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Tong J, Tan Y, Ouyang W, Chang H. Targeting immune checkpoints in hepatocellular carcinoma therapy: toward combination strategies with curative potential. Exp Hematol Oncol 2025; 14:65. [PMID: 40317077 PMCID: PMC12046748 DOI: 10.1186/s40164-025-00636-5] [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: 01/20/2025] [Accepted: 03/07/2025] [Indexed: 05/04/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a primary liver cancer characterized by poor immune cell infiltration and a strongly immunosuppressive microenvironment. Traditional treatments have often yielded unsatisfactory outcomes due to the insidious onset of the disease. Encouragingly, the introduction of immune checkpoint inhibitors (ICIs) has significantly transformed the approach to HCC treatment. Moreover, combining ICIs with other therapies or novel materials is considered the most promising opportunity in HCC, with some of these combinations already being evaluated in large-scale clinical trials. Unfortunately, most clinical trials fail to meet their endpoints, and the few successful ones also face challenges. This indicates that the potential of ICIs in HCC treatment remains underutilized, prompting a reevaluation of this promising therapy. Therefore, this article provides a review of the role of immune checkpoints in cancer treatment, the research progress of ICIs and their combination application in the treatment of HCC, aiming to open up avenues for the development of safer and more efficient immune checkpoint-related strategies for HCC treatment.
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Affiliation(s)
- Jing Tong
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, Guangzhou, 510631, China
- Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, Guangzhou, 510631, China
| | - Yongci Tan
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, Guangzhou, 510631, China
- Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, Guangzhou, 510631, China
| | - Wenwen Ouyang
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, Guangzhou, 510631, China
- Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, Guangzhou, 510631, China
| | - Haocai Chang
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, Guangzhou, 510631, China.
- Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, Guangzhou, 510631, China.
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Sun J, Liu C, Tao X, Yang Y, Jin H, Cheng S, Shi H, Yan M, Shi J. Prognostic comparison between pulmonary metastasectomy and combination immunotherapy with targeted molecular therapies for advanced hepatocellular carcinoma with pulmonary metastasis: A propensity score matching analysis. LIVER RESEARCH (BEIJING, CHINA) 2025; 9:29-35. [PMID: 40206434 PMCID: PMC11977282 DOI: 10.1016/j.livres.2025.01.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 01/24/2025] [Accepted: 01/26/2025] [Indexed: 04/11/2025]
Abstract
Background and aims Advanced hepatocellular carcinoma (HCC) with pulmonary metastasis (PM) has a poor prognosis, and optimal treatment strategies remain controversial. This study aimed to compare the long-term outcomes of patients with advanced HCC with PM who were treated with resection of pulmonary metastases versus those treated with targeted therapies combined with immunotherapy. Methods A retrospective analysis was conducted on the medical records of HCC patients with PM who underwent either pulmonary metastasectomy or immunotherapy combined with targeted therapies at the Eastern Hepatobiliary Surgery Hospital, Changhai Hospital of Shanghai, Fujian Provincial Hospital, and West China Hospital of Sichuan University from September 2013 to October 2022. One-to-one propensity score matching (PSM) was employed to control the influence of potential confounders, and the survival outcomes were compared. Results A total of 119 HCC patients with PM were included in this study. The overall survival (OS) of patients who underwent pulmonary metastasectomy was significantly longer than that of patients who received immunotherapy targeted combinations (OS: 1-year, 80.0% vs. 59.3%; 2-year, 31.7% vs. 20.3%; 3-year, 20.0% vs. 0; P < 0.001). After PSM, the long-term prognosis of the pulmonary metastasectomy group remained significantly better than that of the immunotherapy combination group (OS: 1-year, 87.0% vs. 69.6%; 2-year, 34.8% vs. 30.4%; 3-year, 21.7% vs. 0; P = 0.005). Multivariate analysis revealed that treatment allocation (hazard ratio (HR) = 2.177, 95% confidence interval (CI) = 1.068-4.439) and hepatic tumor T stage (HR = 2.342, 95% CI = 1.209-4.538) were independent risk factors for OS. Conclusions Pulmonary metastasectomy was associated with improved survival compared to immunotherapy combined with targeted therapies and may represent an optimal treatment option for highly selected HCC patients with resectable PM.
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Affiliation(s)
- Juxian Sun
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Chang Liu
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Xiandong Tao
- Department of Thoracic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Yu Yang
- Department of Medical Oncology, Cancer Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Hai Jin
- Department of Thoracic Surgery, Changhai Hospital of Shanghai, Naval Medical University, Shanghai, China
| | - Shuqun Cheng
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Huazheng Shi
- Shanghai University Cloud Medical Imaging Diagnostic Center, Shanghai, China
| | - Maolin Yan
- Department of Hepatobiliary Surgery, Fujian Provincial Hospital, Fujian Medical University, Fuzhou, Fujian, China
| | - Jie Shi
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
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Qin G, Chen Z, Tian W, Chen H, Zhang Y, Wei W. Exploring RPA1-ETAA1 axis via high-throughput data analysis: implications for PD-L1 nuclear translocation and tumor-immune dynamics in liver cancer. Front Immunol 2024; 15:1492531. [PMID: 39660144 PMCID: PMC11628550 DOI: 10.3389/fimmu.2024.1492531] [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: 09/07/2024] [Accepted: 10/29/2024] [Indexed: 12/12/2024] Open
Abstract
Introduction ETAA1 is recruited to DNA damage sites via its RPA -binding and ATR -activating domain (AAD) motifs, where RPA binding is crucial for ETAA1's regulation of ATR activity. Methods & results Our findings associate Programmed Death- Ligand1 (PD-L1) with the RPA1-ETAA1 axis, suggesting that upregulated RPA1 -dependent ETAA1 may facilitate PD-L1 nuclear accumulation. We observed strong correlations between ETAA1 and RPA1 with the components involved in HDAC2-mediated deacetylation, clathrin -dependent endocytosis, and PD-L1 nucleocytoplasmic shuttling, aligning with the established regulatory pathway of PD-L1 nuclear translocation. Moreover, nuclear PD-L1 transactivates a panel of pro-inflammatory and immune response transcription factors, potentially reshaping the tumor immune microenvironment. We identified a landscape of infiltrating lymphocytes influenced by ETAA1, finding that levels of ETAA1 were negatively correlated with CD8+ T and Natural Killer T (NKT) cells, but positively correlated with CD4+ T helper 2 (Th2) cells, cancer-associated fibroblasts (CAFs), myeloid-derived suppressor cells (MDSCs), neutrophils and regulatory T cells (Tregs), suggesting a potential role in immune evasion. Further analysis shows that the RPA1-ETAA1 axis is significantly associated with multiple metastasis mediators and unfavorable liver cancer progression, with higher expression observed in advanced stages and poorly differentiated subgroups. Discussion & conclusion These findings expand the role of the RPA1-ETAA1 axis beyond DNA repair, highlighting its potential as a target for cancer therapy.
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Affiliation(s)
- Gaofeng Qin
- Liaoning Technology and Engineering Center for Tumor Immunology and Molecular Theranotics, Collaborative Innovation Center for Age-related Disease, Life Science Institute, Jinzhou Medical University, Jinzhou, Liaoning, China
- College of Basic Medical Science, Jinzhou Medical University, Jinzhou, Liaoning, China
| | - Zengkuan Chen
- Liaoning Technology and Engineering Center for Tumor Immunology and Molecular Theranotics, Collaborative Innovation Center for Age-related Disease, Life Science Institute, Jinzhou Medical University, Jinzhou, Liaoning, China
- College of Basic Medical Science, Jinzhou Medical University, Jinzhou, Liaoning, China
| | - Weihong Tian
- Liaoning Technology and Engineering Center for Tumor Immunology and Molecular Theranotics, Collaborative Innovation Center for Age-related Disease, Life Science Institute, Jinzhou Medical University, Jinzhou, Liaoning, China
| | - Hongbo Chen
- Department of Intensive Care Medicine, Yingkou Central Hospital, Yingkou, Liaoning, China
| | - Yu Zhang
- Liaoning Technology and Engineering Center for Tumor Immunology and Molecular Theranotics, Collaborative Innovation Center for Age-related Disease, Life Science Institute, Jinzhou Medical University, Jinzhou, Liaoning, China
- College of Basic Medical Science, Jinzhou Medical University, Jinzhou, Liaoning, China
| | - Wangzhi Wei
- Liaoning Technology and Engineering Center for Tumor Immunology and Molecular Theranotics, Collaborative Innovation Center for Age-related Disease, Life Science Institute, Jinzhou Medical University, Jinzhou, Liaoning, China
- College of Basic Medical Science, Jinzhou Medical University, Jinzhou, Liaoning, China
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Liu Y, Wu Y, Li Z, Wan D, Pan J. Targeted Drug Delivery Strategies for the Treatment of Hepatocellular Carcinoma. Molecules 2024; 29:4405. [PMID: 39339402 PMCID: PMC11434448 DOI: 10.3390/molecules29184405] [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: 08/21/2024] [Revised: 09/12/2024] [Accepted: 09/14/2024] [Indexed: 09/30/2024] Open
Abstract
Hepatocellular carcinoma (HCC) ranks among the most prevalent malignant tumors, exhibiting a high incidence rate that presents a substantial threat to human health. The use of sorafenib and lenvatinib, commonly employed as single-agent targeted inhibitors, complicates the treatment process due to the absence of definitive targeting. Nevertheless, the advent of nanotechnology has injected new optimism into the domain of liver cancer therapy. Nanocarriers equipped with active targeting or passive targeting mechanisms have demonstrated the capability to deliver drugs to tumor cells with high efficiency. This approach not only facilitates precise delivery to the affected site but also enables targeted drug release, thereby enhancing therapeutic efficacy. As medical technology progresses, there is an increasing call for innovative treatment modalities, including novel chemotherapeutic agents, gene therapy, phototherapy, immunotherapy, and combinatorial treatments for HCC. These emerging therapies are anticipated to yield improved clinical outcomes for patients, while minimizing systemic toxicity and adverse effects. Consequently, the application of nanotechnology is poised to significantly improve HCC treatment. This review focused on targeted strategies for HCC and the application of nanotechnology in this area.
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Affiliation(s)
- Yonghui Liu
- School of Chemistry, Tiangong University, Tianjin 300387, China; (Y.L.)
| | - Yanan Wu
- School of Chemistry, Tiangong University, Tianjin 300387, China; (Y.L.)
| | - Zijian Li
- School of Chemical Engineering and Technology, Tiangong University, Tianjin 300387, China
| | - Dong Wan
- School of Chemistry, Tiangong University, Tianjin 300387, China; (Y.L.)
- School of Chemical Engineering and Technology, Tiangong University, Tianjin 300387, China
| | - Jie Pan
- School of Chemistry, Tiangong University, Tianjin 300387, China; (Y.L.)
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Li D, Zhang T, Guo Y, Bi C, Liu M, Wang G. Biological impact and therapeutic implication of tumor-associated macrophages in hepatocellular carcinoma. Cell Death Dis 2024; 15:498. [PMID: 38997297 PMCID: PMC11245522 DOI: 10.1038/s41419-024-06888-z] [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: 03/11/2024] [Revised: 06/26/2024] [Accepted: 07/02/2024] [Indexed: 07/14/2024]
Abstract
The tumor microenvironment is a complex space comprised of normal, cancer and immune cells. The macrophages are considered as the most abundant immune cells in tumor microenvironment and their function in tumorigenesis is interesting. Macrophages can be present as M1 and M2 polarization that show anti-cancer and oncogenic activities, respectively. Tumor-associated macrophages (TAMs) mainly have M2 polarization and they increase tumorigenesis due to secretion of factors, cytokines and affecting molecular pathways. Hepatocellular carcinoma (HCC) is among predominant tumors of liver that in spite of understanding its pathogenesis, the role of tumor microenvironment in its progression still requires more attention. The presence of TAMs in HCC causes an increase in growth and invasion of HCC cells and one of the reasons is induction of glycolysis that such metabolic reprogramming makes HCC distinct from normal cells and promotes its malignancy. Since M2 polarization of TAMs stimulates tumorigenesis in HCC, molecular networks regulating M2 to M1 conversion have been highlighted and moreover, drugs and compounds with the ability of targeting TAMs and suppressing their M2 phenotypes or at least their tumorigenesis activity have been utilized. TAMs increase aggressive behavior and biological functions of HCC cells that can result in development of therapy resistance. Macrophages can provide cell-cell communication in HCC by secreting exosomes having various types of biomolecules that transfer among cells and change their activity. Finally, non-coding RNA transcripts can mainly affect polarization of TAMs in HCC.
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Affiliation(s)
- Deming Li
- Department of Anesthesiology, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, PR China
| | - Ting Zhang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, 110001, PR China
| | - Ye Guo
- Department of Intervention, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, PR China
| | - Cong Bi
- Department of Radiology, The First Hospital of China Medical University, Shenyang, 110001, PR China.
| | - Ming Liu
- Department of Oral Radiology, School of Stomatology, China Medical University, Shenyang, Liaoning, 110002, PR China.
| | - Gang Wang
- Department of Intervention, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, PR China.
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Salem R, Greten TF. Interventional radiology meets immuno-oncology for hepatocellular carcinoma. J Hepatol 2024; 80:967-976. [PMID: 35988688 DOI: 10.1016/j.jhep.2022.08.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 07/28/2022] [Accepted: 08/05/2022] [Indexed: 12/04/2022]
Abstract
Locoregional and systemic therapies are the most used treatment options for patients with hepatocellular carcinoma (HCC). Interventional radiologists have improved and developed novel protocols and devices for both intratumoural ablative approaches with curative intent and various transarterial intrahepatic treatment options, which have continuously improved patient outcomes. Two large phase III randomised clinical trials have demonstrated the efficacy of different immune checkpoint inhibitors either as single agents or in combination in the first-line setting and immunotherapy has become the standard first-line treatment option for patients with advanced HCC. Herein, we discuss advances and perspectives in the area of interventional radiology (IR) and immune-oncology (IO). We summarise results from recent studies and provide an overview of ongoing studies in IR and IO. Based on the significant advances in both areas, we propose that IR and IO need to cover the emerging "discipline" of IR-IO, in which we develop and test novel approaches to combine locoregional therapies with immunotherapy, in order to develop sufficient evidence for them to be considered standard of care for patients with HCC in the near future.
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Affiliation(s)
- Riad Salem
- Department of Radiology, Northwestern Feinberg School of Medicine, Chicago, IL, USA.
| | - Tim F Greten
- Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, Bethesda MD, USA; NCI CCR Liver Cancer Program, Center for Cancer Research, NCI, Bethesda MD, USA
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Li Q, Li F, Song X, Lu N, Jing X, Wen H, Ma P, Zhang H, Yao W, Wang X, Zhang M. Pan-cancer analysis of ARFs family and ARF5 promoted the progression of hepatocellular carcinoma. Heliyon 2024; 10:e29099. [PMID: 38617932 PMCID: PMC11015141 DOI: 10.1016/j.heliyon.2024.e29099] [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: 11/15/2023] [Revised: 03/29/2024] [Accepted: 03/31/2024] [Indexed: 04/16/2024] Open
Abstract
Background ARF family proteins are a kind of small GTPases, which are involved in regulating a variety of basic functions of cells. In recent years, the role and molecular regulatory mechanisms of ARFs in tumor progression have received increasing attention, and research reports on most of their family members are increasing. However, research on the clinical and pathological relevance of ARF5 in cancer, especially in hepatocellular carcinoma, still needs to be improved. Methods RNA-seq data in the Cancer Genome Atlas (TCGA) and genome tissue expression (GTEx) databases were used to analyze the expression and pathological data of ARFs family in Pan-cancer. Kaplan-Meier and Cox regression were used for prognostic analysis of ARF5 and Pan-cancer. Combined with ImmuCellAI database and TIMER2 database, the relationship between ARF5 expression and immune cell tumor infiltration in hepatocellular carcinoma (HCC) was analyzed. WGCNA is used to construct the co-expression gene network related to ARF5 expression in HCC and screen important modules and central genes. GO and KEGG path enrichment analysis were carried out for the genes in the modules with clinical significance. GSEA analysis was performed to take into account the role of genes with small differences. Finally, ceRNA network analysis was used to explore the molecular mechanism of miRNAs and lncRNAs regulating ARF5 expression. Results ARFs family (ARF1, ARF3, ARF4, ARF5, ARF6) are generally highly expressed in Pan-cancer. ARF5 is significantly highly expressed in 29 cancers, and the high expression of ARF5 in HCC patients is significantly negatively correlated with OS, DFI, PFI and DSS, which may lead to cancer deterioration by participating in tumor immune infiltration of HCC. Through WGCNA analysis, the expression of ARF5 in HCC may be involved in many cellular processes that consume a lot of energy, such as ribosome formation, RNA and protein synthesis and lipids, as well as COVID-19, nonalcoholic fatty liver, neurodegenerative diseases and other disease pathways. Conclusion ARFs, especially ARF5, are overexpressed in many human tumors. This study shows for the first time that ARF5 is significantly correlated with the poor prognosis of HCC patients, which may play a role as an oncogene, suggesting that ARF5 has the potential as a biomarker for the diagnosis and treatment of HCC.
