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Huang M, Ji Q, Huang H, Wang X, Wang L. Gut microbiota in hepatocellular carcinoma immunotherapy: immune microenvironment remodeling and gut microbiota modification. Gut Microbes 2025; 17:2486519. [PMID: 40166981 PMCID: PMC11970798 DOI: 10.1080/19490976.2025.2486519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 03/05/2025] [Accepted: 03/25/2025] [Indexed: 04/02/2025] Open
Abstract
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, with limited treatment options at advanced stages. The gut microbiota, a diverse community of microorganisms residing in the gastrointestinal tract, plays a pivotal role in regulating immune responses through the gut-liver axis. Emerging evidence underscores its impact on HCC progression and the efficacy of immunotherapy. This review explores the intricate interactions between gut microbiota and the immune system in HCC, with a focus on key immune cells and pathways involved in tumor immunity. Additionally, it highlights strategies for modulating the gut microbiota - such as fecal microbiota transplantation, dietary interventions, and probiotics - as potential approaches to enhancing immunotherapy outcomes. A deeper understanding of these mechanisms could pave the way for novel therapeutic strategies aimed at improving patient prognosis.
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Affiliation(s)
- Mingyao Huang
- School of Basic Medicine, Putian University, Putian, Fujian, China
- Department of Breast Surgery, Clinical Oncology School of Fujian Medical University, Fuzhou, Fujian, China
| | - Quansong Ji
- Department of Urology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Huiyan Huang
- Ward 3, De’an Hospital, Xianyou County, Putian, Fujian, China
| | - Xiaoqian Wang
- Department of Rehabilitation Medicine, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Lin Wang
- Department of Orthopedics, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
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Xiao Q, Liu Y, Li T, Wang C, He S, Zhai L, Yang Z, Zhang X, Wu Y, Liu Y. Viral oncogenesis in cancer: from mechanisms to therapeutics. Signal Transduct Target Ther 2025; 10:151. [PMID: 40350456 PMCID: PMC12066790 DOI: 10.1038/s41392-025-02197-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 01/22/2025] [Accepted: 03/03/2025] [Indexed: 05/14/2025] Open
Abstract
The year 2024 marks the 60th anniversary of the discovery of the Epstein-Barr virus (EBV), the first virus confirmed to cause human cancer. Viral infections significantly contribute to the global cancer burden, with seven known Group 1 oncogenic viruses, including hepatitis B virus (HBV), human papillomavirus (HPV), EBV, Kaposi sarcoma-associated herpesvirus (KSHV), hepatitis C virus (HCV), human T-cell leukemia virus type 1 (HTLV-1), and human immunodeficiency virus (HIV). These oncogenic viruses induce cellular transformation and cancer development by altering various biological processes within host cells, particularly under immunosuppression or co-carcinogenic exposures. These viruses are primarily associated with hepatocellular carcinoma, gastric cancer, cervical cancer, nasopharyngeal carcinoma, Kaposi sarcoma, lymphoma, and adult T-cell leukemia/lymphoma. Understanding the mechanisms of viral oncogenesis is crucial for identifying and characterizing the early biological processes of virus-related cancers, providing new targets and strategies for treatment or prevention. This review first outlines the global epidemiology of virus-related tumors, milestone events in research, and the process by which oncogenic viruses infect target cells. It then focuses on the molecular mechanisms by which these viruses induce tumors directly or indirectly, including the regulation of oncogenes or tumor suppressor genes, induction of genomic instability, disruption of regular life cycle of cells, immune suppression, chronic inflammation, and inducing angiogenesis. Finally, current therapeutic strategies for virus-related tumors and recent advances in preclinical and clinical research are discussed.
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Affiliation(s)
- Qing Xiao
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Yi Liu
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Tingting Li
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Chaoyu Wang
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Sanxiu He
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Liuyue Zhai
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Zailin Yang
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Xiaomei Zhang
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China.
| | - Yongzhong Wu
- Department of Radiation Oncology, Chongqing University Cancer Hospital, Chongqing, China.
| | - Yao Liu
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China.
