C, Wang Y, Wang D, Li L. Exosomal miR-142-3p secreted by hepatitis B virus (HBV)-hepatocellular carcinoma (HCC) cells promotes ferroptosis of M1-type macrophages through SLC3A2 and the mechanism of HCC progression. J Gastrointest Oncol 2022; 13:754-767. [PMID: 35557596 PMCID: PMC9086054 DOI: 10.21037/jgo-21-916] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Accepted: 03/10/2022] [Indexed: 08/18/2023] Open
Abstract
BACKGROUND Most patients with hepatitis B virus (HBV) infection will develop hepatocellular carcinoma (HCC). This study aimed to explore the potential mechanism of miR-142-3p in HCC caused by HBV infection. METHODS HepG2 cells and M1 macrophages were cocultured and then infected with HBV to establish an in vitro model. MicroRNA (miRNA) and messenger RNA (mRNA) expression was analyzed by quantitative reverse transcription polymerase chain reaction (RT-qPCR) and Western blot. The protein expressions of COX2, ACSL4, PTGS2, GPX4, and NOX1 were analyzed by Western blot. Flow cytometry and TUNEL assays were used to assess cell reactive oxygen species (ROS) and ferroptosis, respectively. Cell invasion and migration were measured by Transwell assay. To evaluate the ferroptosis of M1-type macrophages, glutathione (GSH), malondialdehyde (MDA), and Fe2+ content was detected by corresponding kits. Dual luciferase reporter gene detection verified the targeting relationship between miR-142-3p and SLC3A2. RESULTS MiR-142-3p was highly expressed in HBV-infected HCC patients and HBV-infected M1-type macrophages. Inhibition of miR-142-3p or overexpression of SLC3A2 reversed ferroptosis and inhibited the proliferation, migration, and invasion of HCC cells. CONCLUSIONS Our findings indicated that miR-142-3p promoted HBV-infected M1-type macrophage ferroptosis through SLC3A2, affecting the production of GSH, MDA, and Fe2+ and accelerating the development of HCC. The regulation of miR-142-3p and its target genes will help to clarify the pathogenesis of HCC induced by HBV infection and provide new theoretical foundations and therapeutic targets.
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Affiliation(s)
- Zongqiang Hu
- Hepato-Pancreato-Biliary Surgery Department, The First People’s Hospital of Kunming & The Calmette Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Yanfeng Yin
- The Central Laboratory, The First People’s Hospital of Kunming & The Calmette Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Jie Jiang
- Hepato-Pancreato-Biliary Surgery Department, The First People’s Hospital of Kunming & The Calmette Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Chuntao Yan
- The Central Laboratory, The First People’s Hospital of Kunming & The Calmette Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Yiting Wang
- The Central Laboratory, The First People’s Hospital of Kunming & The Calmette Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Dongdong Wang
- Hepato-Pancreato-Biliary Surgery Department, The First People’s Hospital of Kunming & The Calmette Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Li Li
- Hepato-Pancreato-Biliary Surgery Department, The First People’s Hospital of Kunming & The Calmette Affiliated Hospital of Kunming Medical University, Kunming, China
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Tumor Microenvironment of Hepatocellular Carcinoma: Challenges and Opportunities for New Treatment Options. Int J Mol Sci 2022; 23:ijms23073778. [PMID: 35409139 PMCID: PMC8998420 DOI: 10.3390/ijms23073778] [Citation(s) in RCA: 106] [Impact Index Per Article: 35.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/25/2022] [Accepted: 03/26/2022] [Indexed: 02/06/2023] Open
Abstract
The prevalence of liver cancer is constantly rising, with increasing incidence and mortality in Europe and the USA in recent decades. Among the different subtypes of liver cancers, hepatocellular carcinoma (HCC) is the most commonly diagnosed liver cancer. Besides advances in diagnosis and promising results of pre-clinical studies, HCC remains a highly lethal disease. In many cases, HCC is an effect of chronic liver inflammation, which leads to the formation of a complex tumor microenvironment (TME) composed of immune and stromal cells. The TME of HCC patients is a challenge for therapies, as it is involved in metastasis and the development of resistance. However, given that the TME is an intricate system of immune and stromal cells interacting with cancer cells, new immune-based therapies are being developed to target the TME of HCC. Therefore, understanding the complexity of the TME in HCC will provide new possibilities to design novel and more effective immunotherapeutics and combinatorial therapies to overcome resistance to treatment. In this review, we describe the role of inflammation during the development and progression of HCC by focusing on TME. We also describe the most recent therapeutic advances for HCC and possible combinatorial treatment options.