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Affiliation(s)
- Qian Li
- The First Affiliated Hospital of Xi'an Medical University, Xi'an, 710077, Shaanxi, China
| | - Fang Li
- Institute of Genetics and Development Biology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Xinqiu Song
- Medical College of Yan'an University, Yan'an, 716000, Shaanxi, China
| | - Ning Lu
- The First Affiliated Hospital of Xi'an Medical University, Xi'an, 710077, Shaanxi, China
| | - Xintao Jing
- Institute of Genetics and Development Biology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Hua Wen
- The First Affiliated Hospital of Xi'an Medical University, Xi'an, 710077, Shaanxi, China
| | - Peihan Ma
- The First Affiliated Hospital of Xi'an Medical University, Xi'an, 710077, Shaanxi, China
| | - Hua Zhang
- The First Affiliated Hospital of Xi'an Medical University, Xi'an, 710077, Shaanxi, China
| | - Wenzhu Yao
- Xi'an Medical University, Xi'an, 710021, Shaanxi, China
| | - Xiaofei Wang
- Biomedical Experimental Center, Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Mingxin Zhang
- The First Affiliated Hospital of Xi'an Medical University, Xi'an, 710077, Shaanxi, China
- Shaanxi University of Traditional Chinese Medicine, Xianyang, 712046, Shaanxi, China
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Wen J, Xue L, Wei Y, Liang J, Jia W, Yong T, Chu L, Li H, Han S, Liao J, Chen Z, Liu Y, Liu Q, Ding Z, Liang H, Gan L, Chen X, Huang Z, Zhang B. YTHDF2 Is a Therapeutic Target for HCC by Suppressing Immune Evasion and Angiogenesis Through ETV5/PD-L1/VEGFA Axis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2307242. [PMID: 38247171 PMCID: PMC10987122 DOI: 10.1002/advs.202307242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 01/11/2024] [Indexed: 01/23/2024]
Abstract
N6-methyladenosine (m6A) modification orchestrates cancer formation and progression by affecting the tumor microenvironment (TME). For hepatocellular carcinoma (HCC), immune evasion and angiogenesis are characteristic features of its TME. The role of YTH N6-methyladenosine RNA binding protein 2 (YTHDF2), as an m6A reader, in regulating HCC TME are not fully understood. Herein, it is discovered that trimethylated histone H3 lysine 4 and H3 lysine 27 acetylation modification in the promoter region of YTHDF2 enhanced its expression in HCC, and upregulated YTHDF2 in HCC predicted a worse prognosis. Animal experiments demonstrated that Ythdf2 depletion inhibited spontaneous HCC formation, while its overexpression promoted xenografted HCC progression. Mechanistically, YTHDF2 recognized the m6A modification in the 5'-untranslational region of ETS variant transcription factor 5 (ETV5) mRNA and recruited eukaryotic translation initiation factor 3 subunit B to facilitate its translation. Elevated ETV5 expression induced the transcription of programmed death ligand-1 and vascular endothelial growth factor A, thereby promoting HCC immune evasion and angiogenesis. Targeting YTHDF2 via small interference RNA-containing aptamer/liposomes successfully both inhibited HCC immune evasion and angiogenesis. Together, this findings reveal the potential application of YTHDF2 in HCC prognosis and targeted treatment.
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Affiliation(s)
- Jingyuan Wen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
- Clinical Medical Research Center of Hepatic Surgery at Hubei ProvinceWuhan430030China
- Hubei Key Laboratory of Hepato‐Pancreatic‐Biliary Diseases, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Lin Xue
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
- Clinical Medical Research Center of Hepatic Surgery at Hubei ProvinceWuhan430030China
- Hubei Key Laboratory of Hepato‐Pancreatic‐Biliary Diseases, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Yi Wei
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
- Clinical Medical Research Center of Hepatic Surgery at Hubei ProvinceWuhan430030China
- Hubei Key Laboratory of Hepato‐Pancreatic‐Biliary Diseases, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Junnan Liang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
- Clinical Medical Research Center of Hepatic Surgery at Hubei ProvinceWuhan430030China
- Hubei Key Laboratory of Hepato‐Pancreatic‐Biliary Diseases, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Wenlong Jia
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
- Clinical Medical Research Center of Hepatic Surgery at Hubei ProvinceWuhan430030China
- Hubei Key Laboratory of Hepato‐Pancreatic‐Biliary Diseases, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Tuying Yong
- National Engineering Research Center for Nanomedicine College of Life Science and TechnologyHuazhong University of Science and TechnologyWuhan430074China
| | - Liang Chu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
- Clinical Medical Research Center of Hepatic Surgery at Hubei ProvinceWuhan430030China
- Hubei Key Laboratory of Hepato‐Pancreatic‐Biliary Diseases, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Han Li
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
- Clinical Medical Research Center of Hepatic Surgery at Hubei ProvinceWuhan430030China
- Hubei Key Laboratory of Hepato‐Pancreatic‐Biliary Diseases, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Shenqi Han
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
- Clinical Medical Research Center of Hepatic Surgery at Hubei ProvinceWuhan430030China
- Hubei Key Laboratory of Hepato‐Pancreatic‐Biliary Diseases, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Jingyu Liao
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
- Clinical Medical Research Center of Hepatic Surgery at Hubei ProvinceWuhan430030China
- Hubei Key Laboratory of Hepato‐Pancreatic‐Biliary Diseases, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Zeyu Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
- Clinical Medical Research Center of Hepatic Surgery at Hubei ProvinceWuhan430030China
- Hubei Key Laboratory of Hepato‐Pancreatic‐Biliary Diseases, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Yiyang Liu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
- Clinical Medical Research Center of Hepatic Surgery at Hubei ProvinceWuhan430030China
- Hubei Key Laboratory of Hepato‐Pancreatic‐Biliary Diseases, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Qiumeng Liu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
- Clinical Medical Research Center of Hepatic Surgery at Hubei ProvinceWuhan430030China
- Hubei Key Laboratory of Hepato‐Pancreatic‐Biliary Diseases, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Zeyang Ding
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
- Clinical Medical Research Center of Hepatic Surgery at Hubei ProvinceWuhan430030China
- Hubei Key Laboratory of Hepato‐Pancreatic‐Biliary Diseases, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Huifang Liang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
- Clinical Medical Research Center of Hepatic Surgery at Hubei ProvinceWuhan430030China
- Hubei Key Laboratory of Hepato‐Pancreatic‐Biliary Diseases, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Lu Gan
- National Engineering Research Center for Nanomedicine College of Life Science and TechnologyHuazhong University of Science and TechnologyWuhan430074China
| | - Xiaoping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
- Clinical Medical Research Center of Hepatic Surgery at Hubei ProvinceWuhan430030China
- Hubei Key Laboratory of Hepato‐Pancreatic‐Biliary Diseases, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
- Key Laboratory of Organ Transplantation, Ministry of Education; Key Laboratory of Organ Transplantation, National Health Commission; Key Laboratory of Organ TransplantationChinese Academy of Medical ScienceWuhan430030China
| | - Zhao Huang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
- Clinical Medical Research Center of Hepatic Surgery at Hubei ProvinceWuhan430030China
- Hubei Key Laboratory of Hepato‐Pancreatic‐Biliary Diseases, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
- Clinical Medical Research Center of Hepatic Surgery at Hubei ProvinceWuhan430030China
- Hubei Key Laboratory of Hepato‐Pancreatic‐Biliary Diseases, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
- Key Laboratory of Organ Transplantation, Ministry of Education; Key Laboratory of Organ Transplantation, National Health Commission; Key Laboratory of Organ TransplantationChinese Academy of Medical ScienceWuhan430030China
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9
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Gupta T, Jarpula NS. Hepatocellular carcinoma immune microenvironment and check point inhibitors-current status. World J Hepatol 2024; 16:353-365. [PMID: 38577535 PMCID: PMC10989304 DOI: 10.4254/wjh.v16.i3.353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 01/24/2024] [Accepted: 03/04/2024] [Indexed: 03/27/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver and has a high mortality rate. The Barcelona Clinic Liver Cancer staging system in addition to tumor staging also links the modality of treatment available to a particular stage. The recent description of the tumor microenvironment (TME) in HCC has provided a new concept of immunogenicity within the HCC. Virus-related HCC has been shown to be more immunogenic with higher expression of cytotoxic T lymphocytes and decreased elements for immunosuppression such as regulatory T cells. This immunogenic milieu provides a better response to immunotherapy especially immune checkpoint inhibitors (ICIs). In addition, the recent data on combining locoregional therapies and other strategies may convert the less immunogenic state of the TME towards higher immunogenicity. Therefore, data are emerging on the use of combinations of locoregional therapy and ICIs in unresectable or advanced HCC and has shown better survival outcomes in this difficult population.
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Affiliation(s)
- Tarana Gupta
- Division of Hepatology, Department of Medicine, Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences, Rohtak 124001, Haryana, India.
| | - Nikhil Sai Jarpula
- Division of Hepatology, Department of Medicine, Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences, Rohtak 124001, Haryana, India
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10
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Zhang H, Xu Z. Gut-lung axis: role of the gut microbiota in non-small cell lung cancer immunotherapy. Front Oncol 2023; 13:1257515. [PMID: 38074650 PMCID: PMC10701269 DOI: 10.3389/fonc.2023.1257515] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 11/03/2023] [Indexed: 11/02/2024] Open
Abstract
Immunotherapy for non-small cell lung cancer (NSCLC) has advanced considerably over the past two decades. In particular, immune checkpoint inhibitors are widely used for treating NSCLC. However, the overall cure and survival rates of patients with NSCLC remain low. Therefore, continuous investigation into complementary treatments is necessary to expand the clinical advantages of immunotherapy to a larger cohort of patients with NSCLC. Recently, the distinctive role of the gut microbiota (GM) in the initiation, progression, and dissemination of cancer has attracted increasing attention. Emerging evidence indicates a close relationship between the gut and lungs, known as the gut-lung axis (GLA). In this review, we aim to provide a comprehensive summary of the current knowledge regarding the connection between the GM and the outcomes of immunotherapy in NSCLC, with particular focus on the recent understanding of GLA. Overall, promising GM-based therapeutic strategies have been observed to improve the effectiveness or reduce the toxicity of immunotherapy in patients with NSCLC, thus advancing the utilization of microbiota precision medicine.
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Affiliation(s)
- Huaiyuan Zhang
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, China
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Ziyuan Xu
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, China
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
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11
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Chang C, Pei Y, Zhang C, Zhang W, Qin Y, Shi S. Combination therapy with dendritic cell loaded-exosomes supplemented with PD-1 inhibition at different time points have superior antitumor effect in hepatocellular carcinoma. Cancer Immunol Immunother 2023; 72:3727-3738. [PMID: 37665374 PMCID: PMC10991982 DOI: 10.1007/s00262-023-03525-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 08/10/2023] [Indexed: 09/05/2023]
Abstract
Hepatocellular carcinoma (HCC), a prevalent cause of cancer-related deaths, is insensitive to traditional treatments. At different time intervals, the combined antitumor effects of DC-TEX and the programmed death protein 1 (PD-1) antibody (Ab) have not been investigated. In this study, HCC models were established and treated at different time intervals with DC-TEX alone or in combination with PD-1 Ab. In addition, we developed an orthotopic HCC model in BALB/c nude mice and restored T cells. Results demonstrated that the PD-1 + CD8 + T-cell population also increased significantly after DC-TEX treatment, in addition to the increased number of CD8 + T cells. The number of CD8 + T cells increased 72 h after DC-TEX administration. Similar observations were made for PD-1 + CD8 + T cells. Subsequently, PD-1 Ab was administered in combination with DC-TEX at different time points (0, 24, 72, 96, 120, or 168 h). Surprisingly, the combination treatment demonstrated a strong antitumor effect, which was very prominent when PD-1 Ab was administered at 72 h. PD-1 Ab significantly reversed the proliferative ability of PD-1 + CD8 + T cells at 72 h in vitro. The combined antitumor effects of PD-1 Ab and DC-TEX occurred mainly by stimulating CD8 + T cell proliferation and inhibiting T cell exhaustion. In conclusion, our results indicate that the combination of DC-TEX and PD-1 Ab significantly inhibits tumor growth in a murine HCC model and that the timing of PD-1 Ab administration impacts the antitumor effect.
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Affiliation(s)
- Chunxiao Chang
- Department of Gastrointestinal Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, #440 Jiyan Road, Huaiyin District, Jinan, 250117, Shandong, China
| | - Yanqing Pei
- Department of Infection Management, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, China
| | - Chuangnian Zhang
- Institute of Biomedical Engineering, Chinese Academy of Medical Sciences, Peking Union Medical College, Tianjin Key Laboratory of Biomaterial Research, Tianjin, 300192, China
| | - Wenyu Zhang
- Department of Gastrointestinal Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, #440 Jiyan Road, Huaiyin District, Jinan, 250117, Shandong, China
| | - Yibo Qin
- Institute of Biomedical Engineering, Chinese Academy of Medical Sciences, Peking Union Medical College, Tianjin Key Laboratory of Biomaterial Research, Tianjin, 300192, China
| | - Shengbin Shi
- Department of Gastrointestinal Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, #440 Jiyan Road, Huaiyin District, Jinan, 250117, Shandong, China.
- Institute of Biomedical Engineering, Chinese Academy of Medical Sciences, Peking Union Medical College, Tianjin Key Laboratory of Biomaterial Research, Tianjin, 300192, China.
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12
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Qin A, Qin Y, Lee J, Musket A, Ying M, Krenciute G, Marincola FM, Yao ZQ, Musich PR, Xie Q. Tyrosine kinase signaling-independent MET-targeting with CAR-T cells. J Transl Med 2023; 21:682. [PMID: 37779207 PMCID: PMC10544186 DOI: 10.1186/s12967-023-04521-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 09/11/2023] [Indexed: 10/03/2023] Open
Abstract
BACKGROUND Recent progress in cancer immunotherapy encourages the expansion of chimeric antigen receptor (CAR) T cell therapy in solid tumors including hepatocellular carcinoma (HCC). Overexpression of MET receptor tyrosine kinase is common in HCC; however, MET inhibitors are effective only when MET is in an active form, making patient stratification difficult. Specific MET-targeting CAR-T cells hold the promise of targeting HCC with MET overexpression regardless of signaling pathway activity. METHODS MET-specific CARs with CD28ζ or 4-1BBζ as co-stimulation domains were constructed. MET-CAR-T cells derived from healthy subjects (HS) and HCC patients were evaluated for their killing activity and cytokine release against HCC cells with various MET activations in vitro, and for their tumor growth inhibition in orthotopic xenograft models in vivo. RESULTS MET-CAR.CD28ζ and MET-CAR.4-1BBζ T cells derived from both HS and HCC patients specifically killed MET-positive HCC cells. When stimulated with MET-positive HCC cells in vitro, MET-CAR.CD28ζ T cells demonstrated a higher level of cytokine release and expression of programmed cell death protein 1 (PD-1) than MET-CAR.4-1BBζ T cells. When analyzed in vivo, MET-CAR.CD28ζ T cells more effectively inhibited HCC orthotopic tumor growth in mice when compared to MET-CAR.4-1BBζ T cells. CONCLUSION We generated and characterized MET-specific CAR-T cells for targeting HCC with MET overexpression regardless of MET activation. Compared with MET-CAR.4-1BBζ, MET-CAR.CD28ζ T cells showed a higher anti-HCC potency but also a higher level of T cell exhaustion. While MET-CAR.CD28ζ is preferred for further development, overcoming the exhaustion of MET-CAR-T cells is necessary to improve their therapeutic efficacy in vivo.
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Affiliation(s)
- Anna Qin
- Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA
| | - Yuan Qin
- Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA
| | - Joseph Lee
- Department of Surgery, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA
| | - Anna Musket
- Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA
| | - Mingyao Ying
- Department of Neurology, Hugo W. Moser Research Institute at Kennedy Krieger, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Giedre Krenciute
- Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | | | - Zhi Q Yao
- Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA
- Center of Excellence for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA
| | - Phillip R Musich
- Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA
| | - Qian Xie
- Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA.