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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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Miri H, Rahimzadeh P, Hashemi M, Nabavi N, Aref AR, Daneshi S, Razzaghi A, Abedi M, Tahmasebi S, Farahani N, Taheriazam A. Harnessing immunotherapy for hepatocellular carcinoma: Principles and emerging promises. Pathol Res Pract 2025; 269:155928. [PMID: 40184729 DOI: 10.1016/j.prp.2025.155928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 03/12/2025] [Accepted: 03/26/2025] [Indexed: 04/07/2025]
Abstract
HCC is considered as one of the leadin causes of death worldwide, with the ability of resistance towards therapeutics. Immunotherapy, particularly ICIs, have provided siginficant insights towards harnessing the immune system. The present review introduces the concepts and possibilities of immunotherapy for HCC treatment, emphasizing its underlying mechanisms and capacity to enhance patient results, focusing on both pre-clinical and clinical insights. The functions of TME and immune evasion mechanisms typical of HCC would be evaluated along with how contemporary immunotherapeutic approaches are designed to address these challenges. Furthermore, the clinical application of immunotherapy in HCC is discussed, emphasizing recent trial findings demonstrating the effectiveness and safety of drugs. In addition, the problems caused by immune evasion and resistance would be discussed to increase potential of immunotherapy along with combination therapy.
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Affiliation(s)
- Hossein Miri
- Faculty of Medicine, Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran
| | - Payman Rahimzadeh
- Surgical Research Society (SRS), Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Noushin Nabavi
- Independent Researcher, Victoria, British Columbia V8V 1P7, Canada
| | - Amir Reza Aref
- Department of Vitro Vision, DeepkinetiX, Inc, Boston, MA, USA
| | - Salman Daneshi
- Department of Public Health, School of Health, Jiroft University Of Medical Sciences, Jiroft, Iran
| | - Alireza Razzaghi
- Social Determinants of Health Research Center, Research Institute for Prevention of Non-Communicable Diseases, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Maryam Abedi
- Department of Pathology, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran.
| | - Safa Tahmasebi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Najma Farahani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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Wang Y, Pan S, Tian J, Wang J, Yu Y, Wang S, Li F, Yang L, Liu X, Shen Y, Qiu Q, Luan J, Jia M, Xiong C, Duan X, Wang FS, Meng F. Cadonilimab, a PD-1/CTLA-4 bispecific antibody in unresectable hepatocellular carcinoma: a real-world study. Cancer Immunol Immunother 2025; 74:186. [PMID: 40293533 PMCID: PMC12037968 DOI: 10.1007/s00262-025-04038-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Accepted: 03/26/2025] [Indexed: 04/30/2025]
Abstract
OBJECTIVE This study retrospectively evaluated the safety and efficacy of cadonilimab combined with tyrosine kinase inhibitors (TKI) for the treatment of unresectable hepatocellular carcinoma (uHCC). PATIENTS AND METHODS Seventy-eight patients who received cadonilimab + TKI were included; 42 and 36 received it as first-line (1 L) and second-line and above (≥ 2 L) systemic treatment, respectively. Besides, ninety-five patients who received PD-1 inhibitor + TKI as first-line treatments were included. Safety was the primary endpoint; secondary endpoints were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). RESULTS Treatment-related adverse events (TRAEs) of any grade occurred in 84.6% of the patients, with grade ≥ 3 in 20.5%. In patients with a Child-Pugh score of ≥ 8 (CP ≥ 8), any grade TRAEs occurred in 88.2%, and grade ≥ 3 in 20.6%. The overall cohort's median progression-free survival (mPFS) was 3.6 months, whereas the median overall survival (mOS) was 8.8 months. In the 1 L group, mPFS was 6.7 months versus 2.3 months in ≥ 2 L. In the 1 L group, mOS was 13.7 months versus 3.2 months in ≥ 2 L. For CP < 8, 1 L mPFS was 7.6 months, mOS not reached; CP ≥ 8 had mPFS of 5.2 months, mOS of 5.6 months. For CP < 8 in ≥ 2 L, mPFS was 3.1 months, mOS 8.8 months; CP ≥ 8 had mPFS of 1.4 months, mOS of 2.2 months. After propensity score matching (PSM), the incidence of TRAEs of any grade was 77.1%, with grade ≥ 3 accounting for 17.1% in the PD-1 group. In the PD-1/CTLA-4 group, the incidence of TRAEs of any grade was 80.0%, and that of grade ≥ 3 TRAEs was 17.1%. The mPFS was 6.7 months in the PD-1/CTLA-4 group versus 3.3 months in the PD-1 group. The mOS was 13.7 months in the PD-1/CTLA-4 group versus 6.7 months in the PD-1 group. CONCLUSION Cadonilimab + TKI showed a favorable trend in safety and efficacy, especially when applied as first-line systemic therapy for uHCC. This study offers a clinical reference for its use in systemic uHCC therapy, particularly in patients with advanced liver dysfunction.