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She S, Ren L, Chen P, Wang M, Chen D, Wang Y, Chen H. Functional Roles of Chemokine Receptor CCR2 and Its Ligands in Liver Disease. Front Immunol 2022; 13:812431. [PMID: 35281057 PMCID: PMC8913720 DOI: 10.3389/fimmu.2022.812431] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 02/08/2022] [Indexed: 12/12/2022] Open
Abstract
Chemokines are a family of cytokines that orchestrate the migration and positioning of immune cells within tissues and are critical for the function of the immune system. CCR2 participates in liver pathology, including acute liver injury, chronic hepatitis, fibrosis/cirrhosis, and tumor progression, by mediating the recruitment of immune cells to inflammation and tumor sites. Although a variety of chemokines have been well studied in various diseases, there is no comprehensive review presenting the roles of all known chemokine ligands of CCR2 (CCL2, CCL7, CCL8, CCL12, CCL13, CCL16, and PSMP) in liver disease, and this review aims to fill this gap. The introduction of each chemokine includes its discovery, its corresponding chemotactic receptors, physiological functions and roles in inflammation and tumors, and its impact on different immune cell subgroups.
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Affiliation(s)
- Shaoping She
- Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People’s Hospital, Beijing, China
| | - Liying Ren
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Pu Chen
- Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People’s Hospital, Beijing, China
| | - Mingyang Wang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Dongbo Chen
- Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People’s Hospital, Beijing, China
| | - Ying Wang
- Department of Immunology, School of Basic Medical Sciences, and NHC Key Laboratory of Medical Immunology, Peking University, Beijing, China
| | - Hongsong Chen
- Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People’s Hospital, Beijing, China
- *Correspondence: Hongsong Chen,
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IL-2 Modulates TAMs Derived Exosomal MiRNAs to Ameliorate Hepatocellular Carcinoma Development and Progression. JOURNAL OF ONCOLOGY 2022; 2022:3445350. [PMID: 36284632 PMCID: PMC9588329 DOI: 10.1155/2022/3445350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Accepted: 12/20/2021] [Indexed: 11/18/2022]
Abstract
Background. Interleukin-2 (IL-2) is proved to play an irreplaceable role in antitumor regulation in numerous experimental and clinical trials. Tumor-associated macrophages (TAMs) are able to release exosomes to promote the development and progression of hepatocellular carcinoma (HCC) as essential component of microenvironment. In this study, our intention is to explore the effects of the exosomes from TAMs with IL-2 treatment on HCC development. TAMs were collected and cultured from HCC tissues. The exosomes from the TAMs treated with IL-2 (ExoIL2-TAM) or not (ExoTAM) were identified and used to treat HCC cells in vivo and in vitro. The proliferation, apoptosis, and metastasis of HCC cells were measured. The changes of miRNAs in exosomes were explored to clarify the possible mechanisms. Both decrease of cell proliferation and metastasis and increase of apoptosis were observed with ExoIL2-TAM treatment compared with ExoTAMin vivo and in vitro. miR-375 was obviously augmented in ExoIL2-TAM and HCC cells treated with ExoIL2-TAM. Taken together, IL-2 may modulate exosomal miRNAs from TAMs to ameliorate hepatocellular carcinoma development. This study provides a new perspective to explain the mechanism by which IL-2 inhibits hepatocellular carcinoma and implies the potential clinical value of exosomal miRNAs released by TAMs.