- Center of Excellence for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA.
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13
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Wan F, Li H, Huang S, Sun J, Li J, Li Y, Yang L, He M. Vasorin promotes proliferation and migration via STAT3 signaling and acts as a promising therapeutic target of hepatocellular carcinoma. Cell Signal 2023; 110:110809. [PMID: 37454705 DOI: 10.1016/j.cellsig.2023.110809] [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: 06/01/2023] [Revised: 07/04/2023] [Accepted: 07/13/2023] [Indexed: 07/18/2023]
Abstract
Abnormal expression of Vasorin (VASN) is related to many types of cancer, but the signaling pathway and mechanism of how VASN contributes to the carcinogenesis of hepatocellular carcinoma (HCC) are poorly understood. Here, we found that VASN was up-regulated in serum/serum exosome and tissues of HCC patients. The expression of VASN in serum improve the detection rate of HCC in alpha-fetoprotein-negative HCC patients. Immunohistochemistry revealed that VASN was highly expressed in HCC tissues and associated with different stages of HCC. Noticeably, when serum VASN combined with α-fetoprotein, the area under the curve (AUC), sensitivity, and specificity of HCC patients compared with healthy patients reached 0.918 (95% CI: 0.869-0.967, P < 0.001), 90.91%, and 90.20%, respectively. VASN knockout HCC cells were obtained by CRISPR/Cas9 and a VASN-specific monoclonal antibody was prepared by hybridoma technology. Knockout of VASN or the addition of VASN-specific monoclonal antibody suppressed the proliferation and migration of HCC. Mechanistically, VASN promote the proliferation and migration of HCC by regulating the phosphorylation of STAT3 and the expression of downstream genes CCND1 and MMP2. In conclusion, our findings suggest that VASN plays a crucial role in the activation of STAT3 signaling pathway in HCC, which is a promising target for the diagnosis and therapy of HCC.
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Affiliation(s)
- Fengjie Wan
- School of Public Health, Guangxi Medical University, Nanning 530021, China
| | - Hui Li
- School of Public Health, Guangxi Medical University, Nanning 530021, China
| | - Shiping Huang
- School of Public Health, Guangxi Medical University, Nanning 530021, China
| | - Junming Sun
- Laboratory Animal Center, Guangxi Medical University, Nanning 530021, China
| | - Jiafu Li
- Laboratory Animal Center, Guangxi Medical University, Nanning 530021, China
| | - Yasi Li
- Department of Public Health Sciences, College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA
| | - Lichao Yang
- Laboratory Animal Center, Guangxi Medical University, Nanning 530021, China.
| | - Min He
- School of Public Health, Guangxi Medical University, Nanning 530021, China; Laboratory Animal Center, Guangxi Medical University, Nanning 530021, China; Key Laboratory of High-Incidence-Tumor Prevention & Treatment (Guangxi Medical University), Ministry of Education, Nanning 530021, China.
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14
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Wang S, Xu N, Wang J, Chen Y, Li W, Chen H, Shen C, Xu C, Wei X, Lu D, Qiu N, Zheng S, Wei Q, Xu X. BMI1-induced CD127+KLRG1+ memory T cells enhance the efficacy of liver cancer immunotherapy. Cancer Lett 2023; 571:216336. [PMID: 37562671 DOI: 10.1016/j.canlet.2023.216336] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 08/02/2023] [Accepted: 08/03/2023] [Indexed: 08/12/2023]
Abstract
The efficacy of HCC (hepatocellular carcinoma) immunotherapy is hindered by the limited reactivity and short duration of tumor-infiltrating T cells. These deficiencies may be ascribed to the proliferative ability of T cells. The primary objective of this study was to identify the key factor regulating tumor-infiltrating lymphocytes (TIL) proliferation within the HCC microenvironment. Through the utilization of tissue-infiltrated T cell proteomics and fraction proteomics, we analyzed the differential proteins in T cells among HCC, liver fibrosis, and hemangioma (serving as controls) groups. Additionally, we examined the differential regulatory TFs of T cells between the HCC and VH (volunteer healthy, as a control) groups. Using cyTOF and flow cytometry technologies, as well as generating CD8+ T-specific BMI1 knockout mice, we confirmed that BMI1 controls CD127+KLRG1+ memory cell differentiation. Through RNA-seq and MeRIP-seq, we verified that BMI1 regulates TCF1 expression independently of its classical function. Furthermore, by conducting Tyramide signal amplification (TSA) IHC analysis, employing a hydrodynamic mouse HCC model, and utilizing liver-specific nanoparticle targeting therapy, we demonstrated that BMI1 in HCC influences the proliferation of infiltrating CD8+T. BMI1 inhibition promotes effector T cell differentiation while suppressing memory T cell differentiation. Moreover, liver-specific BMI1 knockdown proves beneficial in ameliorating T cell dysfunction and decelerating HCC progression. Our research group has pioneered the exploration of the proteomics of HCC-infiltrated T cells, shedding light on the pivotal role of BMI1 in controlling CD127+KLRG1+ memory CD8+ T cell differentiation, which serves as the cornerstone for achieving immunotherapy efficacy in HCC.
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Affiliation(s)
- Shuai Wang
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Nan Xu
- Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Jianguo Wang
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Yiyuan Chen
- The Forth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Wangyao Li
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Huan Chen
- The Forth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Chenchen Shen
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Chen Xu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Xuyong Wei
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Di Lu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Nasha Qiu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Shusen Zheng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, China; Shulan (Hangzhou) Hospital, Zhejiang Shuren University School of Medicine, Hangzhou, 310022, China
| | - Qiang Wei
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China; State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, China.
| | - Xiao Xu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China; Zhejiang University School of Medicine, Hangzhou, 310058, China; State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, China.
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15
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Brown ZJ, Ruff SM, Pawlik TM. The effect of liver disease on hepatic microenvironment and implications for immune therapy. Front Pharmacol 2023; 14:1225821. [PMID: 37608898 PMCID: PMC10441240 DOI: 10.3389/fphar.2023.1225821] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Accepted: 07/31/2023] [Indexed: 08/24/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the fourth leading cause of cancer-related death worldwide. HCC often occurs in the setting of chronic liver disease or cirrhosis. Recent evidence has highlighted the importance of the immune microenvironment in the development and progression of HCC, as well as its role in the potential response to therapy. Liver disease such as viral hepatitis, alcohol induced liver disease, and non-alcoholic fatty liver disease is a major risk factor for the development of HCC and has been demonstrated to alter the immune microenvironment. Alterations in the immune microenvironment may markedly influence the response to different therapeutic strategies. As such, research has focused on understanding the complex relationship among tumor cells, immune cells, and the surrounding liver parenchyma to treat HCC more effectively. We herein review the immune microenvironment, as well as the relative effect of liver disease on the immune microenvironment. In addition, we review how changes in the immune microenvironment can lead to therapeutic resistance, as well as highlight future strategies aimed at developing the next-generation of therapies for HCC.
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Affiliation(s)
- Zachary J. Brown
- Department of Surgery, New York University Long Island School of Medicine, Mineola, NY, United States
| | - Samantha M. Ruff
- James Comprehensive Cancer Center, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Timothy M. Pawlik
- James Comprehensive Cancer Center, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, United States
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16
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Li Z, Zhang Y, Zhang B, Guo R, He M, Liu ZL, Yang L, Wang H. Bibliometric study of immunotherapy for hepatocellular carcinoma. Front Immunol 2023; 14:1210802. [PMID: 37600802 PMCID: PMC10436521 DOI: 10.3389/fimmu.2023.1210802] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 07/20/2023] [Indexed: 08/22/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC), recognized as a significant global health concern, ranks as the sixth most prevalent form of cancer and is the third leading cause of cancer-associated mortality. Over half of HCC patients are diagnosed at advanced stages, an unfortunate phenomenon primarily attributed to the liver's robust compensatory mechanisms. Given the limited availability of donor livers, existing clinical surgical approaches have yet to provide universally applicable treatment strategies offering substantial prognostic improvement for late-stage cancer. Although the past few decades have witnessed significant advancements in chemotherapy and targeted therapy for HCC, the emergence of drug resistance poses a substantial impediment to their successful execution. Furthermore, issues such as diminished quality of life post-treatment and high treatment costs warrant critical attention. Consequently, the imperative for an effective treatment strategy for advanced liver cancer is unequivocal. In recent years, notable progress in the development and application of immunotherapy has sparked a revolution in advanced liver cancer treatment. This study aims to elucidate a more comprehensive understanding of the current landscape, knowledge framework, research focal points, and nascent breakthrough trends in the domain of immunotherapy for hepatocellular carcinoma via bibliometric analysis. METHOD Our study involved conducting a comprehensive literature search spanning from 1999 through December 31, 2022, by utilizing the Science Citation Index Expanded (SCI-Expanded) database. Our aim was to amass all the papers and reviews related to immunotherapy for hepatocellular carcinoma. Our search strategy yielded a total of 4,486 papers. After exclusion of self-citations, we focused our analysis on 68,925 references. These references were cited 119,523 times (excluding 97,941 self-citations), boasting an average citation frequency of 26.64 times per paper, and achieved an h-index of 135. We employed analytical software tools like Citespace and VOSviewer to perform an intricate analysis of the amassed literature, covering various aspects, including geographical location, research institutions, publishing journals, authors, references, and keywords. Our method incorporated timeline analysis, burst detection, and co-occurrence analysis. The application of these tools facilitated a thorough evaluation of research hotspots, knowledge structure, and emerging advancements within the sphere of immunotherapy for hepatocellular carcinoma. RESULTS Our bibliometric analysis disclosed a noteworthy escalation in the number of publications in the realm of hepatocellular carcinoma immunotherapy during the years 2021-2022, surpassing the aggregate number of papers published in the preceding decade (2011-2020). This surge underscores a sharp upturn in research interest within this field. Additionally, the research hotspot in hepatocellular carcinoma immunotherapy has perceptibly deviated from the preceding decade's trends. In terms of geographical distribution, China emerged as the leading country, producing 50.08% of the total publications. This was followed by the United States, with 963 papers, and Japan, contributing 335 papers. Among research institutions, Sun Yat-sen University was the most prolific, while Tim F. Greten stood out as the most published author with 42 papers to his credit. A co-reference network examination uncovered a shift in research emphasis within the field of hepatocellular carcinoma immunotherapy, highlighting the evolving nature of this important area of study. CONCLUSION Our bibliometric study highlights the significant evolution and growth in HCC immunotherapy research over the past two decades. Looking ahead, research will focus on improving the microenvironment post-drug resistance from immune combination therapy, harnessing adoptive cellular immunity (as CAR-T), subclassify the population and developing new tumor markers. Incorporation of technologies such as nanotechnology, microbiology, and gene editing will further advance HCC treatments. This progressive trajectory in the field promises a brighter future for individuals suffering from HCC.
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Affiliation(s)
- Zhiyi Li
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Ying Zhang
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Baipan Zhang
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Rui Guo
- Department of Clinical Laboratory, First Affiliated Hospital of Jilin University, Changchun, China
| | - Minhua He
- College of Computer Science and Technology, Jilin University, Changchun, China
| | - Zi-Ling Liu
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Lei Yang
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Hong Wang
- Cancer Center, The First Hospital of Jilin University, Changchun, China
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17
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Li R, Liu X, Deng K, Wang X. M7G methylated core genes (METTL1 and WDR4) and associated RNA risk signatures are associated with prognosis and immune escape in HCC. BMC Med Genomics 2023; 16:179. [PMID: 37528384 PMCID: PMC10394781 DOI: 10.1186/s12920-023-01614-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 07/21/2023] [Indexed: 08/03/2023] Open
Abstract
N7 methylguanosine (m7G) has a crucial role the development of hepatocellular carcinoma (HCC). This study aimed to investigate the impact of the m7G methylation core genes (METTL1 and WDR4) and associated RNA risk signatures on HCC. we found m7G methylation core genes (METTL1 and WDR4) were upregulated in four HCC cell lines, and downregulation of METTL1 and WDR4 attenuated HCC cell proliferation, migration, and invasion. Moreover, METTL1 and WDR4 are upregulated in HCC tissues, and that there is a significant positive correlation between them. METTL1 and WDR4 were identified as independent prognostic markers for HCC by employing overall survival (OS), disease-specific survival (DSS), Progression Free Interval survival (PFI), and univariate/multivariate Cox analyses. We identified 1479 coding RNAs (mRNAs) and 232 long non-coding RNAs (lncRNAs) associated with METTL1 / WDR4 by using weighted coexpression network analysis (WGCNA) and co-clustering analysis. The least absolute shrinkage and selection operator (lasso) were used to constructing mRNA and lncRNA risk signatures associated with the METTL1 / WDR4. These risk were independent poor prognostic factors in HCC. Furthermore, we found that METTL1 / WDR4 expression and mRNA / lncRNA risk scores were closely associated with TP53 mutations. Clinicopathological features correlation results showed that METTL1 / WDR4 expression and mRNA / lncRNA risk score were associated with the stage and invasion depth (T) of HCC. To predict the overall survival of HCC individuals, we constructed a nomogram with METTL1/WDR4 expression, mRNA/lncRNA risk score, and clinicopathological features. In addition, we combined single-cell sequencing datasets and immune escape-related checkpoints to construct an immune escape-related protein-protein interaction(PPI) network. In conclusion, M7G methylated core genes (METTL1 and WDR4) and associated RNA risk signatures are associated with prognosis and immune escape in HCC.
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Affiliation(s)
- Rui Li
- Jiangnan University Medical Center, WuXi, China
- Wuxi No.2 People's Hospital, WuXi, China
- The Affiliated Wuxi No.2 People's Hospital of Clinical College of Nantong University, WuXi, China
| | | | - Kaiyuan Deng
- Jiangnan University Medical Center, WuXi, China
- Wuxi No.2 People's Hospital, WuXi, China
- The Affiliated Wuxi No.2 People's Hospital of Clinical College of Nantong University, WuXi, China
| | - Xin Wang
- Jiangnan University Medical Center, WuXi, China.
- Wuxi No.2 People's Hospital, WuXi, China.
- The Affiliated Wuxi No.2 People's Hospital of Clinical College of Nantong University, WuXi, China.
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18
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Yadav S. Advanced therapeutics avenues in hepatocellular carcinoma: a novel paradigm. Med Oncol 2023; 40:239. [PMID: 37442842 DOI: 10.1007/s12032-023-02104-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 06/21/2023] [Indexed: 07/15/2023]
Abstract
Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer, and it poses a significant risk to patients health and longevity due to its high morbidity and fatality rates. Surgical ablation, radiotherapy, chemotherapy, and, most recently, immunotherapy have all been investigated for HCC, but none have yielded the desired outcomes. Several unique nanocarrier drug delivery techniques have been studied for their potential therapeutic implications in the treatment of HCC. Nanoparticle-based imaging could be effective for more accurate HCC diagnosis. Since its inception, nanomedicine has significantly transformed the approach to both the treatment and diagnostics of liver cancer. Nanoparticles (NPs) are being studied as a potential treatment for liver cancer because of their ability to carry small substances, such as treatment with chemotherapy, microRNA, and therapeutic genes. The primary focus of this study is on the most current discoveries and practical uses of nanomedicine-based diagnostic and therapeutic techniques for liver cancer. In this section, we had gone over what we know about metabolic dysfunction in HCC and the treatment options that attempt to fix it by targeting metabolic pathways. Furthermore, we propose a multi-target metabolic strategy as a viable HCC treatment option. Based on the findings given here, the scientists believe that smart nanomaterials have great promise for improving cancer theranostics and opening up new avenues for tumor diagnosis and treatment.
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Affiliation(s)
- Shikha Yadav
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Plot No.2, Sector 17-A, Yamuna Expressway, Gautam Buddhnagar, Greater Noida, Uttar Pradesh, 201310, India.