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Affiliation(s)
- Yilin Wang
- Medical School of Chinese PLA, No. 28, Fuxing Road, Beijing, 100853, China
- Department of Infectious Diseases, The Fifth Medical Centre of Chinese PLA General Hospital, National Clinical Research Centre for Infectious Diseases, Beijing, 100853, China
| | - Shida Pan
- Capital Medical University, Beijing, 100069, China
| | - Jiahe Tian
- Peking University 302 Clinical Medical School, Beijing, 100191, China
| | - Jianing Wang
- Peking University 302 Clinical Medical School, Beijing, 100191, China
| | - Yingying Yu
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China
| | - Siyu Wang
- Department of Infectious Diseases, The Fifth Medical Centre of Chinese PLA General Hospital, National Clinical Research Centre for Infectious Diseases, Beijing, 100853, China
| | - Fengyi Li
- Department of Infectious Diseases, The Fifth Medical Centre of Chinese PLA General Hospital, National Clinical Research Centre for Infectious Diseases, Beijing, 100853, China
| | - Luo Yang
- Department of Infectious Diseases, The Fifth Medical Centre of Chinese PLA General Hospital, National Clinical Research Centre for Infectious Diseases, Beijing, 100853, China
| | - Xiaomeng Liu
- Department of Infectious Diseases, The Fifth Medical Centre of Chinese PLA General Hospital, National Clinical Research Centre for Infectious Diseases, Beijing, 100853, China
| | - Yingjuan Shen
- Department of Infectious Diseases, The Fifth Medical Centre of Chinese PLA General Hospital, National Clinical Research Centre for Infectious Diseases, Beijing, 100853, China
| | - Qin Qiu
- Department of Infectious Diseases, The Fifth Medical Centre of Chinese PLA General Hospital, National Clinical Research Centre for Infectious Diseases, Beijing, 100853, China
| | - Junqing Luan
- Department of Infectious Diseases, The Fifth Medical Centre of Chinese PLA General Hospital, National Clinical Research Centre for Infectious Diseases, Beijing, 100853, China
| | - Mengdie Jia
- Medical School of Chinese PLA, No. 28, Fuxing Road, Beijing, 100853, China
| | - Chuyue Xiong
- Peking University 302 Clinical Medical School, Beijing, 100191, China
| | - Xuanxuan Duan
- Medical School of Chinese PLA, No. 28, Fuxing Road, Beijing, 100853, China
| | - Fu-Sheng Wang
- Medical School of Chinese PLA, No. 28, Fuxing Road, Beijing, 100853, China.
- Department of Infectious Diseases, The Fifth Medical Centre of Chinese PLA General Hospital, National Clinical Research Centre for Infectious Diseases, Beijing, 100853, China.
| | - Fanping Meng
- Medical School of Chinese PLA, No. 28, Fuxing Road, Beijing, 100853, China.
- Department of Infectious Diseases, The Fifth Medical Centre of Chinese PLA General Hospital, National Clinical Research Centre for Infectious Diseases, Beijing, 100853, China.
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Fatima N, Fatima H, Ahmad S, Hashmi MATS, Sheikh N. Understanding the role of Hedgehog signaling pathway and gut dysbiosis in fueling liver cancer. Mol Biol Rep 2025; 52:411. [PMID: 40261446 DOI: 10.1007/s11033-025-10504-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 04/09/2025] [Indexed: 04/24/2025]
Abstract
Liver cancer is one of the most prevalent types of cancer worldwide with less than 20% of patients surviving in the past half a decade. Several molecular pathways have been uncovered that may lead to the development of liver cancer but more recently the Hedgehog pathway (HH) and its interactions with the gut microbiota has emerged as an underlying cause of the development of liver cancer. Gut-liver axis is vital to maintaining homeostasis. The HH pathway controls cellular differentiation, proliferation, and apoptosis evasions, its abnormal activation can lead to uncontrolled proliferation of liver cancer stem cells. Additionally, the intricate interplay between HH signaling and the gut microbiota introduces a novel dimension. Recent investigations suggest that potential modulation of HH activity by gut microbiota influence HCC progression. This review explores a crosstalk between HH signaling and the gut microbiota, uncovering intricate mechanisms by which it fuels liver cancer development. This interplay provides insights into gut dysbiosis, HCC etiology and potential therapeutic avenues, highlighting the cooperative role of HH signaling and gut microbiota in shaping the overall HCC landscape.