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Wang J, Li Y, Zhang C, Chen X, Zhu L, Luo T. A hypoxia-linked gene signature for prognosis prediction and evaluating the immune microenvironment in patients with hepatocellular carcinoma. Transl Cancer Res 2022; 10:3979-3992. [PMID: 35116696 PMCID: PMC8798548 DOI: 10.21037/tcr-21-741] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 07/30/2021] [Indexed: 12/22/2022]
Abstract
Background Previous research indicates that hypoxia critically affects the initiation and progression of hepatocellular carcinoma (HCC). Nevertheless, the molecular mechanisms responsible for HCC development are poorly understood. Herein, we purposed to build a prognostic model using hypoxia-linked genes to predict patient prognosis and investigate the relationship of hypoxia with immune status in the tumor microenvironment (TME). Methods The training cohort included transcriptome along with clinical data abstracted from The Cancer Genome Atlas (TCGA). The validation cohort was abstracted from Gene Expression Omnibus (GEO). Univariate along with multivariate Cox regression were adopted to create the prediction model. We divided all patients into low- and high-risk groups using median risk scores. The estimation power of the prediction model was determined with bioinformatic tools. Results Six hypoxia-linked genes, HMOX1, TKTL1, TPI1, ENO2, LDHA, and SLC2A1, were employed to create an estimation model. Kaplan-Meier, ROC curve, and risk plot analyses demonstrated that the estimation potential of the risk model was satisfactory. Univariate along with multivariate regression data illustrated that the risk model could independently predict the overall survival (OS). A nomogram integrating the risk signature and clinicopathological characteristics showed a good potential to estimate HCC prognosis. Gene set enrichment analysis (GSEA) revealed that genes associated with cell proliferation and metabolism cascades were abundant in high-risk group. Furthermore, the signature showed a strong ability to distinguish the two groups in terms of immune status. Conclusions A prediction model for predicting HCC prognosis using six hypoxia-linked genes was designed in this study, facilitating the diagnosis and treatment of HCC.
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Affiliation(s)
- Jukun Wang
- Department of General Surgery, Xuanwu Hospital of Capital Medical University, Beijing, China
| | - Yu Li
- Department of General Surgery, Xuanwu Hospital of Capital Medical University, Beijing, China
| | - Chao Zhang
- Department of General Surgery, Xuanwu Hospital of Capital Medical University, Beijing, China
| | - Xin Chen
- Department of General Surgery, Xuanwu Hospital of Capital Medical University, Beijing, China
| | - Linzhong Zhu
- Department of General Surgery, Xuanwu Hospital of Capital Medical University, Beijing, China
| | - Tao Luo
- Department of General Surgery, Xuanwu Hospital of Capital Medical University, Beijing, China
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Li Y, Zhang R, Xu Z, Wang Z. Advances in Nanoliposomes for the Diagnosis and Treatment of Liver Cancer. Int J Nanomedicine 2022; 17:909-925. [PMID: 35250267 PMCID: PMC8893038 DOI: 10.2147/ijn.s349426] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Accepted: 01/26/2022] [Indexed: 12/12/2022] Open
Abstract
The mortality rate of liver cancer is gradually increasing worldwide due to the increasing risk factors such as fatty liver, diabetes, and alcoholic cirrhosis. The diagnostic methods of liver cancer include ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI), among others. The treatment of liver cancer includes surgical resection, transplantation, ablation, and chemoembolization; however, treatment still faces multiple challenges due to its insidious development, high rate of recurrence after surgical resection, and high failure rate of transplantation. The emergence of liposomes has provided new insights into the treatment of liver cancer. Due to their excellent carrier properties and maneuverability, liposomes can be used to perform a variety of functions such as aiding in imaging diagnoses, combinatorial therapies, and integrating disease diagnosis and treatment. In this paper, we further discuss such advantages.