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19
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Dasanu CA, Alani M, Habibi S, Codreanu I. Immune checkpoint inhibition in advanced colorectal cancer with inherited and acquired microsatellite instability: Current state and future directions. J Oncol Pharm Pract 2023:10781552231178293. [PMID: 37246506 DOI: 10.1177/10781552231178293] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
Abstract
OBJECTIVE This paper reviews comprehensively the most relevant data on single-agent and combination therapies for advanced colorectal cancer with inherited and acquired microsatellite instability (MSI). DATA SOURCES We performed a systematic search on PubMed and MEDLINE articles published from inception to December 2022. We have also searched independent websites including U.S. Food and Drug Administration and ClinicalTrials.gov. DATA SUMMARY Performing microsatellite stability testing, tumor mutational burden (TMB), and germline mutation analysis could identify patients with metastatic colorectal cancer that benefit from immune checkpoint inhibitor (ICI) therapy. Single-agent pembrolizumab has proven superiority over traditional chemotherapy in these patients. The nivolumab-ipilimumab is the only combination ICI therapy approved in this space. Recently, the anti-PD-1 antibody dostarlimab was granted Food and Drug Administration approval in refractory tissue-agnostic advanced solid cancers with deficient mismatch repair (dMMR). ICIs are also being studied in the adjuvant/neoadjuvant setting in colon cancer patients with dMMR. Newer agents are being scrutinized in this space as well. More solid data on biomarkers predicting responses in patients with MSI-high or TMB-H to various therapies are needed. Given its both clinical and financial toxicity, it is imperative to determine the optimal duration of ICI therapy in individual patients. CONCLUSIONS Overall, the outlook in advanced colorectal cancer patients with MSI appears optimistic as new and efficacious ICI drugs and combinations are being added to the existing therapeutic armamentarium.
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Affiliation(s)
- Constantin A Dasanu
- Lucy Curci Cancer Center, Eisenhower Health, Rancho Mirage, CA, USA
- Department of Medical Oncology and Hematology, UC San Diego Health System, San Diego, CA, USA
| | - Mohammed Alani
- Department of Medicine, Eisenhower Health, Rancho Mirage, CA, USA
| | | | - Ion Codreanu
- Translational Imaging Center, Houston Methodist Research Institute, Houston, TX, USA
- Department of Radiology, Nicolae Testemitanu State University of Medicine and Pharmacy, Chisinau, Republic of Moldova
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20
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Shen C, Li M, Duan Y, Jiang X, Hou X, Xue F, Zhang Y, Luo Y. HDAC inhibitors enhance the anti-tumor effect of immunotherapies in hepatocellular carcinoma. Front Immunol 2023; 14:1170207. [PMID: 37304265 PMCID: PMC10250615 DOI: 10.3389/fimmu.2023.1170207] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 05/18/2023] [Indexed: 06/13/2023] Open
Abstract
Hepatocellular carcinoma (HCC), the most common liver malignancy with a poor prognosis and increasing incidence, remains a serious health problem worldwide. Immunotherapy has been described as one of the ideal ways to treat HCC and is transforming patient management. However, the occurrence of immunotherapy resistance still prevents some patients from benefiting from current immunotherapies. Recent studies have shown that histone deacetylase inhibitors (HDACis) can enhance the efficacy of immunotherapy in a variety of tumors, including HCC. In this review, we present current knowledge and recent advances in immunotherapy-based and HDACi-based therapies for HCC. We highlight the fundamental dynamics of synergies between immunotherapies and HDACis, further detailing current efforts to translate this knowledge into clinical benefits. In addition, we explored the possibility of nano-based drug delivery system (NDDS) as a novel strategy to enhance HCC treatment.
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Affiliation(s)
- Chen Shen
- Department of Laboratory Medicine, Medical Equipment Innovation Research Center/Medical Device Regulatory Research and Evaluation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Mei Li
- Department of Laboratory Medicine, Medical Equipment Innovation Research Center/Medical Device Regulatory Research and Evaluation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yujuan Duan
- School of Chemical Science and Engineering, Tongji University, Shanghai, China
- School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Xin Jiang
- Department of Laboratory Medicine, Medical Equipment Innovation Research Center/Medical Device Regulatory Research and Evaluation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaoming Hou
- Department of Laboratory Medicine, Medical Equipment Innovation Research Center/Medical Device Regulatory Research and Evaluation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Fulai Xue
- Department of Laboratory Medicine, Medical Equipment Innovation Research Center/Medical Device Regulatory Research and Evaluation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yinan Zhang
- School of Chemical Science and Engineering, Tongji University, Shanghai, China
| | - Yao Luo
- Department of Laboratory Medicine, Medical Equipment Innovation Research Center/Medical Device Regulatory Research and Evaluation Center, West China Hospital, Sichuan University, Chengdu, China
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21
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Yin KL, Li M, Liao R, Shi ZR, Qiu JG, Lan X, Duan YX, Ye WT, Wu ZY, Du CY, Xiao H. The combination of a prolonged treatment time window and alpha-fetoprotein benefits the tumor response of hepatocellular carcinoma patients as evaluated by the imRECIST: a single-center, retrospective study. J Gastrointest Oncol 2023; 14:932-942. [PMID: 37201094 PMCID: PMC10186499 DOI: 10.21037/jgo-23-167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 04/17/2023] [Indexed: 05/20/2023] Open
Abstract
BACKGROUND The combined immunotargeting therapy of hepatocellular carcinoma (HCC) have brought remarkable results. There are still some drawbacks to the application of the immune-modified Response Evaluation Criteria in Solid Tumors to Immunotherapy (imRECIST). How many weeks does it take to confirm the true disease progression for HCC patients who had reported disease progression for the first time based on imRECIST. Whether alpha-fetoprotein (AFP), an important indicator in the progression and prognosis of liver cancer, has the same value in immunotherapy. This prompted more clinical data to gather evidence that the immunotherapy time window issue contradicts the potential benefit of therapy. METHODS This study retrospectively analyzed the clinical data of 32 patients who had undergone immunotherapy plus targeted therapy at the First Affiliated Hospital of Chongqing Medical University from June 2019 to June 2022. ImRECIST was used to evaluate the therapeutic efficacy among the patients. Before initial treatment and each immunotherapy cycle, each patient underwent standard abdominal computed tomography (CT) imaging and some biochemical indicators to assess physical condition and tumor response. All patients included will be divided into 8 groups. The differences in the survival outcomes of each treatment group were analysed. RESULTS Among the 32 advanced HCC patients, 9 patients achieved stable disease (SD), 12 patients showed progressive disease (PD), 3 patients showed a complete response (CR), and 8 patients showed a partial response (PR). There is no difference in baseline characteristics between subgroups. In relation to patients with PD, a prolonged therapeutic time window and the provision of continuous medication may lead to a PR, prolonging their overall survival (P=0.5864). Compared to the patients with continuous PD, there was no significant difference in the survival of patients with increased AFP concentrations after treatment who achieved PR or SD and ultimately showed PD (P=0.6600). CONCLUSIONS In our study, the time window for treatment may need to be extended in the process of immunotherapy for HCC patients. An analysis of AFP may assist the imRECIST by providing a more accurate evaluation of tumor progression.
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Affiliation(s)
- Kun-Li Yin
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ming Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Rui Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zheng-Rong Shi
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jian-Guo Qiu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiang Lan
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yu-Xin Duan
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wen-Tao Ye
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhou-Yu Wu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Cheng-You Du
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Heng Xiao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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22
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Xi G, Cheng R, Liang L, Che N, Wang Y, Zhao N, Liang X, Shao B, Zhao X, Zhang D. High expression of RNF31 is associated with tumor immune cell infiltration and leads to poor prognosis in liver hepatocellular carcinoma. Sci Rep 2023; 13:6957. [PMID: 37117215 PMCID: PMC10147728 DOI: 10.1038/s41598-023-32692-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 03/31/2023] [Indexed: 04/30/2023] Open
Abstract
Ring finger protein 31 (RNF31) has been found to play an important role in tumor immunity. However, the role of RNF31 in liver hepatocellular carcinoma (LIHC) has not been reported. Therefore, we investigated the expression and prognostic value of RNF31 in patients with LIHC and explored its relationship with immune cell infiltration. The Cancer Genome Atlas liver hepatocellular carcinoma (TCGA-LIHC) dataset was downloaded to analyse the impact of RNF31 on the prognosis and immune cell infiltration of LIHC. The Tumor Immune Estimation Resource (TIMER) database was used to analyse the correlation between RNF31 and tumor immune cell infiltration in LIHC. Additionally, we analysed the relationship between RNF31 and tumor necrosis factor (TNF) as well as the interferon-gamma (IFN-γ) signaling pathway. The expression of RNF31 in LIHC was significantly higher than that in normal tissues. Increased RNF31 expression was associated with decreased overall survival (OS) and relapse-free survival (RFS). An increase in RNF31 expression was closely related to the infiltration levels of immune cells (e.g., natural killer (NK) cells, CD8 + T cells, and B cells). RNF31 was also positively correlated with the expression of immune checkpoint genes in LIHC. Moreover, RNF31 may participate in TNF and IFN-γ signaling pathways. In conclusion, RNF31 is a potentially valuable prognostic biomarker in LIHC. RNF31 is also associated with immune cell infiltration in LIHC. RNF31 may be a potential target for immunotherapy of LIHC.
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Affiliation(s)
- Guifu Xi
- Department of Pathology, Tianjin Medical University, Tianjin, 300070, China
| | - Runfen Cheng
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China
| | - Leiting Liang
- Department of Pathology, Tianjin Medical University, Tianjin, 300070, China
| | - Na Che
- Department of Pathology, Tianjin Medical University, Tianjin, 300070, China
| | - Yalei Wang
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China
| | - Nan Zhao
- Department of Pathology, Tianjin Medical University, Tianjin, 300070, China
| | - Xiaohui Liang
- Department of Pathology, Tianjin Medical University, Tianjin, 300070, China
| | - Bing Shao
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China
| | - Xiulan Zhao
- Department of Pathology, Tianjin Medical University, Tianjin, 300070, China.
| | - Danfang Zhang
- Department of Pathology, Tianjin Medical University, Tianjin, 300070, China.
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23
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Li Z, Huang L, Li J, Yang W, Li W, Long Q, Dai X, Wang H, Du G. Immunological role and prognostic value of the SKA family in pan-cancer analysis. Front Immunol 2023; 14:1012999. [PMID: 37180139 PMCID: PMC10169755 DOI: 10.3389/fimmu.2023.1012999] [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: 08/06/2022] [Accepted: 02/27/2023] [Indexed: 05/15/2023] Open
Abstract
Background The spindle and kinetochore associated (SKA) complex, which plays important roles in proper chromosome segregation during mitosis by maintaining the stabilization of kinetochore-spindle microtubule attachment during mitosis, has recently been reported to exert regulatory effects on the initiation and progression of various human cancer types. Nevertheless, the prognostic significance and immune infiltration of the SKA family across cancers have not been well elucidated. Methods Using data from three large public datasets, including The Cancer Genome Atlas, Genotype-Tissue Expression, and Gene Expression Omnibus databases, a novel scoring system (termed the SKA score) was developed to quantify the SKA family level across cancers. We then evaluated the prognostic impact of the SKA score on survival and assessed the effect of the SKA score on immunotherapy at the pan-cancer level using multiomics bioinformatic analyses. The correlation of the SKA score and the tumor microenvironment (TME) was also explored in depth. Potential small molecular compounds and chemotherapeutic agents were assessed by CTRP and GDSC analyses. Immunohistochemistry was performed to verify the expression of the SKA family genes. Results Our results demonstrated a close correlation between the SKA score and tumor development and prognosis in multiple cancers. The SKA score was positively related to cell cycle pathways and DNA replication across cancers, such as E2F targets, the G2M checkpoint, MYC targets V1/V2, mitotic spindles and DNA repair. Additionally, the SKA score was negatively related to the infiltration of various immune cells with antitumor effects in the TME. In addition, the potential value of the SKA score was identified to predict immunotherapy response for melanoma and bladder cancer. We also demonstrated a correlation between SKA1/2/3 and the response to drug treatment across cancers and the promising potential of the SKA complex and its genes as therapeutic targets in cancer. Immunohistochemistry demonstrated that the expression differences of SKA1/2/3 were significant between the breast cancer group and the paracancerous group. Conclusion The SKA score plays a critical role in 33 cancer types and is highly related to tumor prognosis. Patients with elevated SKA scores have a clear immunosuppressive TME. The SKA score may serve as a predictor for patients receiving anti-PD-1/L1 therapy.
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Affiliation(s)
- Zhengtian Li
- Department of Bone and Joint Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Lanying Huang
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jiachen Li
- Department of Gastrointestinal and Gland Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Wenkang Yang
- Department of Gastrointestinal and Gland Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Weichao Li
- Department of Bone and Joint Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Qiuzhong Long
- Department of Bone and Joint Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xinyu Dai
- Department of Bone and Joint Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Hongtao Wang
- Department of Bone and Joint Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Gang Du
- Department of Bone and Joint Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
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Minaei N, Ramezankhani R, Tamimi A, Piryaei A, Zarrabi A, Aref AR, Mostafavi E, Vosough M. Immunotherapeutic approaches in Hepatocellular carcinoma: Building blocks of hope in near future. Eur J Cell Biol 2023; 102:151284. [PMID: 36584598 DOI: 10.1016/j.ejcb.2022.151284] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 11/30/2022] [Accepted: 12/16/2022] [Indexed: 12/23/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary hepatic cancer and is among the major causes of mortality due to cancer. Due to the lack of efficient conventional therapeutic options for this cancer, particularly in advanced cases, novel treatments including immunotherapy have been considered. However, despite the encouraging clinical outcomes after implementing these innovative approaches, such as oncolytic viruses (OVs), adoptive cell therapies (ACT), immune checkpoint blockades (ICBs), and cancer vaccines, several factors have restricted their therapeutic effect. The main concern is the existence of an immunosuppressive tumor microenvironment (TME). Combination of different ICBs or ICBs plus tyrosine kinase inhibitors have shown promising results in overcoming these limiting factors to some extent. Combination of programmed cell death ligand-1 (PD-L1) antibody Atezolizumab and vascular endothelial growth factor (VEGF) antibody Bevacizumab has become the standard of care in the first-line therapy for untestable HCC, approved by regulatory agencies. This paper highlighted a wide overview of the direct and indirect immunotherapeutic strategies proposed for the treatment of HCC patients and the common challenges that have hindered their further clinical applications.
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Affiliation(s)
- Neda Minaei
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran; Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
| | - Roya Ramezankhani
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran; Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran; Department of Development and Regeneration, KU Leuven Stem Cell Institute, Leuven, Belgium
| | - Atena Tamimi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
| | - Abbas Piryaei
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul 34396, Turkey
| | - Amir Reza Aref
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Ebrahim Mostafavi
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran; Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran; Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institutet and Karolinska University Hospital-Huddinge, Sweden.
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25
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You S, Luo Z, Cheng N, Wu M, Lai Y, Wang F, Zheng X, Wang Y, Liu X, Liu J, Zhao B. Magnetically responsive nanoplatform targeting circRNA circ_0058051 inhibits hepatocellular carcinoma progression. Drug Deliv Transl Res 2023; 13:782-794. [PMID: 36114310 PMCID: PMC9892167 DOI: 10.1007/s13346-022-01237-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/03/2022] [Indexed: 02/05/2023]
Abstract
Circular RNAs (circRNAs) are a class of highly stable and closed-loop noncoding RNA that are involved in the occurrence and development of hepatocellular carcinoma (HCC). However, little is known about the therapeutic role of circRNAs in HCC. We found that high circ_0058051 expression was negatively correlated with the prognosis of HCC patients. Circ_0058051 knockdown attenuated the proliferation and colony formation, meanwhile inhibited migration of HCC cells. Circ_0058051 may be used as a target for HCC gene therapy. We synthesized a novel small interfering RNA (siRNA) delivery system, PEG-PCL-PEI-C14-SPIONs (PPPCSs), based on superparamagnetic iron oxide nanoparticles (SPIONs). PPPCSs protected the siRNA of circ_0058051 from degradation in serum and effectively delivered siRNA into SMMC-7721 cells. Meanwhile, intravenous injection of the PPPCSs/siRNA complex could inhibit tumor growth in the subcutaneous tumor model. In addition, the nanocomposite is not toxic to the organs of nude mice. The above results show that PPPCSs/si-circ_0058051 complex may provide a novel and promising method of HCC treatment.
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Affiliation(s)
- Song You
- Department of Hepatobiliary Surgery, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, 350014, People's Republic of China
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People's Republic of China
- The Third Clinical Medical College, Fujian Medical University, Fuzhou, 350122, People's Republic of China
| | - Zijin Luo
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People's Republic of China
| | - Niangmei Cheng
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People's Republic of China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, People's Republic of China
| | - Ming Wu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People's Republic of China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, People's Republic of China
| | - Yongping Lai
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People's Republic of China
| | - Fei Wang
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People's Republic of China
| | - Xiaoyuan Zheng
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People's Republic of China
| | - Yingchao Wang
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People's Republic of China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, People's Republic of China
| | - Xiaolong Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People's Republic of China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, People's Republic of China
| | - Jingfeng Liu
- Department of Hepatobiliary Surgery, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, 350014, People's Republic of China.
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People's Republic of China.
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, People's Republic of China.
| | - Bixing Zhao
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People's Republic of China.
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, People's Republic of China.