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Affiliation(s)
- Naz Fatima
- Department of Zoology, Faculty of Science and Technology, University of Central Punjab, Lahore, Pakistan.
- Department of Internal Medicine & Gastroenterology, University of Michigan, Ann Arbor, 48109, USA.
| | - Hooriya Fatima
- Institute of Zoology, University of Punjab (Quaid-i-Azam Campus), Lahore, 54590, Pakistan
| | - Sadia Ahmad
- Institute of Zoology, University of Punjab (Quaid-i-Azam Campus), Lahore, 54590, Pakistan
| | | | - Nadeem Sheikh
- Institute of Zoology, University of Punjab (Quaid-i-Azam Campus), Lahore, 54590, Pakistan
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Moeckli B, Wassmer CH, El Hajji S, Kumar R, Rodrigues Ribeiro J, Tabrizian P, Feng H, Schnickel G, Kulkarni AV, Allaire M, Asthana S, Karvellas CJ, Meeberg G, Wei L, Chouik Y, Kumar P, Gartrell RD, Martinez M, Kang E, Sogbe M, Sangro B, Schwacha-Eipper B, Schmiderer A, Krendl FJ, Goossens N, Lacotte S, Compagnon P, Toso C. Determining safe washout period for immune checkpoint inhibitors prior to liver transplantation: An international retrospective cohort study. Hepatology 2025:01515467-990000000-01187. [PMID: 40042053 DOI: 10.1097/hep.0000000000001289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Accepted: 01/28/2025] [Indexed: 04/05/2025]
Abstract
BACKGROUND AND AIMS Immune checkpoint inhibitors (ICIs) are increasingly used in patients with advanced HCC patients awaiting liver transplantation (LT). However, concerns about the risk of posttransplant rejection persist. APPROACH AND RESULTS We conducted an international retrospective cohort study including 119 HCC patients who received ICIs prior to LT. We analyzed the incidence of allograft rejection, graft loss, and posttransplant recurrence with a particular focus on the washout period between the last ICI dose and LT. In this study, 24 of the 119 (20.2%) patients experienced allograft rejection with a median time to rejection of 9 days (IQR 6-10) post-LT. A linear relationship was observed between shorter washout periods and higher rejection risk. Washout periods <30 days (OR: 21.3, 95% CI: 5.93-103, p< 0.001) and between 30 and 50 days (OR: 9.48, 95% CI 2.47-46.8, p =0.002) were significantly associated with higher rejection rates in the univariate analysis compared to the washout period above 50 days. Graft loss as a result of rejection occurred in 6 patients (25%) with rejection. No factors related to grafts were associated with rejection. A longer washout period was not associated with a lower recurrence-free survival posttransplantation at 36 months (71% vs. 67%, p =0.71). CONCLUSIONS Our findings suggest that a washout period longer than 50 days for ICIs before LT appears to be safe with respect to rejection risk. While these results may help guide clinical decision-making, future prospective studies are essential to establish definitive guidelines.