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Affiliation(s)
- Yitong Li
- NHC Key Laboratory of Radiobiology (Jilin University), School of Public Health, Jilin University, Changchun, 130021, Jilin, People’s Republic of China
| | - Ruihang Zhang
- Second Clinical Medical College, Henan University of Traditional Chinese Medicine, Zhengzhou, 450052, Henan, People’s Republic of China
| | - Zhen Xu
- NHC Key Laboratory of Radiobiology (Jilin University), School of Public Health, Jilin University, Changchun, 130021, Jilin, People’s Republic of China
| | - Zhicheng Wang
- NHC Key Laboratory of Radiobiology (Jilin University), School of Public Health, Jilin University, Changchun, 130021, Jilin, People’s Republic of China
- Correspondence: Zhicheng Wang, NHC Key Laboratory of Radiobiology (Jilin University), School of Public Health, Jilin University, 1163 Xinmin Street, Changchun, 130021, Jilin, People’s Republic of China, Tel +86 13843131059, Fax +86 431185619443, Email
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Jin S, Zeng H, Liu Z, Jin K, Liu C, Yan S, Yu Y, You R, Zhang H, Chang Y, Xu L, Xu J, Wang Z, Zhu Y. Stromal Tumor-Associated Macrophage Infiltration Predicts Poor Clinical Outcomes in Muscle-Invasive Bladder Cancer Patients. Ann Surg Oncol 2022; 29:2495-2503. [DOI: 10.1245/s10434-021-11155-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 11/15/2021] [Indexed: 01/23/2023]
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Long non-coding RNA HOMER3-AS1 drives hepatocellular carcinoma progression via modulating the behaviors of both tumor cells and macrophages. Cell Death Dis 2021; 12:1103. [PMID: 34815380 PMCID: PMC8611033 DOI: 10.1038/s41419-021-04309-z] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 10/07/2021] [Accepted: 10/07/2021] [Indexed: 12/21/2022]
Abstract
The crosstalk between cancer cells and tumor microenvironment plays critical roles in hepatocellular carcinoma (HCC). The identification of long non-coding RNAs (lncRNAs) mediating the crosstalk might promote the development of new therapeutic strategies against HCC. Here, we identified a lncRNA, HOMER3-AS1, which is over-expressed in HCC and correlated with poor survival of HCC patients. HOMER3-AS1 promoted HCC cellular proliferation, migration, and invasion, and reduced HCC cellular apoptosis. Furthermore, HOMER3-AS1 promoted macrophages recruitment and M2-like polarization. In vivo, HOMER3-AS1 significantly facilitated HCC progression. Mechanism investigations revealed that HOMER3-AS1 activated Wnt/β-catenin signaling via upregulating HOMER3. Functional rescue experiments revealed that HOMER3/Wnt/β-catenin axis mediated the roles of HOMER3-AS1 in promoting HCC cellular malignant phenotypes. Furthermore, colony stimulating factor-1 (CSF-1) was also identified as a critical downstream target of HOMER3-AS1. HOMER3-AS1 increased CSF-1 expression and secretion. Blocking CSF-1 reversed the roles of HOMER3-AS1 in inducing macrophages recruitment and M2 polarization. Furthermore, positive correlations between HOMER3-AS1 and HOMER3 expression, HOMER3-AS1 and CSF-1 expression, and HOMER3-AS1 expression and M2-like macrophages infiltration were found in human HCC tissues. In summary, our findings demonstrated that HOMER3-AS1 drives HCC progression via modulating the behaviors of both tumor cells and macrophages, which are dependent on the activation of HOMER3/Wnt/β-catenin axis and CSF-1, respectively. HOMER3-AS1 might be a promising prognostic and therapeutic target for HCC.
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Deust A, Chobert MN, Demontant V, Gricourt G, Denaës T, Thiolat A, Ruiz I, Rodriguez C, Pawlotsky JM, Teixeira-Clerc F. Macrophage autophagy protects against hepatocellular carcinogenesis in mice. Sci Rep 2021; 11:18809. [PMID: 34552122 PMCID: PMC8458469 DOI: 10.1038/s41598-021-98203-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 09/01/2021] [Indexed: 02/08/2023] Open
Abstract
Autophagy is a lysosomal degradation pathway of cellular components that regulates macrophage properties. Macrophages are critically involved in tumor growth, metastasis, angiogenesis and immune suppression. Here, we investigated whether macrophage autophagy may protect against hepatocellular carcinoma (HCC). Experiments were performed in mice with deletion of the autophagy gene Atg5 in the myeloid lineage (ATG5Mye-/- mice) and their wild-type (WT) littermates. As compared to WT, ATG5Mye-/- mice were more susceptible to diethylnitrosamine (DEN)-induced hepatocarcinogenesis, as shown by enhanced tumor number and volume. Moreover, DEN-treated ATG5Mye-/- mice exhibited compromised immune cell recruitment and activation in the liver, suggesting that macrophage autophagy invalidation altered the antitumoral immune response. RNA sequencing showed that autophagy-deficient macrophages sorted from DEN mice are characterized by an enhanced expression of immunosuppressive markers. In vitro studies demonstrated that hepatoma cells impair the autophagy flux of macrophages and stimulate their expression of programmed cell death-ligand 1 (PD-L1), a major regulator of the immune checkpoint. Moreover, pharmacological activation of autophagy reduces hepatoma cell-induced PD-L1 expression in cultured macrophages while inhibition of autophagy further increases PD-L1 expression suggesting that autophagy invalidation in macrophages induces an immunosuppressive phenotype. These results uncover macrophage autophagy as a novel protective pathway regulating liver carcinogenesis.