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26
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Zhang W, Yang C, Hu Y, Yi K, Xiao W, Xu X, Chen Z. Comprehensive analysis of the correlation of the pan-cancer gene HAUS5 with prognosis and immune infiltration in liver cancer. Sci Rep 2023; 13:2409. [PMID: 36765148 PMCID: PMC9918732 DOI: 10.1038/s41598-023-28653-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 01/23/2023] [Indexed: 02/12/2023] Open
Abstract
Liver hepatocellular carcinoma (LIHC) is one of the most common malignancies and places a heavy burden on patients worldwide. HAUS augmin-like complex subunit 5 (HAUS5) is involved in the occurrence and development of various cancers. However, the functional role and significance of HAUS5 in LIHC remain unclear. The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Cancer Cell Line Encyclopedia (CCLE) and Gene Expression Omnibus (GEO) databases were used to analyze the mRNA expression of HAUS5. The value of HAUS5 in predicting LIHC prognosis and the relationship between HAUS5 and clinicopathological features were assessed by the Kaplan-Meier plotter and UALCAN databases. Functional enrichment analyses and nomogram prediction model construction were performed with the R packages. The LinkedOmics database was searched to reveal co-expressed genes associated with HAUS5. The relationship between HAUS5 expression and immune infiltration was explored by searching the TISIDB database and single-sample gene set enrichment analysis (ssGSEA). The Clinical Proteomic Tumor Analysis Consortium (CPTAC) and the Human Protein Atlas (HPA) databases were used to evaluate HAUS5 protein expression. Finally, the effect of HAUS5 on the proliferation of hepatoma cells was verified by CCK-8, colony formation and EdU assays. HAUS5 is aberrantly expressed and associated with a poor prognosis in most tumors, including LIHC. The expression of HAUS5 is significantly correlated with clinicopathological indicators in patients with LIHC. Functional enrichment analysis showed that HAUS5 was closely related to DNA replication, cell cycle and p53 signaling pathway. HAUS5 may serve as an independent risk factor for LIHC prognosis. The nomogram based on HAUS5 had area under the curve (AUC) values of 0.74 and 0.77 for predicting the 3-year and 5-year overall survival (OS) of LIHC patients. Immune correlation analysis showed that HAUS5 was significantly associated with immune infiltration. Finally, the results of in vitro experiments showed that when HAUS5 was knocked down, the proliferation of hepatoma cells was significantly decreased. The pan-oncogene HAUS5 is a positive regulator of LIHC progression and is closely associated with a poor prognosis in LIHC. Moreover, HAUS5 is involved in immune infiltration in LIHC. HAUS5 may be a new prognostic marker and therapeutic target for LIHC patients.
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Affiliation(s)
- Wenbing Zhang
- Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
- Department of General Surgery, The First People's Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, No. 58 Changsheng South Road, Taicang, Suzhou, 215400, Jiangsu, People's Republic of China
| | - Chi Yang
- Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
- Department of General Surgery, The First People's Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, No. 58 Changsheng South Road, Taicang, Suzhou, 215400, Jiangsu, People's Republic of China
| | - Yan Hu
- Central Laboratory, The First People's Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, No. 58 Changsheng South Road, Taicang, Suzhou, 215400, Jiangsu, People's Republic of China
| | - Ke Yi
- Central Laboratory, The First People's Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, No. 58 Changsheng South Road, Taicang, Suzhou, 215400, Jiangsu, People's Republic of China
| | - Wangwen Xiao
- Central Laboratory, The First People's Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, No. 58 Changsheng South Road, Taicang, Suzhou, 215400, Jiangsu, People's Republic of China
| | - Xiaohui Xu
- Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China.
- Department of General Surgery, The First People's Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, No. 58 Changsheng South Road, Taicang, Suzhou, 215400, Jiangsu, People's Republic of China.
- Central Laboratory, The First People's Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, No. 58 Changsheng South Road, Taicang, Suzhou, 215400, Jiangsu, People's Republic of China.
| | - Zhihua Chen
- Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China.
- Department of General Surgery, The First People's Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, No. 58 Changsheng South Road, Taicang, Suzhou, 215400, Jiangsu, People's Republic of China.
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Qi Y, Song Y, Cai M, Li J, Yu Z, Li Y, Huang J, Jiang Y, Peng C, Jiang B, Liu S. Vascular endothelial growth factor A is a potential prognostic biomarker and correlates with immune cell infiltration in hepatocellular carcinoma. J Cell Mol Med 2023; 27:538-552. [PMID: 36729917 PMCID: PMC9930434 DOI: 10.1111/jcmm.17678] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 09/30/2022] [Accepted: 01/06/2023] [Indexed: 02/03/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths among cancer patients. Vascular endothelial growth factor A (VEGFA) is involved in regulating biological processes, such as angiogenesis and vascular permeability, and is very closely related to the pathogenesis of various tumours, especially vascular-rich, solid tumours. Clinical data of patients with HCC and other tumours were analysed through public databases, such as the TCGA database, Gene Expression Omnibus database, Human Protein Atlas database, STRING, Tumour Immune Estimation Resource and Kaplan-Meier Plotter. The tumour tissues and adjacent normal tissues of patients with HCC from Hunan Provincial People's Hospital were collected to verify the expression of VEGFA by immunohistochemistry, immunofluorescence, Western blotting and qPCR. VEGFA expression is elevated in multiple tumour types and correlates with the prognosis of tumour patients. VEGFA is involved in regulating the tumour microenvironment and immune cell function in tumour development. Inhibition of VEGFA reduces proliferation, invasion, and migration and promotes apoptosis in HCC cells. VEGFA is a potential predictive biomarker for the diagnosis and prognosis of HCC.
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Affiliation(s)
- Yuchen Qi
- Department of Hepatobiliary SurgeryHunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal UniversityChangshaChina
- Department of CardiologyXiangdong Hospital Affiliated to Hunan Normal UniversityLilingChina
- Central Laboratory of Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal UniversityChangshaChina
| | - Yinghui Song
- Department of Hepatobiliary SurgeryHunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal UniversityChangshaChina
- Central Laboratory of Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal UniversityChangshaChina
| | - Mengting Cai
- Department of Nuclear MedicineHunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal UniversityChangshaChina
| | - Jianwen Li
- Department of CardiologyXiangdong Hospital Affiliated to Hunan Normal UniversityLilingChina
| | - Zhangtao Yu
- Department of Hepatobiliary SurgeryHunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal UniversityChangshaChina
| | - Yuhang Li
- Department of Hepatobiliary SurgeryHunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal UniversityChangshaChina
| | - Junkai Huang
- Department of Hepatobiliary SurgeryHunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal UniversityChangshaChina
| | - Yu Jiang
- Institute of Emergency Medicine/Hunan Provincial Key Laboratory of Emergency and Critical Care MetabonomicsHunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal UniversityChangshaChina
| | - Chuang Peng
- Department of Hepatobiliary SurgeryHunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal UniversityChangshaChina
| | - Bo Jiang
- Department of Hepatobiliary SurgeryHunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal UniversityChangshaChina
| | - Sulai Liu
- Department of Hepatobiliary SurgeryHunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal UniversityChangshaChina
- Central Laboratory of Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal UniversityChangshaChina
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Xie T, Wei Y, Xu L, Li Q, Che F, Xu Q, Cheng X, Liu M, Yang M, Wang X, Zhang F, Song B, Liu M. Self-supervised contrastive learning using CT images for PD-1/PD-L1 expression prediction in hepatocellular carcinoma. Front Oncol 2023; 13:1103521. [PMID: 36937385 PMCID: PMC10020705 DOI: 10.3389/fonc.2023.1103521] [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: 11/20/2022] [Accepted: 02/03/2023] [Indexed: 03/06/2023] Open
Abstract
Background and purpose Programmed cell death protein-1 (PD-1) and programmed cell death-ligand-1 (PD-L1) expression status, determined by immunohistochemistry (IHC) of specimens, can discriminate patients with hepatocellular carcinoma (HCC) who can derive the most benefits from immune checkpoint inhibitor (ICI) therapy. A non-invasive method of measuring PD-1/PD-L1 expression is urgently needed for clinical decision support. Materials and methods We included a cohort of 87 patients with HCC from the West China Hospital and analyzed 3094 CT images to develop and validate our prediction model. We propose a novel deep learning-based predictor, Contrastive Learning Network (CLNet), which is trained with self-supervised contrastive learning to better extract deep representations of computed tomography (CT) images for the prediction of PD-1 and PD-L1 expression. Results Our results show that CLNet exhibited an AUC of 86.56% for PD-1 expression and an AUC of 83.93% for PD-L1 expression, outperforming other deep learning and machine learning models. Conclusions We demonstrated that a non-invasive deep learning-based model trained with self-supervised contrastive learning could accurately predict the PD-1 and PD-L1 expression status, and might assist the precision treatment of patients withHCC, in particular the use of immune checkpoint inhibitors.
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Affiliation(s)
- Tianshu Xie
- Yangtze Delta Region Institute (Quzhou), University of Electronic Science and Technology of China, Quzhou, China
| | - Yi Wei
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
| | - Lifeng Xu
- The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, Quzhou, China
| | - Qian Li
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
| | - Feng Che
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
| | - Qing Xu
- Institute of Clinical Pathology, West China Hospital, Sichuan University, Chengdu, China
| | - Xuan Cheng
- School of Computer Science and Engineering, University of Electronic Science and Technology of China, Chengdu, China
| | - Minghui Liu
- School of Computer Science and Engineering, University of Electronic Science and Technology of China, Chengdu, China
| | - Meiyi Yang
- School of Computer Science and Engineering, University of Electronic Science and Technology of China, Chengdu, China
| | - Xiaomin Wang
- School of Computer Science and Engineering, University of Electronic Science and Technology of China, Chengdu, China
| | - Feng Zhang
- The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, Quzhou, China
| | - Bin Song
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
- Department of Radiology, Sanya People’s Hospital, Sanya, China
- *Correspondence: Ming Liu, ; Bin Song,
| | - Ming Liu
- The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, Quzhou, China
- School of Computer Science and Engineering, University of Electronic Science and Technology of China, Chengdu, China
- *Correspondence: Ming Liu, ; Bin Song,
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Identification of tumor-specific neoantigens and immune clusters of hepatocellular carcinoma for mRNA vaccine development. J Cancer Res Clin Oncol 2023; 149:623-637. [PMID: 36239794 PMCID: PMC9561321 DOI: 10.1007/s00432-022-04285-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 08/11/2022] [Indexed: 11/27/2022]
Abstract
BACKGROUND To screen efficacious neoantigens for the development of LIHC mRNA vaccines, construct LIHC immune clusters, and therefore select patients who might benefit from vaccination. METHODS RNA-seq data and clinical information of 371 TCGA-LIHC and 231 ICGC-LIHC cohorts were downloaded. Differentially expressed genes and their associations with prognosis were analyzed by GEPIA, genetic alterations were examined in the cBioPortal portal, and the association between genes and immune infiltrating cells was explored by TIMER. The immune clusters were constructed by consistency clustering, and the immune landscape was described using CIBERSORT. RESULTS POLR3C and KPNA2 were identified as LIHC tumor neoantigens related to inferior prognosis and antigen-presenting cell infiltration. In addition, three immune clusters (IC1, IC2 and IC3) with significant differences in molecular, immune cytological, and clinical features were identified in both the TCGA and ICGC LIHC cohorts. Immune "hot" phenotype IC3 displayed a better survival than IC2, and immune "cold" phenotype IC1 exhibited a high tumor mutation burden. CONCLUSION In conclusion, for the development of anti-LIHC mRNA vaccines, we identified efficacious neoantigens POLR3C and KPNA2, profiled the tumor microenvironment of LIHC, and identified IC1 patients as the subgroup who might not most benefit from vaccination.
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Chen J, Jin H, Zhou H, Hei X, Liu K. Research into the characteristic molecules significantly affecting liver cancer immunotherapy. Front Immunol 2023; 14:1029427. [PMID: 36860864 PMCID: PMC9968832 DOI: 10.3389/fimmu.2023.1029427] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Accepted: 02/01/2023] [Indexed: 02/15/2023] Open
Abstract
Background The past decade has witnessed unprecedented scientific breakthroughs, including immunotherapy, which has great potential in clinical applications for liver cancer. Methods Public data were obtained from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases and analyzed with R software. Results The LASSO and SVM-RFE machine learning algorithms identified 16 differentially expressed genes (DEGs) related to immunotherapy, namely, GNG8, MYH1, CHRNA3, DPEP1, PRSS35, CKMT1B, CNKSR1, C14orf180, POU3F1, SAG, POU2AF1, IGFBPL1, CDCA7, ZNF492, ZDHHC22, and SFRP2. Moreover, a logistic model (CombinedScore) was established based on these DEGs, showing an excellent prediction performance for liver cancer immunotherapy. Patients with a low CombinedScore might respond better to immunotherapy. Gene Set Enrichment Analysis showed that many metabolism pathways were activated in patients with a high CombinedScore, including butanoate metabolism, bile acid metabolism, fatty acid metabolism, glycine serine and threonine metabolism, and propanoate metabolism. Our comprehensive analysis showed that the CombinedScore was negatively correlated with the levels of most tumor-infiltrating immune cells and the activities of key steps of cancer immunity cycles. Continually, the CombinedScore was negatively associated with the expression of most immune checkpoints and immunotherapy response-related pathways. Moreover, patients with a high and a low CombinedScore exhibited diverse genomic features. Furthermore, we found that CDCA7 was significantly correlated with patient survival. Further analysis showed that CDCA7 was positively associated with M0 macrophages and negatively associated with M2 macrophages, suggesting that CDCA7 could influence the progression of liver cancer cells by affecting macrophage polarization. Next, single-cell analysis showed that CDCA7 was mainly expressed in prolif T cells. Immunohistochemical results confirmed that the staining intensity of CDCA7 was prominently increased in the nucleus in primary liver cancer tissues compared to adjacent non-tumor tissues. Conclusions Our results provide novel insights into the DEGs and factors affecting liver cancer immunotherapy. Meanwhile, CDCA7 was identified as a potential therapeutic target in this patient population.
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Affiliation(s)
- Junhong Chen
- Department of Hepatobiliary and Pancreatic Surgery II, General Surgery Center, The First Hospital of Jilin University, Changchun, China
| | - Hengwei Jin
- Department of Hepatobiliary and Pancreatic Surgery II, General Surgery Center, The First Hospital of Jilin University, Changchun, China
| | - Hao Zhou
- Department of Hepatobiliary and Pancreatic Surgery II, General Surgery Center, The First Hospital of Jilin University, Changchun, China
| | - Xufei Hei
- Department of Hepatobiliary and Pancreatic Surgery II, General Surgery Center, The First Hospital of Jilin University, Changchun, China
| | - Kai Liu
- Department of Hepatobiliary and Pancreatic Surgery II, General Surgery Center, The First Hospital of Jilin University, Changchun, China
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31
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Kim HY, Min HK, Song HW, Yoo A, Lee S, Kim KP, Park JO, Choi YH, Choi E. Delivery of human natural killer cell-derived exosomes for liver cancer therapy: an in vivo study in subcutaneous and orthotopic animal models. Drug Deliv 2022; 29:2897-2911. [PMID: 36068970 PMCID: PMC9467548 DOI: 10.1080/10717544.2022.2118898] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Exosomes are nanosized extracellular vesicles secreted by various cell types, including those of the immune system, such as natural killer (NK) cells. They play a role in intercellular communication by transporting signal molecules between the cells. Recent studies have reported that NK cell-derived exosomes (NK-exo) contain cytotoxic proteins-induced cell death. However, the characteristics and potential functions of NK-exo, especially for the liver cancer are poorly understood. In this study, we investigated the anti-tumor effects of NK-exo in the primary liver cancer, hepatocellular carcinoma (HCC), using the orthotopic and subcutaneous tumor model. We found that NK-exo expressed both typical exosomal markers (e.g. CD63, CD81, and Alix) and cytotoxic proteins (e.g. perforin, granzyme B, FasL, and TRAIL). NK-exo were selectively taken up by HCC cells (e.g. Hep3B, HepG2, and Huh 7). Interestingly, Hep3B cells induced the highest cytotoxicity compared with HepG2 and Huh7 cells, and substantially enhanced the apoptosis by NK-exo. Furthermore, we demonstrated that NK-exo inhibited the phosphorylation of serine/threonine protein kinases (e.g. AKT and ERK1/2), and enhanced the activation of specific apoptosis markers (e.g. caspase-3, -7, -8, -9, and PARP) in Hep3B cells. NK-exo also exhibit the active targeting ability and potent therapeutic effects in both orthotopic and subcutaneous HCC mouse models. Overall, these results suggest that NK-exo indicate strong anti-tumor effects in HCC, which are mediated by novel regulatory mechanisms involved in serine/threonine kinase pathway-associated cell proliferation and caspase activation pathway-associated apoptosis.