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Affiliation(s)
- Beat Moeckli
- Faculty of Medicine, Department of Surgery, University of Geneva, Switzerland
| | | | - Sofia El Hajji
- Faculty of Medicine, Department of Surgery, University of Geneva, Switzerland
| | - Rohan Kumar
- Faculty of Medicine, Department of Surgery, University of Geneva, Switzerland
| | | | - Parissa Tabrizian
- Recanati/Miller Institute, Mount Sinai Medical Center, New York, USA
| | - Hao Feng
- Department of Liver Surgery, Renji Hospital, Shanghai, China
| | - Gabriel Schnickel
- Division of Transplant and Hepatobiliary Surgery, Department of Surgery, University of California San Diego, San Diego, California, USA
| | | | - Manon Allaire
- AP-HP Sorbonne Université, Hôpital Universitaire Pitié-Salpêtrière, Service d'Hépato-gastroentérologie, Paris, France
| | - Sonal Asthana
- Department of Hepatobiliary Surgery and Transplantation, Aster Hospitals, Bangalore, India
| | - Constantine J Karvellas
- Faculty of Medicine and Dentistry, College of Health Sciences and School of Public Health, University of Alberta
| | - Glenda Meeberg
- Faculty of Medicine and Dentistry, College of Health Sciences and School of Public Health, University of Alberta
| | - Lai Wei
- Institute of Organ Transplantation, Tongji Hospital, Wuhan, China
| | - Yasmina Chouik
- Department of Hepatology, Croix-Rousse Hospital, Lyon, France
| | - Pramod Kumar
- Department of Hepatology, BGS Gleneagles Global Hospital, Bengaluru, India
| | - Robyn D Gartrell
- Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, USA
- Division of Pediatric Oncology, Department of Oncology, Johns Hopkins School of Medicine, Baltimore, USA
| | - Mercedes Martinez
- Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, USA
| | - Elise Kang
- Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, USA
| | - Miguel Sogbe
- Hepatology Unit, Department of Internal Medicine, Clinica Universidad de Navarra and CIBEREHD, Pamplona, Spain
| | - Bruno Sangro
- Hepatology Unit, Department of Internal Medicine, Clinica Universidad de Navarra and CIBEREHD, Pamplona, Spain
| | | | - Andreas Schmiderer
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Felix J Krendl
- Department of Visceral, Transplant and Thoracic Surgery, Center for Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Nicolas Goossens
- Faculty of Medicine, Department of Surgery, University of Geneva, Switzerland
| | - Stephanie Lacotte
- Faculty of Medicine, Department of Surgery, University of Geneva, Switzerland
| | - Philippe Compagnon
- Faculty of Medicine, Department of Surgery, University of Geneva, Switzerland
| | - Christian Toso
- Faculty of Medicine, Department of Surgery, University of Geneva, Switzerland
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Di Marco L, Romanzi A, Pivetti A, De Maria N, Ravaioli F, Salati M, Villa E, Di Benedetto F, Magistri P, Dominici M, Colecchia A, Di Sandro S, Spallanzani A. Suppressing, stimulating and/or inhibiting: The evolving management of HCC patient after liver transplantation. Crit Rev Oncol Hematol 2025; 207:104607. [PMID: 39725094 DOI: 10.1016/j.critrevonc.2024.104607] [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: 05/23/2024] [Revised: 12/20/2024] [Accepted: 12/22/2024] [Indexed: 12/28/2024] Open
Abstract
Liver transplantation (LT) is a curative strategy for hepatocellular carcinoma (HCC), but the risk of HCC recurrence remains a challenging problem. In patients with HCC recurrence after LT (HCC-R_LT), the locoregional and surgical approaches are complex, and the guidelines do not report evidence-based strategies for the management of immunosuppression. In recent years, immunotherapy has become an effective option for patients with advanced HCC in pre-transplant settings. However, due to the risk of potentially fatal allograft rejection, the use of immunotherapy is avoided in post-transplant settings. Combining immunosuppressants with immunotherapy in transplant patients is also challenging due to the complex tumor microenvironment and immunoreactivity. The fear of acute liver rejection and the lack of predictive factors hinder the successful clinical application of immunotherapy for post-liver transplantation HCC recurrence. This review aims to comprehensively summarize the risk of HCC-R_LT, the available evidence for the efficacy of immunotherapy in patients with HCC-R_LT, and the clinical issues regarding the innovative management of this patient population.
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Affiliation(s)
- Lorenza Di Marco
- Department of Oncology and Hematology, Oncology Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41124, Italy; Department of Biomedical, Metabolic and Neural Sciences, Clinical and Experimental Medicine Program, University of Modena and Reggio Emilia, Modena 41124, Italy.
| | - Adriana Romanzi
- Chimomo Department, Gastroenterology Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41125, Italy.
| | - Alessandra Pivetti
- Chimomo Department, Gastroenterology Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41125, Italy.
| | - Nicola De Maria
- Chimomo Department, Gastroenterology Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41125, Italy.
| | - Federico Ravaioli
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum University of Bologna, Bologna 40138, Italy.
| | - Massimiliano Salati
- Department of Oncology and Hematology, Oncology Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41124, Italy.
| | - Erica Villa
- Chimomo Department, Gastroenterology Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41125, Italy; National Institute of Gastroenterology IRCCS "Saverio de Bellis", Research Hospital, Castellana Grotte 70013, Italy.
| | - Fabrizio Di Benedetto
- Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41125, Italy.
| | - Paolo Magistri
- Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41125, Italy.
| | - Massimo Dominici
- Department of Oncology and Hematology, Oncology Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41124, Italy.
| | - Antonio Colecchia
- Chimomo Department, Gastroenterology Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41125, Italy.
| | - Stefano Di Sandro
- Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41125, Italy.
| | - Andrea Spallanzani
- Department of Oncology and Hematology, Oncology Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41124, Italy.