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Affiliation(s)
- Anthony Deust
- INSERM U955, Institut Mondor de Recherche Biomédicale, Créteil, France.,Université Paris-Est, UMR-S955, Créteil, France
| | - Marie-Noële Chobert
- INSERM U955, Institut Mondor de Recherche Biomédicale, Créteil, France.,Université Paris-Est, UMR-S955, Créteil, France
| | - Vanessa Demontant
- INSERM U955, Institut Mondor de Recherche Biomédicale, Créteil, France.,Université Paris-Est, UMR-S955, Créteil, France.,Plateforme de Génomique, Hôpital Henri Mondor, Créteil, France
| | | | - Timothé Denaës
- INSERM U955, Institut Mondor de Recherche Biomédicale, Créteil, France.,Université Paris-Est, UMR-S955, Créteil, France
| | - Allan Thiolat
- INSERM U955, Institut Mondor de Recherche Biomédicale, Créteil, France.,Université Paris-Est, UMR-S955, Créteil, France
| | - Isaac Ruiz
- INSERM U955, Institut Mondor de Recherche Biomédicale, Créteil, France.,Université Paris-Est, UMR-S955, Créteil, France
| | - Christophe Rodriguez
- INSERM U955, Institut Mondor de Recherche Biomédicale, Créteil, France.,Université Paris-Est, UMR-S955, Créteil, France.,Plateforme de Génomique, Hôpital Henri Mondor, Créteil, France
| | - Jean-Michel Pawlotsky
- INSERM U955, Institut Mondor de Recherche Biomédicale, Créteil, France.,Université Paris-Est, UMR-S955, Créteil, France.,Département de Virologie, Hôpital Henri Mondor, Créteil, France
| | - Fatima Teixeira-Clerc
- INSERM U955, Institut Mondor de Recherche Biomédicale, Créteil, France. .,Université Paris-Est, UMR-S955, Créteil, France. .,INSERM U955, Institut Mondor de Recherche Biomédicale, Hôpital Henri Mondor, 94000, Créteil, France.
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Mattos ÂZ, Debes JD, Boonstra A, Vogel A, Mattos AA. Immune aspects of hepatocellular carcinoma: From immune markers for early detection to immunotherapy. World J Gastrointest Oncol 2021; 13:1132-1143. [PMID: 34616518 PMCID: PMC8465446 DOI: 10.4251/wjgo.v13.i9.1132] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 05/02/2021] [Accepted: 07/05/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent cancers and one of the main causes of cancer-related deaths worldwide. Most HCCs develop in an inflammatory microenvironment, and mounting evidence emphasizes the importance of immune aspects in hepatocarcinogenesis. In normal physiology, both innate and adaptive immune responses are responsible for eliminating malignantly transformed cells, thus preventing the development of liver cancer. However, in the setting of impaired natural killer cells and exhaustion of T cells, HCC can develop. The immunogenic features of HCC have relevant clinical implications. There is a large number of immune markers currently being studied for the early detection of liver cancer, which would be critical in order to improve surveillance programs. Moreover, novel immunotherapies have recently been proven to be effective, and the combination of atezolizumab and bevacizumab is currently the most effective treatment for advanced HCC. It is expected that in the near future different subgroups of patients will benefit from specific immunotherapy. The better we understand the immune aspects of HCC, the greater the benefit to patients through surveillance aiming for early detection of liver cancer, which allows for curative treatments, and, in cases of advanced disease, through the selection of the best possible therapy for each individual.