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Affiliation(s)
- Ho Yong Kim
- Korea Institute of Medical Microrobotics, Buk-gu, Gwangju, Republic of Korea
| | - Hyun-Ki Min
- Korea Institute of Medical Microrobotics, Buk-gu, Gwangju, Republic of Korea
| | - Hyeong-Woo Song
- Korea Institute of Medical Microrobotics, Buk-gu, Gwangju, Republic of Korea
| | - Ami Yoo
- Korea Institute of Medical Microrobotics, Buk-gu, Gwangju, Republic of Korea
| | - Seonmin Lee
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Songpa-Gu, Seoul, Republic of Korea
| | - Kyu-Pyo Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Songpa-Gu, Seoul, Republic of Korea
| | - Jong-Oh Park
- Korea Institute of Medical Microrobotics, Buk-gu, Gwangju, Republic of Korea.,School of Mechanical Engineering, Chonnam National University, Buk, Gwangju, Republic of Korea
| | - You Hee Choi
- Korea Institute of Medical Microrobotics, Buk-gu, Gwangju, Republic of Korea
| | - Eunpyo Choi
- Korea Institute of Medical Microrobotics, Buk-gu, Gwangju, Republic of Korea.,School of Mechanical Engineering, Chonnam National University, Buk, Gwangju, Republic of Korea
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Li R, Jin C, Zhao W, Liang R, Xiong H. Development of a novel immune-related lncRNA prognostic signature for patients with hepatocellular carcinoma. BMC Gastroenterol 2022; 22:450. [PMID: 36344926 PMCID: PMC9639314 DOI: 10.1186/s12876-022-02540-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 10/14/2022] [Indexed: 11/09/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common neoplasm and the major cause of cancer-associated death worldwide. The high mortality rate of HCC is mainly attributed to its widespread prevalence and the lack of effective treatment. Immunotherapy as a promising, innovative approach has revolutionised the treatment of solid tumours. However, owing to the heterogeneity and complex tumour microenvironment of HCC, an efficient biomarker for immunotherapy has yet to be identified. We investigated the role of immune-related long non-coding RNAs (lncRNAs) as prognostic biomarkers in patients with HCC from The Cancer Genome Atlas (TCGA) database. Spearman correlation, univariate and multivariate Cox, and lasso regression analyses were utilised to screen lncRNAs associated with prognosis. Four lncRNAs were filtered out to develop an immune-associated lncRNA prognostic signature in TCGA training as well as validation cohorts. Patients with HCC were then categorised into low- and high-risk groups according to the median value of the risk scores to evaluate the ability of the prognostic model between training and validation cohorts. A nomogram (based on risk score and stage) was constructed to appraise the general overall survival (OS) of patients with HCC. Differences in immune cell infiltration, immune checkpoint inhibitor (ICI) treatment response, gene mutation, and drug sensitivity were observed between the two groups. Thus, the lncRNA prognostic signature can serve as a sensitive prognostic biomarker with potential in individualised immunotherapy for HCC patients.
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Affiliation(s)
- Rui Li
- grid.33199.310000 0004 0368 7223Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei China
| | - Chen Jin
- grid.268099.c0000 0001 0348 3990Department of Epidemiology and Biostatistics, School of Public Health and Management, Wenzhou Medical University, Wenzhou, Zhejiang China
| | - Weiheng Zhao
- grid.33199.310000 0004 0368 7223Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei China
| | - Rui Liang
- grid.190737.b0000 0001 0154 0904Biological Engineering Academy, Chongqing University, Chongqing, China
| | - Huihua Xiong
- grid.33199.310000 0004 0368 7223Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei China
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The Prognostic Significance of FKBP1A and Its Related Immune Infiltration in Liver Hepatocellular Carcinoma. Int J Mol Sci 2022; 23:ijms232112797. [PMID: 36361587 PMCID: PMC9659304 DOI: 10.3390/ijms232112797] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 10/06/2022] [Accepted: 10/18/2022] [Indexed: 12/24/2022] Open
Abstract
Liver hepatocellular carcinoma (LIHC) remains a global health challenge with poor prognosis and high mortality. FKBP1A was first discovered as a receptor for the immunosuppressant drug FK506 in immune cells and is critical for various tumors and cancers. However, the relationships between FKBP1A expression, cellular distribution, tumor immunity, and prognosis in LIHC remain unclear. Here, we investigated the expression level of FKBP1A and its prognostic value in LIHC via multiple datasets including ONCOMINE, TIMER, GEPIA, UALCAN, HCCDB, Kaplan–Meier plotter, LinkedOmics, and STRING. Human liver tissue microarray was employed to analyze the characteristics of FKBP1A protein including the expression level and pathological alteration in cellular distribution. FKBP1A expression was significantly higher in LIHC and correlated with tumor stage, grade and metastasis. The expression level of the FKBP1A protein was also increased in LIHC patients along with its accumulation in endoplasmic reticulum (ER). High FKBP1A expression was correlated with a poor survival rate in LIHC patients. The analysis of gene co-expression and the regulatory pathway network suggested that FKBP1A is mainly involved in protein synthesis, metabolism and the immune-related pathway. FKBP1A expression had a significantly positive association with the infiltration of hematopoietic immune cells including B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells. Moreover, M2 macrophage infiltration was especially associated with a poor survival prognosis in LIHC. Furthermore, FKBP1A expression was significantly positively correlated with the expression of markers of M2 macrophages and immune checkpoint proteins such as PD-L1, CTLA-4, LAG3 and HAVCR2. Our study demonstrated that FKBP1A could be a potential prognostic target involved in tumor immune cell infiltration in LIHC.
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Cytotoxic T Cell Expression of Leukocyte-Associated Immunoglobulin-Like Receptor-1 (LAIR-1) in Viral Hepatitis C-Mediated Hepatocellular Carcinoma. Int J Mol Sci 2022; 23:ijms232012541. [PMID: 36293412 PMCID: PMC9604124 DOI: 10.3390/ijms232012541] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 10/10/2022] [Accepted: 10/12/2022] [Indexed: 11/17/2022] Open
Abstract
Virus-related hepatocellular carcinoma (HCC) pathogenesis involves liver inflammation, therefore, despite successful treatment, hepatitis C virus (HCV) may progress to HCC from initiated liver cirrhosis. Cytotoxic T cells (Tcs) are known to be involved in HCV-related cirrhotic complications and HCC pathogenesis. The inhibitory checkpoint leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) is expressed on Tcs. Therefore, we aimed to determine whether the Tc expression level of LAIR-1 is associated with HCC progression and to evaluate LAIR-1 expression as a noninvasive biomarker for HCC progression in the context of liver cirrhosis related to HCV genotype 4 (G4) in Egyptian patients’ peripheral venous blood liquid biopsy. A total of 64 patients with HCC and 37 patients with liver cirrhosis were enrolled in this case-controlled study, and their LAIR-1 expression on Tc related to the progression of liver cirrhosis was examined and compared to that of the apparently healthy control group (n = 20). LAIR-1 expression was analyzed using flow cytometry. Results: The HCC group had significantly higher LAIR-1 expression on Tc and percentage of Tc positive for LAIR-1 (LAIR-1+Tc%) than the HCV G4-related liver cirrhosis group. LAIR-1+Tc% was correlated with the HCC surrogate tumor marker AFP (r = 0.367, p = 0.001) and insulin resistance and inflammation prognostic ratios/indices. A receiver operating characteristic (ROC) curve revealed that adding LAIR-1+Tc% to AFP can distinguish HCC transformation in the Egyptian patients’ cohort. Upregulated LAIR-1 expression on Tc could be a potential screening noninvasive molecular marker for chronic inflammatory HCV G4 related liver cirrhosis. Moreover, LAIR-1 expression on Tc may be one of the players involved in the progression of liver cirrhosis to HCC.
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Gao Z, Ling X, Shi C, Wang Y, Lin A. Tumor immune checkpoints and their associated inhibitors. J Zhejiang Univ Sci B 2022; 23:823-843. [PMID: 36226537 PMCID: PMC9561405 DOI: 10.1631/jzus.b2200195] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 07/13/2022] [Indexed: 11/05/2022]
Abstract
Immunological evasion is one of the defining characteristics of cancers, as the immune modification of an immune checkpoint (IC) confers immune evasion capabilities to tumor cells. Multiple ICs, such as programmed cell death protein-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), can bind to their respective receptors and reduce tumor immunity in a variety of ways, including blocking immune cell activation signals. IC blockade (ICB) therapies targeting these checkpoint molecules have demonstrated significant clinical benefits. This is because antibody-based IC inhibitors and a variety of specific small molecule inhibitors can inhibit key oncogenic signaling pathways and induce durable tumor remission in patients with a variety of cancers. Deciphering the roles and regulatory mechanisms of these IC molecules will provide crucial theoretical guidance for clinical treatment. In this review, we summarize the current knowledge on the functional and regulatory mechanisms of these IC molecules at multiple levels, including epigenetic regulation, transcriptional regulation, and post-translational modifications. In addition, we provide a summary of the medications targeting various nodes in the regulatory pathway, and highlight the potential of newly identified IC molecules, focusing on their potential implications for cancer diagnostics and immunotherapy.
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Affiliation(s)
- Zerui Gao
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou 310058, China
- Cancer Center, Zhejiang University, Hangzhou 310058, China
- Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou 310058, China
- Chu Kochen Honors College of Zhejiang University, Hangzhou 310058, China
| | - Xingyi Ling
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou 310058, China
- Cancer Center, Zhejiang University, Hangzhou 310058, China
- Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou 310058, China
| | - Chengyu Shi
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou 310058, China
- Cancer Center, Zhejiang University, Hangzhou 310058, China
- Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou 310058, China
| | - Ying Wang
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou 310058, China
- Cancer Center, Zhejiang University, Hangzhou 310058, China
- Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou 310058, China
| | - Aifu Lin
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou 310058, China.
- Cancer Center, Zhejiang University, Hangzhou 310058, China.
- Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou 310058, China.
- Breast Center of the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
- International School of Medicine, International Institutes of Medicine, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu 322000, China.
- ZJU-QILU Joint Research Institute, Hangzhou 310058, China.
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Song L, Xu C, Zhang T, Chen S, Hu S, Cheng B, Tong H, Li X. Clinical neutrophil-associated genes as reliable predictors of hepatocellular carcinoma. Front Genet 2022; 13:989779. [PMID: 36276937 PMCID: PMC9582652 DOI: 10.3389/fgene.2022.989779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 09/20/2022] [Indexed: 12/01/2022] Open
Abstract
Background: Growing evidence suggests that infiltrating neutrophils are key players in hepatocellular carcinoma (HCC) tumor progression. However, a comprehensive analysis of the biological roles of neutrophil infiltration and related genes in clinical outcomes and immunotherapy is lacking. Methods: HCC samples were obtained from the TCGA and GEO databases. The CIBERSORT algorithm was used to reveal the TIME landscape. Gene modules significantly associated with neutrophils were found using weighted gene co-expression network analysis (WGCNA), a “dynamic tree-cut” algorithm, and Pearson correlation analysis. Genes were screened using Cox regression analysis and LASSO and prognostic value validation was performed using Kaplan-Meier curves and receiver operating characteristic (ROC) curves. Risk scores (RS) were calculated and nomograms were constructed incorporating clinical variables. Gene set variation analysis (GSVA) was used to calculate signaling pathway activity. Immunophenoscore (IPS) was used to analyze differences in immunotherapy among samples with different risk scores. Finally, the relationship between RS and drug sensitivity was explored using the pRRophetic algorithm. Results: 10530 genes in 424 samples (50 normal samples, 374 tumor samples) were obtained from the TCGA database. Using WGCNA, the “MEbrown” gene module was most associated with neutrophils. Nine genes with prognostic value in HCC (PDLIM3, KLF2, ROR2, PGF, EFNB1, PDZD4, PLN, PCDH17, DOK5) were finally screened. Prognostic nomograms based on RS, gender, tumor grade, clinical stage, T, N, and M stages were constructed. The nomogram performed well after calibration curve validation. There is an intrinsic link between risk score and TMB and TIME. Samples with different risk scores differed in different signaling pathway activity, immunopharmaceutical treatment and chemotherapy sensitivity. Conclusion: In conclusion, a comprehensive analysis of neutrophil-related prognostic features will help in prognostic prediction and advance individualized treatment.
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Liu J, Liu T, Zhang C, He J, Zhou D, Wang Z, Wang R. EIF2S2 is a novel independent prognostic biomarker and correlated with immune infiltrates in hepatocellular carcinoma. Front Genet 2022; 13:992343. [PMID: 36276981 PMCID: PMC9579270 DOI: 10.3389/fgene.2022.992343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 09/20/2022] [Indexed: 11/15/2022] Open
Abstract
Background: Hepatocellular carcinoma (HCC) is a highly malignant disease with poor prognosis. It is urgent to find effective biomarkers. Eukaryotic Translation Initiation Factor 2 Subunit Beta (EIF2S2) is a subunit of heterotrimeric G protein EIF2, and its function is still unclear. We studied the role of EIF2S2 in the malignant progression of liver cancer and its relationship with immune infiltration. Methods: Download the RNA expression and clinical information of EIF2S2 from the Cancer Genome Atlas (TCGA) database, analyze the relationship between the expression of EIF2S2 and the prognosis and clinicopathological characteristics of HCC, analyze the differential genes by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and tumor related immune infiltrating cells. The Protein expression level of EIF2S2 was obtained from Human Protein Atlas (HPA) databases. The relationship between EIF2S2 expression and immune infiltrates in HCC was analyzed on TIMER 2.0. The data processing analysis based on R language. Drug Sensitivity data from Genomics of Drug Sensitivity in Cancer (GDSC). Results: EIF2S2 is highly expressed in HCC patients and is associated with poor prognosis. The expression of EIF2S2 was also correlated with age, clinical stage and pathological grade. Univariate and multivariate COX regression analysis showed that EIF2S2 was an independent risk factor for survival. The receiver operating characteristic (ROC) curve of EIF2S2 also confirmed the diagnostic value of EIF2S2 in HCC patients. Through GO and KEGG enrichment analysis, EIF2S2 expression was found to be closely related to some immune pathways. The expression of EIF2S2 was correlated with memory B cell, plasma B cell, CD8+ T cell, CD4+ resting memory T cell and the expression of some immune checkpoints, such as PDCD1, TIGIT and CTLA-4. It is also more sensitive to paclitaxel, sunitinib and other drugs. Conclusion: This study shows that EIF2S2 can be used as a prognostic factor for HCC, which is closely related to immune infiltration and immune checkpoints, and may play a potential regulatory role in predicting drug sensitivity.
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Affiliation(s)
- Jing Liu
- Department of Medical Oncology, Affiliated Zhongshan Hospital of Dalian University, Dalian, China
- The Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Dalian University, Dalian, China
| | - Tongyu Liu
- Department of Gynecology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou, China
| | - Chuanhao Zhang
- Department of Medical Oncology, Affiliated Zhongshan Hospital of Dalian University, Dalian, China
- The Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Dalian University, Dalian, China
| | - Jiabei He
- Department of Medical Oncology, Affiliated Zhongshan Hospital of Dalian University, Dalian, China
- The Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Dalian University, Dalian, China
| | - Dong Zhou
- Department of Medical Oncology, Affiliated Zhongshan Hospital of Dalian University, Dalian, China
- The Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Dalian University, Dalian, China
| | - Zhe Wang
- Department of Medical Oncology, Affiliated Zhongshan Hospital of Dalian University, Dalian, China
- The Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Dalian University, Dalian, China
- *Correspondence: Zhe Wang, ; Ruoyu Wang,
| | - Ruoyu Wang
- Department of Medical Oncology, Affiliated Zhongshan Hospital of Dalian University, Dalian, China
- The Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Dalian University, Dalian, China
- *Correspondence: Zhe Wang, ; Ruoyu Wang,
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Wu G, Yang Y, Ye R, Yue H, Zhang H, Huang T, Liu M, Zheng Y, Wang Y, Zhou Y, Guo Q. Development and validation of an ECM-related prognostic signature to predict the immune landscape of human hepatocellular carcinoma. BMC Cancer 2022; 22:1036. [PMID: 36195857 PMCID: PMC9531523 DOI: 10.1186/s12885-022-10049-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 08/31/2022] [Indexed: 12/24/2022] Open
Abstract
Background The global burden of hepatocellular carcinoma (HCC) is increasing, negatively impacting social health and economies. The discovery of novel and valuable biomarkers for the early diagnosis and therapeutic guidance of HCC is urgently needed. Methods Extracellular matrix (ECM)-related gene sets, transcriptome data and mutation profiles were downloaded from the Matrisome Project and The Cancer Genome Atlas (TCGA)-LIHC datasets. Coexpression analysis was initially performed with the aim of identifying ECM-related lncRNAs (r > 0.4, p < 0.001). The screened lncRNAs were subjected to univariate analysis to obtain a series of prognosis-related lncRNA sets, which were incorporated into least absolute selection and shrinkage operator (LASSO) regression for signature establishment. Following the grouping of LIHC samples according to risk score, the correlations between the signature and clinicopathological, tumour immune infiltration, and mutational characteristics as well as therapeutic response were also analysed. lncRNA expression levels used for modelling were finally examined at the cellular and tissue levels by real-time PCR. All analyses were based on R software. Results AL031985.3 and MKLN1-AS were ultimately identified as signature-related lncRNAs, and both were significantly upregulated in HCC tissue samples and cell lines. The prognostic value of the signature reflected by the AUC value was superior to that of age, sex, grade and stage. Correlation analysis results demonstrated that high-risk groups exhibited significant enrichment of immune cells (DCs, macrophages and Tregs) and increased expression levels of all immune checkpoint genes. Prominent differences in clinicopathological profiles, immune functions, tumour mutation burden (TMB) and drug sensitivity were noted between the two risk groups. Conclusions Our signature represents a valuable predictive tool in the prognostic management of HCC patients. Further validation of the mechanisms involved is needed. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-10049-w.
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Affiliation(s)
- Guozhi Wu
- The First Clinical Medical College, Lanzhou University, Lanzhou, 730000, Gansu, China.,Department of Gastroenterology, The First Hospital of Lanzhou University, No.1 West Donggang Road, Lanzhou, 730000, Gansu, China.,Gansu Key Laboratory of Gastroenterology, Lanzhou University, Lanzhou, 730000, Gansu, China
| | - Yuan Yang
- The First Clinical Medical College, Lanzhou University, Lanzhou, 730000, Gansu, China.,Department of Gastroenterology, The First Hospital of Lanzhou University, No.1 West Donggang Road, Lanzhou, 730000, Gansu, China.,Gansu Key Laboratory of Gastroenterology, Lanzhou University, Lanzhou, 730000, Gansu, China
| | - Rong Ye
- Department of Radiology, the First Hospital of Lanzhou University, Lanzhou, 730000, Gansu, China
| | - Hanxun Yue
- The First Clinical Medical College, Lanzhou University, Lanzhou, 730000, Gansu, China.,Department of Gastroenterology, The First Hospital of Lanzhou University, No.1 West Donggang Road, Lanzhou, 730000, Gansu, China.,Gansu Key Laboratory of Gastroenterology, Lanzhou University, Lanzhou, 730000, Gansu, China
| | - Huiyun Zhang
- The First Clinical Medical College, Lanzhou University, Lanzhou, 730000, Gansu, China.,Department of Gastroenterology, The First Hospital of Lanzhou University, No.1 West Donggang Road, Lanzhou, 730000, Gansu, China.,Gansu Key Laboratory of Gastroenterology, Lanzhou University, Lanzhou, 730000, Gansu, China
| | - Taobi Huang
- The First Clinical Medical College, Lanzhou University, Lanzhou, 730000, Gansu, China.,Department of Gastroenterology, The First Hospital of Lanzhou University, No.1 West Donggang Road, Lanzhou, 730000, Gansu, China.,Gansu Key Laboratory of Gastroenterology, Lanzhou University, Lanzhou, 730000, Gansu, China
| | - Min Liu
- Department of Gastroenterology, The First Hospital of Lanzhou University, No.1 West Donggang Road, Lanzhou, 730000, Gansu, China.,Gansu Key Laboratory of Gastroenterology, Lanzhou University, Lanzhou, 730000, Gansu, China
| | - Ya Zheng
- Department of Gastroenterology, The First Hospital of Lanzhou University, No.1 West Donggang Road, Lanzhou, 730000, Gansu, China.,Gansu Key Laboratory of Gastroenterology, Lanzhou University, Lanzhou, 730000, Gansu, China
| | - Yuping Wang
- Department of Gastroenterology, The First Hospital of Lanzhou University, No.1 West Donggang Road, Lanzhou, 730000, Gansu, China.,Gansu Key Laboratory of Gastroenterology, Lanzhou University, Lanzhou, 730000, Gansu, China
| | - Yongning Zhou
- Department of Gastroenterology, The First Hospital of Lanzhou University, No.1 West Donggang Road, Lanzhou, 730000, Gansu, China. .,Gansu Key Laboratory of Gastroenterology, Lanzhou University, Lanzhou, 730000, Gansu, China.
| | - Qinghong Guo
- Department of Gastroenterology, The First Hospital of Lanzhou University, No.1 West Donggang Road, Lanzhou, 730000, Gansu, China. .,Gansu Key Laboratory of Gastroenterology, Lanzhou University, Lanzhou, 730000, Gansu, China.
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Chang Z, Zhang Q, Hu Q, Liu Y, Zhang L, Liu R. Tannins in Terminalia bellirica inhibits hepatocellular carcinoma growth via re-educating tumor-associated macrophages and restoring CD8+T cell function. Biomed Pharmacother 2022; 154:113543. [DOI: 10.1016/j.biopha.2022.113543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 08/09/2022] [Accepted: 08/10/2022] [Indexed: 11/02/2022] Open
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He Y, Luo J, Zhang G, Jin Y, Wang N, Lu J, Li C, Guo X, Qin N, Dai J, Chen Y. Single-cell profiling of human CD127 + innate lymphoid cells reveals diverse immune phenotypes in hepatocellular carcinoma. Hepatology 2022; 76:1013-1029. [PMID: 35243668 PMCID: PMC9790738 DOI: 10.1002/hep.32444] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 02/08/2022] [Accepted: 02/25/2022] [Indexed: 12/30/2022]
Abstract
BACKGROUND AND AIMS Innate lymphoid cells (ILCs) are tissue-resident lymphocytes that play critical roles in cytokine-mediated regulation of homeostasis and inflammation. However, relationships between their immune phenotypic characteristics and HCC remain largely unexplored. APPROACH AND RESULTS We performed single-cell RNA sequencing analysis on sorted hepatic ILC cells from human patients with HCC and validated using flow cytometry, multiplex immunofluorescence staining, and functional experiments. Moreover, we applied selection strategies to enrich ILC populations in HCC samples to investigate the effects of B cells on the immune reaction of inducible T cell costimulator (ICOS)+ ILC2 cells. Dysregulation of ILCs was manifested by the changes in cell numbers or subset proportions in HCC. Seven subsets of 3433 ILCs were identified with unique properties, of which ICOS+ ILC2a were preferentially enriched in HCC and correlated with poor prognosis. Mechanistically, we report that B cells, particularly resting naïve B cells, have a previously unrecognized function that is involved in inflammatory differentiation of ILC2 cells. B cell-derived ICOSL signaling was responsible for exacerbating inflammation through the increased production of IL-13 in ICOS+ ILC2a cells. Heat shock protein 70 (HSP70) genes Heat Shock Protein Family A Member 1A (HSPA1A) and Heat Shock Protein Family A Member 1B (HSPA1B) were highly expressed in ILC2s in late-stage HCC, and targeting to ICOS and its downstream effector HSP70 in ILC2s suppressed tumor growth and remodeled the immunosuppressive tumor microenvironment. CONCLUSIONS This in-depth understanding sheds light on B cell-driven innate type 2 inflammation and provides a potential strategy for HCC immunotherapy.
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Affiliation(s)
- Yuanlin He
- State Key Laboratory of Reproductive MedicineNanjing Medical UniversityNanjingJiangsuChina
- Department of Epidemiology and BiostatisticsCenter for Global HealthInternational Joint Research CenterSchool of Public HealthGusu SchoolNanjing Medical UniversityNanjingJiangsuChina
| | - Jiajing Luo
- Department of ImmunologyKey Laboratory of Human Functional Genomics of Jiangsu ProvinceGusu SchoolNanjing Medical UniversityNanjingJiangsuChina
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and TreatmentCollaborative Innovation Center for Cancer Personalized MedicineNanjing Medical UniversityNanjingJiangsuChina
| | - Guannan Zhang
- Department of ImmunologyKey Laboratory of Human Functional Genomics of Jiangsu ProvinceGusu SchoolNanjing Medical UniversityNanjingJiangsuChina
| | - Yu Jin
- Department of ImmunologyKey Laboratory of Human Functional Genomics of Jiangsu ProvinceGusu SchoolNanjing Medical UniversityNanjingJiangsuChina
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and TreatmentCollaborative Innovation Center for Cancer Personalized MedicineNanjing Medical UniversityNanjingJiangsuChina
| | - Nanxi Wang
- Department of Epidemiology and BiostatisticsCenter for Global HealthInternational Joint Research CenterSchool of Public HealthGusu SchoolNanjing Medical UniversityNanjingJiangsuChina
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and TreatmentCollaborative Innovation Center for Cancer Personalized MedicineNanjing Medical UniversityNanjingJiangsuChina
| | - Jinying Lu
- Department of ImmunologyKey Laboratory of Human Functional Genomics of Jiangsu ProvinceGusu SchoolNanjing Medical UniversityNanjingJiangsuChina
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and TreatmentCollaborative Innovation Center for Cancer Personalized MedicineNanjing Medical UniversityNanjingJiangsuChina
| | - Changxian Li
- Liver Transplantation CenterThe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsuChina
| | - Xiaohuan Guo
- Institute for ImmunologyTsinghua UniversityBeijingChina
| | - Na Qin
- Department of Epidemiology and BiostatisticsCenter for Global HealthInternational Joint Research CenterSchool of Public HealthGusu SchoolNanjing Medical UniversityNanjingJiangsuChina
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and TreatmentCollaborative Innovation Center for Cancer Personalized MedicineNanjing Medical UniversityNanjingJiangsuChina
| | - Juncheng Dai
- Department of Epidemiology and BiostatisticsCenter for Global HealthInternational Joint Research CenterSchool of Public HealthGusu SchoolNanjing Medical UniversityNanjingJiangsuChina
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and TreatmentCollaborative Innovation Center for Cancer Personalized MedicineNanjing Medical UniversityNanjingJiangsuChina
| | - Yun Chen
- Department of ImmunologyKey Laboratory of Human Functional Genomics of Jiangsu ProvinceGusu SchoolNanjing Medical UniversityNanjingJiangsuChina
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and TreatmentCollaborative Innovation Center for Cancer Personalized MedicineNanjing Medical UniversityNanjingJiangsuChina
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Molecular docking and in vitro experiments verified that kaempferol induced apoptosis and inhibited human HepG2 cell proliferation by targeting BAX, CDK1, and JUN. Mol Cell Biochem 2022; 478:767-780. [PMID: 36083512 DOI: 10.1007/s11010-022-04546-6] [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: 03/15/2022] [Accepted: 08/12/2022] [Indexed: 10/14/2022]
Abstract
Hepatocellular carcinoma, as a common liver cirrhosis complication, has become the sixth most common cancer worldwide, and its increasing incidence has resulted in considerable medical and economic burdens. As a natural polyphenolic compound, kaempferol has exhibits a wide range of antitumor activities against multiple cancer targets. In this study, the Autodock software was used for molecular docking to simulate the interaction process between kaempferol and HCC targets and the PyMOL software was used for visualization. Proliferation of kaempferol HepG2 cells under the effect of kaempferol was detected using Cell Counting Kit-8 (CCK-8) assay, and the apoptosis rate of HepG2 cells was detected using flow cytometry. The expressions of proteins BAX, CDK1, and JUN protein expressions were detected by Western blot. Molecular docking found that the kaempferol ligand has 3 rotatable bonds, 6 nonpolar hydrogen atoms, and 12 aromatic carbon atoms, and can form complexes with the kaempferol targets P53, BAX, AR, CDK1, and JUN through electrostatic energy. GO (Gene Ontology) enrichment analysis suggests that kaempferol regulates the biological function of hepatocellular carcinoma cells and is related to apoptosis. Cell Counting Kit-8 assay suggested that Kaempferol can significantly inhibited HepG2 cell proliferation, and the inhibition rate increased with the increase in drug concentration and incubation time. Moreover, kaempferol can promoted HepG2 cell apoptosis in a dose-dependent manner. This compound upregulated BAX and JUN expression and downregulated CDK1 expression. Thus, Kaempferol can promote HepG2 cell apoptosis, and the regulatory mechanism may be related to the regulation of the expression levels of the apoptosis-related proteins BAX, CDK1, and JUN.
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Xie Q, Zhang P, Wang Y, Mei W, Zeng C. Overcoming resistance to immune checkpoint inhibitors in hepatocellular carcinoma: Challenges and opportunities. Front Oncol 2022; 12:958720. [PMID: 36119533 PMCID: PMC9478417 DOI: 10.3389/fonc.2022.958720] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 08/15/2022] [Indexed: 11/23/2022] Open
Abstract
Hepatocellular carcinoma is one of the leading causes of cancer mortality globally, and its incidence is increasing. Immune checkpoint therapy has revolutionized the treatment of hepatocellular carcinoma over the past few years. However, only a limited proportion of patients with hepatocellular carcinoma respond to immunotherapy. Despite the significant breakthroughs, the molecular mechanisms that drive immune responses and evasion are largely unresolved. Predicting tumor response and resistance to immune checkpoint inhibitors is a significant challenge. In this review, we focus on the current research progress of immune checkpoint inhibitors in hepatocellular carcinoma. Importantly, this review highlights the underlying mechanisms of resistance to immune checkpoint inhibitors and summarizes potential strategies to overcome the resistance to immune checkpoint inhibitors in hepatocellular carcinoma.
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Affiliation(s)
- Qingqing Xie
- Department of Medical Laboratory, Shenzhen Longhua District Central Hospital, Guangdong Medical University, Shenzhen, China
| | - Pengfei Zhang
- Department of Medical Laboratory, Shenzhen Longhua District Central Hospital, Guangdong Medical University, Shenzhen, China
| | - Yuanyuan Wang
- Xianning Medical College, Hubei University of Science and Technology, Xianning, China
| | - Wuxuan Mei
- Xianning Medical College, Hubei University of Science and Technology, Xianning, China
| | - Changchun Zeng
- Department of Medical Laboratory, Shenzhen Longhua District Central Hospital, Guangdong Medical University, Shenzhen, China
- *Correspondence: Changchun Zeng,
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Chen S, Gao Y, Wang Y, Daemen T. The combined signatures of hypoxia and cellular landscape provides a prognostic and therapeutic biomarker in hepatitis B virus-related hepatocellular carcinoma. Int J Cancer 2022; 151:809-824. [PMID: 35467769 PMCID: PMC9543189 DOI: 10.1002/ijc.34045] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 03/13/2022] [Accepted: 04/05/2022] [Indexed: 11/18/2022]
Abstract
Prognosis and treatment options of hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) are generally based on tumor burden and liver function. Yet, tumor growth and therapeutic resistance of HBV-HCC are strongly influenced by intratumoral hypoxia and cells infiltrating the tumor microenvironment (TME). We, therefore, studied whether linking parameters associated with hypoxia and TME cells could have a better prediction of prognosis and therapeutic responses. Quantification of 109 hypoxia-related genes and 64 TME cells was performed in 452 HBV-HCC tumors. Prognostic hypoxia and TME cells signatures were determined based on Cox regression and meta-analysis for generating the Hypoxia-TME classifier. Thereafter, the prognosis, tumor, and immune characteristics as well as the benefit of therapies in Hypoxia-TME defined subgroups were analyzed. Patients in the Hypoxialow /TMEhigh subgroup showed a better prognosis and therapeutic responses than any other subgroups, which can be well elucidated based on the differences in terms of immune-related molecules, tumor somatic mutations, and cancer cellular signaling pathways. Notably, our analysis furthermore demonstrated the synergistic influence of hypoxia and TME on tumor metabolism and proliferation. Besides, the classifier allowed a further subdivision of patients with early- and late-HCC stages. In addition, the Hypoxia-TME classifier was validated in another independent HBV-HCC cohort (n = 144) and several pan-cancer cohorts. Overall, the Hypoxia-TME classifier showed a pretreatment predictive value for prognosis and therapeutic responses, which might provide new directions for strategizing patients with optimal therapies.