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Affiliation(s)
- Ângelo Z Mattos
- Graduate Program in Medicine: Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, Brazil
- Gastroenterology and Hepatology Unit, Irmandade Santa Casa de Misericórdia de Porto Alegre, Porto Alegre 90020-090, Brazil
| | - Jose D Debes
- Department of Medicine, Division of Gastroenterology and Infectious Diseases, University of Minnesota, Minneapolis, MN 55812, United States
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam NL-3015, The Netherlands
| | - Andre Boonstra
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam NL-3015, The Netherlands
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover 30625, Germany
| | - Angelo A Mattos
- Graduate Program in Medicine: Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, Brazil
- Gastroenterology and Hepatology Unit, Irmandade Santa Casa de Misericórdia de Porto Alegre, Porto Alegre 90020-090, Brazil
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Lopez-Yrigoyen M, Cassetta L, Pollard JW. Macrophage targeting in cancer. Ann N Y Acad Sci 2021; 1499:18-41. [PMID: 32445205 DOI: 10.1111/nyas.14377] [Citation(s) in RCA: 142] [Impact Index Per Article: 35.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 04/22/2020] [Accepted: 04/30/2020] [Indexed: 12/14/2022]
Abstract
Tumorigenesis is not only determined by the intrinsic properties of cancer cells but also by their interactions with components of the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) are among the most abundant immune cells in the TME. During initial stages of tumor development, macrophages can either directly promote antitumor responses by killing tumor cells or indirectly recruit and activate other immune cells. As genetic changes occur within the tumor or T helper 2 (TH 2) cells begin to dominate the TME, TAMs begin to exhibit an immunosuppressive protumor phenotype that promotes tumor progression, metastasis, and resistance to therapy. Thus, targeting TAMs has emerged as a strategy for cancer therapy. To date, TAM targeting strategies have focused on macrophage depletion and inhibition of their recruitment into the TME. However, these strategies have shown limited therapeutic efficacy, although trials are still underway with combination therapies. The fact that macrophages have the potential for antitumor activity has moved the TAM targeting field toward the development of TAM-reprogramming strategies to support this antitumor immune response. Here, we discuss the various roles of TAMs in cancer therapy and their immunosuppressive properties, as well as implications for emerging checkpoint inhibitor-based immunotherapies. We review state-of-the-art TAM-targeting strategies, focusing on current ones at the preclinical and clinical trial stages that aim to reprogram TAMs as an oncological therapy.
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Affiliation(s)
- Martha Lopez-Yrigoyen
- MRC Centre for Reproductive Health, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom
| | - Luca Cassetta
- MRC Centre for Reproductive Health, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom
| | - Jeffrey W Pollard
- MRC Centre for Reproductive Health, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom
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Zhou D, Luan J, Huang C, Li J. Tumor-Associated Macrophages in Hepatocellular Carcinoma: Friend or Foe? Gut Liver 2021; 15:500-516. [PMID: 33087588 PMCID: PMC8283292 DOI: 10.5009/gnl20223] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 08/21/2020] [Accepted: 08/22/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, and it has diverse etiologies with multiple mechanisms. The diagnosis of HCC typically occurs at advanced stages when there are limited therapeutic options. Hepatocarcinogenesis is considered a multistep process, and hepatic macrophages play a critical role in the inflammatory process leading to HCC. Emerging evidence has shown that tumor-associated macrophages (TAMs) are crucial components defining the HCC immune microenvironment and represent an appealing option for disrupting the formation and development of HCC. In this review, we summarize the current knowledge of the polarization and function of TAMs in the pathogenesis of HCC, as well as the mechanisms underlying TAM-related anti-HCC therapies. Eventually, novel insights into these important aspects of TAMs and their roles in the HCC microenvironment might lead to promising TAM-focused therapeutic strategies for HCC.
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Affiliation(s)
- Dexi Zhou
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu, China.,Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wuhu, China.,School of Pharmacy, Wannan Medical College, Wuhu, China
| | - Jiajie Luan
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu, China.,Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wuhu, China.,School of Pharmacy, Wannan Medical College, Wuhu, China
| | - Cheng Huang
- School of Pharmacy, Anhui Medical University, Hefei, China
| | - Jun Li
- School of Pharmacy, Anhui Medical University, Hefei, China
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Xin H, Liang D, Zhang M, Ren D, Chen H, Zhang H, Li S, Ding G, Zhang C, Ding Z, Wu L, Han W, Zhou W, Chen Y, Luo H, Wang Y, Zhang H, Liu S, Li N. The CD68+ macrophages to CD8+ T-cell ratio is associated with clinical outcomes in hepatitis B virus (HBV)-related hepatocellular carcinoma. HPB (Oxford) 2021; 23:1061-1071. [PMID: 33309570 DOI: 10.1016/j.hpb.2020.11.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 10/28/2020] [Accepted: 11/09/2020] [Indexed: 01/27/2023]
Abstract
BACKGROUND Tumor microenvironment plays an essential role during the progression of hepatocellular carcinoma (HCC). Tumor infiltrating immune cells (TILs) was an important component of tumor microenvironment. However, whether TIL features are correlated with the prognosis of HCC patients remains unclear. METHODS Cancer tissue and paired paracancerous tissues from 220 stage II∼III HBV-related HCC patients were collected. TILs were analyzed using a tyramide signal amplification system combined with immunohistochemistry. Kaplan-Meier survival analysis was conducted to investigate the associations between the prognosis and the infiltrating pattern of TILs. RESULTS The patients were classified into three distinct subgroups (Clusters (C)1-3) with different overall survival (OS) and disease-free survival (DFS) according to the distribution pattern of TILs. The CD68/CD8 ratio in the cancer SA was correlated with the prognosis. Patients with a higher CD68/CD8 ratio exhibited poorer OS and DFS than those with a lower ratio. The CD68/CD8 ratio in the cancer SA was an independent factor for OS prediction but not DFS. CONCLUSION CD68+ macrophages and CD8+ T-cells are essential immunological determinants for HBV-related HCC prognosis, and the CD68/CD8 ratio in cancer SA is a novel, prognostic factor for OS prediction in HBV-related HCC patients.
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Affiliation(s)
- Haibei Xin
- Department of Hepatic Surgery I (Ward I), Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | | | - Minfeng Zhang
- Department of Hepatic Surgery I (Ward I), Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Dandan Ren
- Genecast Biotechnology Co., Ltd, Wuxi, China
| | - Huan Chen
- Genecast Biotechnology Co., Ltd, Wuxi, China
| | - Hao Zhang
- Department of Surgery Huashan Hospital Affiliated to Fudan University, Shanghai, China
| | - Shanshan Li
- Department of Hepatic Surgery I (Ward I), Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Guanghui Ding
- Department of Hepatic Surgery I (Ward I), Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Cunzhen Zhang
- Department of Hepatic Surgery I (Ward I), Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Zhiwen Ding
- Department of Hepatic Surgery I (Ward I), Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Lihong Wu
- Genecast Biotechnology Co., Ltd, Wuxi, China
| | - Wenbo Han
- Genecast Biotechnology Co., Ltd, Wuxi, China
| | - Wei Zhou
- Genecast Biotechnology Co., Ltd, Wuxi, China
| | - Yanhui Chen
- Genecast Biotechnology Co., Ltd, Wuxi, China
| | - Hongli Luo
- Genecast Biotechnology Co., Ltd, Wuxi, China
| | - Yating Wang
- Genecast Biotechnology Co., Ltd, Wuxi, China
| | - Henghui Zhang
- Genecast Biotechnology Co., Ltd, Wuxi, China; Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China.
| | - Shupeng Liu
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China.
| | - Nan Li
- Department of Hepatic Surgery I (Ward I), Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China.