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Affiliation(s)
- Shipeng Chen
- Department of Medical Microbiology and Infection Prevention, Tumor Virology and Cancer ImmunotherapyUniversity Medical Center Groningen, University of GroningenGroningenThe Netherlands
| | - Yuzhen Gao
- Department of Clinical LaboratorySir Run Run Shaw Hospital, Zhejiang University School of MedicineHangzhouZhejiangChina
| | - Ying Wang
- Department of Laboratory MedicineShanghai Eastern Hepatobiliary Surgery HospitalShanghaiChina
- Research Center for Translational MedicineShanghai East Hospital, School of Life Sciences and Technology, Tongji UniversityShanghaiChina
| | - Toos Daemen
- Department of Medical Microbiology and Infection Prevention, Tumor Virology and Cancer ImmunotherapyUniversity Medical Center Groningen, University of GroningenGroningenThe Netherlands
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Dai YY, Gao YP, Chen LX, Liu JS, Zeng C, Zhou JD, Wu HL. Predicting prognosis and immune responses in hepatocellular carcinoma based on N7-methylguanosine-related long noncoding RNAs. Front Genet 2022; 13:930446. [PMID: 36110218 PMCID: PMC9468367 DOI: 10.3389/fgene.2022.930446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 07/12/2022] [Indexed: 11/16/2022] Open
Abstract
Background: Hepatocellular carcinoma (HCC), which has high rates of recurrence and metastasis and is the main reason and the most common tumor for cancer mortality worldwide, has an unfavorable prognosis. N7-methylguanosine (m7G) modification can affect the formation and development of tumors by affecting gene expression and other biological processes. In addition, many previous studies have confirmed the unique function of long noncoding RNAs (lncRNAs) in tumor progression; however, studies exploring the functions of m7G-related lncRNAs in HCC patients has been limited. Methods: Relevant RNA expression information was acquired from The Cancer Genome Atlas (TCGA, https://portal.gdc.cancer.gov), and m7G-related lncRNAs were identified via gene coexpression analysis. Afterward, univariate Cox regression, least absolute shrinkage and selection operator (LASSO) regression, and multivariate regression analyses were implemented to construct an ideal risk model whose validity was verified using Kaplan–Meier survival, principal component, receiver operating characteristic (ROC) curve, and nomogram analyses. In addition, the potential functions of lncRNAs in the novel signature were explored through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) analyses and gene set enrichment analysis (GSEA). At last, in both risk groups and subtypes classified based on the expression of the risk-related lncRNAs, we analyzed the immune characteristics and drug sensitivity of patients. Results: After rigorous screening processes, we built a model based on 11 m7G-related lncRNAs for predicting patient overall survival (OS). The results suggested that the survival status of patients with high-risk scores was lower than that of patients with low-risk scores, and a high-risk score was related to malignant clinical features. Cox regression analysis showed that the m7G risk score was an independent prognostic parameter. Moreover, immune cell infiltration and immunotherapy sensitivity differed between the risk groups. Conclusion: The m7G risk score model constructed based on 11 m7G-related lncRNAs can effectively assess the OS of HCC patients and may offer support for making individualized treatment and immunotherapy decisions for HCC patients.
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Affiliation(s)
- Yu-yang Dai
- Department of Radiology, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu Province, China
- Department of Radiology, The Wujin Clinical College of Xuzhou Medical University, Changzhou, Jiangsu, China
| | - Yi-ping Gao
- Department of Interventional Radiology, Nanfang Hospital Affiliated to Southern Medical University, Guangzhou, Guangdong, China
| | - Lin-xin Chen
- State Key Laboratory of Ophthalmology, Optometry and Vision Science, Eye Hospital, School of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jin-song Liu
- Department of Oncology, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, China
- Department of Oncology, The Wujin Clinical College of Xuzhou Medical University, Changzhou, Jiangsu, China
| | - Cheng Zeng
- Department of Oncology, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, China
- Department of Oncology, The Wujin Clinical College of Xuzhou Medical University, Changzhou, Jiangsu, China
| | - Jian-dong Zhou
- Department of Nephrology, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, China
- Department of Nephrology, The Wujin Clinical College of Xuzhou Medical University, Changzhou, Jiangsu, China
| | - Hong-lin Wu
- Department of Radiology, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu Province, China
- Department of Radiology, The Wujin Clinical College of Xuzhou Medical University, Changzhou, Jiangsu, China
- *Correspondence: Hong-lin Wu,
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Chen J, Zhang D, Yuan Y. Anti-PD-1/PD-L1 immunotherapy in conversion treatment of locally advanced hepatocellular carcinoma. Clin Exp Med 2022:10.1007/s10238-022-00873-6. [PMID: 36018466 DOI: 10.1007/s10238-022-00873-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Accepted: 08/08/2022] [Indexed: 12/24/2022]
Abstract
Curative surgery and locoregional therapy are radical therapies for patients with HCC. But more than 80% of HCC patients cannot be fitful for radical therapies because of local progression or distant metastasis at initial diagnosis. Among patients with unresectable locally advanced hepatocellular carcinoma (HCC), some patients can be converted to be technically resectable by conversion treatment and salvage surgery. For unresectable locally advanced hepatocellular, conversion treatment prior to salvage surgery with transcatheter arterial chemoembolization (TACE) and other locoregional therapies improve outcomes. PD-1/PD-L1 inhibitors as immune checkpoint inhibitor (ICI) therapy which show high antineoplastic activity in HCC patients by preclinical and clinical researches can also be a good choice for conversion therapy. PD-1/PD-L1 inhibitor combined with locoregional therapy plus antiangiogenic agents or not is most potential conversion therapy comparing to PD-1 inhibitor monotherapy and PD-1/PD-L1 inhibitor combined with antiangiogenic agents or CTLA-4 inhibitor. As more clinical evidence reported, PD-1/PD-L1 immunotherapy would be widely used in conversion treatment of locally advanced hepatocellular carcinoma.
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Affiliation(s)
- Jiaqi Chen
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, Zhejiang, China
| | - Ding Zhang
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, Zhejiang, China
| | - Ying Yuan
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, Zhejiang, China. .,Cancer Center, Zhejiang University, Hangzhou, 310058, Zhejiang, China.
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Ye R, Lu X, Liu J, Duan Q, Xiao J, Duan X, Yue Z, Liu F. CircSOD2 Contributes to Tumor Progression, Immune Evasion and Anti-PD-1 Resistance in Hepatocellular Carcinoma by Targeting miR-497-5p/ANXA11 Axis. Biochem Genet 2022; 61:597-614. [PMID: 36008700 DOI: 10.1007/s10528-022-10273-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 06/22/2022] [Indexed: 11/25/2022]
Abstract
Circular RNAs (circRNAs) can function as functional molecules in hepatocellular carcinoma (HCC). Herein, circRNA superoxide dismutase 2 (circSOD2) was researched in HCC progression and immune system. The real-time polymerase chain reaction (qRT-PCR) was used for quantification of circSOD2, microRNA-497-5p (miR-497-5p) and Annexin A11 (ANXA11). Cell assays were performed by 3-(4, 5-dimethylthiazol-2-y1)-2, 5-diphenyl tetrazolium bromide (MTT) and colony formation assays for proliferation, flow cytometry for apoptosis and cell cycle, wound healing assay for migration and transwell assay for migration/invasion. ANXA11 and metastatic protein levels were measured by western blot. Dual-luciferase reporter and RNA immunoprecipitation (RIP) assays were performed to analyze target binding. CD8+ T cell immunity was assessed by Immunohistochemistry (IHC) assay, and the effect of circSOD2 on programmed cell death 1 (PD-1) immune checkpoint inhibitors (anti-PD-1) therapy was evaluated by mice xenograft assay. CircSOD2 was upregulated in HCC tissues and cells. Knockdown of circSOD2 resulted in HCC cell growth inhibition, apoptosis promotion, cell cycle arrest and metastasis suppression. Mechanically, circSOD2 promoted HCC development by acting as a miR-497-5p sponge and miR-497-5p played a tumor-inhibitory role in HCC cells by targeting ANXA11. Moreover, circSOD2 induced upregulation of ANXA11 expression by interacting with miR-497-5p. Also, the promoting effects of circSOD2 on immune evasion and anti-PD-1 resistance were related to miR-497-5p/ANXA11 axis. This study elucidated the pivotal function of circSOD2 in HCC progression and immunosuppression by mediating miR-497-6p/ANXA11 axis. CircSOD2/miR-497-5p/ANXA11 axis was a novel view of circRNA research in HCC.
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Affiliation(s)
- Rong Ye
- Department of General Surgery 3, The First Affiliated Hospital of Gannan Medical University, No. 128 Jinling Road, Jingkai District, Ganzhou, 341000, China
| | - Xingyu Lu
- Outpatient department, Ganzhou City Third People's Hospital, Ganzhou, 341001, China
| | - Jianping Liu
- Department of General Surgery 3, The First Affiliated Hospital of Gannan Medical University, No. 128 Jinling Road, Jingkai District, Ganzhou, 341000, China
| | - Qing Duan
- Department of General Surgery 3, The First Affiliated Hospital of Gannan Medical University, No. 128 Jinling Road, Jingkai District, Ganzhou, 341000, China
| | - Junqi Xiao
- Department of General Surgery 3, The First Affiliated Hospital of Gannan Medical University, No. 128 Jinling Road, Jingkai District, Ganzhou, 341000, China
| | - Xunhong Duan
- Department of General Surgery 3, The First Affiliated Hospital of Gannan Medical University, No. 128 Jinling Road, Jingkai District, Ganzhou, 341000, China
| | - Zhibiao Yue
- Department of General Surgery 3, The First Affiliated Hospital of Gannan Medical University, No. 128 Jinling Road, Jingkai District, Ganzhou, 341000, China.
| | - Fengen Liu
- Department of General Surgery 3, The First Affiliated Hospital of Gannan Medical University, No. 128 Jinling Road, Jingkai District, Ganzhou, 341000, China.
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Cai Q, Duan J, Ding L. Prognostic model of immune-related genes for patients with hepatocellular carcinoma. Front Surg 2022; 9:819491. [PMID: 35937592 PMCID: PMC9349350 DOI: 10.3389/fsurg.2022.819491] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Accepted: 06/30/2022] [Indexed: 11/30/2022] Open
Abstract
Background Immune-related genes (IRGs) are closely connected to the occurrence and development of tumors. Their influence on the prognosis of patients with HCC, however, remains unclear. Methods From the TCGA database, we integrated 365 liver cancer tissues and 50 normal tissues to identify differential immune genes related to prognosis. Multivariate COX analysis was used to establish a new prognostic index on account of IRGs, whereby risk score = (Expression level of HSPA4*0.022) + (Expression level of PSMD14*0.042) + (Expression level of RBP2*0.019) + (Expression level of MAPT*0.197) + (Expression level of TRAF3*0.146) + (Expression level of NDRG1*(0.006) + (Expression level of NRAS*0.027) + (Expression level of IL17D*0.075). Results The risk score was clearly correlated with an unfavorable survival rate and with clinical characteristics. By integrating the immune-related risk score model with clinical features, a nomogram was constructed to predict the survival rate of HCC patients (1-, 3- and 5-year AUC of 0.721, 0.747 and 0.781, respectively). Conclusion We have established a valuable prognostic risk score for HCC patients that may be a better predictor of survival than the present method. With the risk score's strong predictive value for immune cells and functions, it may provide clinical guidance for the diagnosis and prognosis of different immunophenotypes, and provide multiple therapeutic targets for the treatment of HCC patients based on subtype-specific immune molecules.
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Affiliation(s)
- Qun Cai
- Department of Infectious Diseases and Liver Diseases, Ningbo Medical Center Lihuili Hospital, Affiliated Lihuili Hospital of Ningbo University, Ningbo, China
- Correspondence: Qun Cai
| | - Jinnan Duan
- Department of Infectious Diseases, Shaoxing People's Hospital, Shaoxing, China
| | - Liang Ding
- Department of Infectious Diseases, Shaoxing People's Hospital, Shaoxing, China
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Mechanisms of resistance to tyrosine kinase inhibitors in liver cancer stem cells and potential therapeutic approaches. Essays Biochem 2022; 66:371-386. [PMID: 35818992 DOI: 10.1042/ebc20220001] [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: 05/24/2022] [Revised: 06/13/2022] [Accepted: 06/17/2022] [Indexed: 12/24/2022]
Abstract
The administration of tyrosine kinase inhibitors (TKIs) for the treatment of advanced-stage patients is common in hepatocellular carcinoma (HCC). However, therapy resistance is often encountered, and its emergence eventually curtails long-term clinical benefits. Cancer stem cells (CSCs) are essential drivers of tumor recurrence and therapy resistance; thus, the elucidation of key hallmarks of resistance mechanisms of liver CSC-driven HCC may help improve patient outcomes and reduce relapse. The present review provides a comprehensive summary of the intrinsic and extrinsic mechanisms of TKI resistance in liver CSCs, which mediate treatment failure, and discusses potential strategies to overcome TKI resistance from a preclinical perspective.
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Ouyang T, Kan X, Zheng C. Immune Checkpoint Inhibitors for Advanced Hepatocellular Carcinoma: Monotherapies and Combined Therapies. Front Oncol 2022; 12:898964. [PMID: 35785169 PMCID: PMC9243530 DOI: 10.3389/fonc.2022.898964] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 05/25/2022] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is an important cause of cancer death and is considered the 3rd most lethal around the world. Hepatectomy, liver transplantation, and ablation therapy are considered curative treatments for early-stage HCC. Transarterial chemoembolization is the preferred therapy for intermediate stage HCC. Ssystemic therapy is recommended for advanced HCC. For more than a decade, sorafenib and lenvatinib were used as the first-line treatment for the advanced HCC. For the great success of immunotherapy in melanoma and lung cancer, some immune-based treatments, such as immune checkpoint inhibitors (ICIs), have been applied in the treatment of HCC. The anti-programmed cell death protein 1 (PD1) antibodies, including nivolumab and pembrolizumab, have been approved by the Food and Drug Administration for sorafenib-pretreated patients. Moreover, due to the results of durable antitumor responses attained from the phase 3 trials, atezolizumab in combination with bevacizumab is now the standard therapy for advanced HCC. Recently, there are a lot of clinical trials involving the ICIs, as monotherapy or combination therapy, with tyrosine kinase inhibitors, antiangiogenic drugs, cytotoxic agents, and locoregional treatments, providing a promising outcome for advanced HCC. Thus, this review summarized the role of ICIs for HCC patients with monotherapy or combination therapy. The success and failures of monotherapy and combination therapy involving ICIs have provided advanced insights into HCC treatment and led to novel avenues to improve therapy efficacy in HCC.
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Affiliation(s)
- Tao Ouyang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Xuefeng Kan
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Chuansheng Zheng
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
- *Correspondence: Chuansheng Zheng,
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Wu SY, Xie ZY, Yan LY, Liu XF, Zhang Y, Wang DA, Dong J, Sun HT. The correlation of EZH2 expression with the progression and prognosis of hepatocellular carcinoma. BMC Immunol 2022; 23:28. [PMID: 35659256 PMCID: PMC9166340 DOI: 10.1186/s12865-022-00502-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 05/24/2022] [Indexed: 12/24/2022] Open
Abstract
Background Enhancer of Zeste homologue 2 (EZH2) is a polycomb group gene and an epigenetic regulator that inhibits transcription, a modification associated with gene silencing. EZH2 plays an essential role in humoral and cell-mediated adaptive immunity. The purpose of the current study is to investigate the prognostic potential of EZH2 and to comprehensively analyse the correlation between EZH2 and immune infiltration in multiple cancer cases, especially liver hepatocellular carcinoma. Methods EZH2 expression across cancers was explored through Oncomine, HPA, and GEPIA2. Additionally, the prognostic value of EZH2 analysis across cancers was based on the GEPIA2, TCGA portal, Kaplan–Meier Plotter, and LOGpc databases. Based on GO and KEGG analyses, GSEA helped demonstrate the biological processes through which EZH2 might lead to HCC development. GEPIA and TIMER were adopted to detect the possible relationship of EZH2 expression with tumour-infiltrating immune cells (TIICs). Results EZH2 overexpression levels were associated with poor prognosis of cancer, especially hepatocellular carcinoma. A high EZH2 expression level is related to a poor prognosis of HCC, especially in disease histology and stage III. The EZH2 expression level was positively correlated with critical gene markers of TAMs, M2 macrophages, M1 macrophages, and monocytes. Further analysis revealed that EZH2 genes were mainly related to DNA recombination, mitotic cell cycle phase transition, and chromosome segregation. Conclusion EZH2 plays an essential role in the immune microenvironment and is a potential prognostic marker and immunotherapy target for hepatocellular carcinoma. Supplementary Information The online version contains supplementary material available at 10.1186/s12865-022-00502-7.
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