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Teplický T, Mateašík A, Balázsiová Z, Kajo K, Vallová M, Filová B, Trnka M, Čunderlíková B. Phenotypical modifications of immune cells are enhanced by extracellular matrix. Exp Cell Res 2021; 405:112710. [PMID: 34174319 DOI: 10.1016/j.yexcr.2021.112710] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 05/20/2021] [Accepted: 06/19/2021] [Indexed: 12/31/2022]
Abstract
Immune cells not only constitute tumour microenvironment but they may even affect disease prognosis as a result of dual functional roles that they may play in tumour tissues. Two frequently used established immune cell lines (lymphocytic Jurkat and monocytic THP-1) were used to test whether microenvironmental factors, especially molecular components of extracellular matrix, can shape the phenotype of immune cells. Proliferation, morphological and phenotypical analyses were applied to compare behaviour of the immune cells, typically cultured as suspensions in culture medium, with their behaviour in collagen type I-based and Matrigel-based 3D cultures. Density of both immune cell types in routine suspension cultures affected their subsequent proliferation in extracellular matrices. THP-1 cells appeared to be more sensitive to their surrounding microenvironment as judged from extracellular matrix type-dependent changes in their cell doubling times and from slight increase in their diameters in both extracellular matrix-containing cell cultures. Moreover, even chemically uninduced monocytic THP-1 cells were present in a minor fraction as CD68 positive cell population in collagen type I matrix indicating their partial differentiation to macrophages. Observed modifications of immune cells by microenvironmental factors may have profound implications for their roles in healthy and pathological tissues.
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Affiliation(s)
- Tibor Teplický
- Institute of Medical Physics, Biophysics, Informatics and Telemedicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia
| | - Anton Mateašík
- International Laser Centre, Slovak Centre of Scientific and Technical Information, Bratislava, Slovakia
| | - Zuzana Balázsiová
- Institute of Medical Physics, Biophysics, Informatics and Telemedicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia
| | - Karol Kajo
- Department of Pathology, St. Elisabeth Cancer Institute, Bratislava, Slovakia; Biomedical Research Centre, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Miroslava Vallová
- Department of Pathology, St. Elisabeth Cancer Institute, Bratislava, Slovakia
| | - Barbora Filová
- Institute of Medical Physics, Biophysics, Informatics and Telemedicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia
| | - Michal Trnka
- Institute of Medical Physics, Biophysics, Informatics and Telemedicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia
| | - Beata Čunderlíková
- Institute of Medical Physics, Biophysics, Informatics and Telemedicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia; International Laser Centre, Slovak Centre of Scientific and Technical Information, Bratislava, Slovakia.
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50
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Wang H, Yung MMH, Ngan HYS, Chan KKL, Chan DW. The Impact of the Tumor Microenvironment on Macrophage Polarization in Cancer Metastatic Progression. Int J Mol Sci 2021; 22:ijms22126560. [PMID: 34207286 PMCID: PMC8235734 DOI: 10.3390/ijms22126560] [Citation(s) in RCA: 150] [Impact Index Per Article: 37.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 06/07/2021] [Accepted: 06/14/2021] [Indexed: 02/07/2023] Open
Abstract
Rather than primary solid tumors, metastasis is one of the hallmarks of most cancer deaths. Metastasis is a multistage event in which cancer cells escape from the primary tumor survive in the circulation and disseminate to distant sites. According to Stephen Paget’s “Seed and Soil” hypothesis, metastatic capacity is determined not only by the internal oncogenic driving force but also by the external environment of tumor cells. Throughout the body, macrophages are required for maintaining tissue homeostasis, even in the tumor milieu. To fulfill these multiple functions, macrophages are polarized from the inflammation status (M1-like) to anti-inflammation status (M2-like) to maintain the balance between inflammation and regeneration. However, tumor cell-enforced tumor-associated macrophages (TAMs) (a high M2/M1 ratio status) are associated with poor prognosis for most solid tumors, such as ovarian cancer. In fact, clinical evidence has verified that TAMs, representing up to 50% of the tumor mass, exert both protumor and immunosuppressive effects in promoting tumor metastasis through secretion of interleukin 10 (IL10), transforming growth factor β (TGFβ), and VEGF, expression of PD-1 and consumption of arginine to inhibit T cell anti-tumor function. However, the underlying molecular mechanisms by which the tumor microenvironment favors reprogramming of macrophages to TAMs to establish a premetastatic niche remain controversial. In this review, we examine the latest investigations of TAMs during tumor development, the microenvironmental factors involved in macrophage polarization, and the mechanisms of TAM-mediated tumor metastasis. We hope to dissect the critical roles of TAMs in tumor metastasis, and the potential applications of TAM-targeted therapeutic strategies in cancer treatment are discussed.
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