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9
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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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10
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Sousa A, Al Masad Q, Pena P, Espat NJ, Calvino AS, Somasundar P, Abdelfattah T, Kwon S. Impact of immunotherapy on the care patterns and outcomes of patients with advanced hepatocellular carcinoma. Clin Res Hepatol Gastroenterol 2025; 49:102542. [PMID: 39870347 DOI: 10.1016/j.clinre.2025.102542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Revised: 11/17/2024] [Accepted: 01/24/2025] [Indexed: 01/29/2025]
Abstract
BACKGROUND Modern immunotherapy with checkpoint inhibitors revolutionized cancer treatment and outcomes. This study aims to demonstrate how immunotherapy has impacted the national landscape of systemic treatment and palliative care in advanced hepatocellular carcinoma (HCC). METHODS Retrospective cohort selecting patients from the U.S.-based National Cancer Database (NCDB) with clinical stages T3b/T4 and stage IV HCC from 2010 to 2021. We performed a multivariable analysis using the Cox proportional hazard for overall survival (OS) comparisons and a logistic regression model to study immunotherapy use. RESULTS Immunotherapy use increased from 0.27 % in 2010 to 33.80 % in 2021. The median OS survival (in months) was 2 for untreated patients, 7.20 for chemotherapy, and 7.46 for immunotherapy. There was a better OS with immunotherapy (HR 0.59, 95 % CI 0.56-0.62). Systemic therapy for palliation increased from 14.41 % in 2010 to 25.32 % in 2021. Compared to surgical palliation, radiation (HR 0.61, 95 % CI 0.52-0.71) and systemic palliative (HR 0.59, 95 % CI 0.51-0.69) therapies improved OS. CONCLUSION From 2010 to 2021, there was a significant increase in the use of immunotherapy, parallel to a large shift toward systemic therapy use for palliative care in patients with advanced HCC. Immunotherapy was associated with a significant OS benefit in the palliative setting.
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Affiliation(s)
- Aryanna Sousa
- Department of Medicine, Rush University Medical Center. 1725 W Harrison St., Suite 319, Chicago, IL 60612, USA
| | - Qusai Al Masad
- Department of Medicine, Roger Williams Medical Center. 825 Chalkstone Ave, Providence, RI 02908, USA
| | - Paola Pena
- Department of Medicine, Roger Williams Medical Center. 825 Chalkstone Ave, Providence, RI 02908, USA
| | - N Joseph Espat
- Department of Surgery, Division of Surgical Oncology, Roger Williams Medical Center. 825 Chalkstone Ave, Providence, RI 02908, USA. Boston University School of Medicine. 72 E Concord St, Boston, MA 02118, USA.
| | - Abdul S Calvino
- Department of Surgery, Division of Surgical Oncology, Roger Williams Medical Center. 825 Chalkstone Ave, Providence, RI 02908, USA. Boston University School of Medicine. 72 E Concord St, Boston, MA 02118, USA.
| | - Ponnandai Somasundar
- Department of Surgery, Division of Surgical Oncology, Roger Williams Medical Center. 825 Chalkstone Ave, Providence, RI 02908, USA. Boston University School of Medicine. 72 E Concord St, Boston, MA 02118, USA.
| | - Thaer Abdelfattah
- Department of Surgery, Division of Surgical Oncology, Roger Williams Medical Center. 825 Chalkstone Ave, Providence, RI 02908, USA. Boston University School of Medicine. 72 E Concord St, Boston, MA 02118, USA.
| | - Steve Kwon
- Department of Surgery, Division of Surgical Oncology, Roger Williams Medical Center. 825 Chalkstone Ave, Providence, RI 02908, USA. Boston University School of Medicine. 72 E Concord St, Boston, MA 02118, USA.
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11
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Abdo EL, Ajib I, El Mounzer J, Husseini M, Kalaoun G, Matta TM, Mosleh R, Nasr F, Richani N, Khalil A, Shayya A, Ghanem H, Faour WH. Molecular biology of the novel anticancer medications: a focus on kinases inhibitors, biologics and CAR T-cell therapy. Inflamm Res 2025; 74:41. [PMID: 39960501 DOI: 10.1007/s00011-025-02008-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 01/28/2025] [Accepted: 02/10/2025] [Indexed: 05/09/2025] Open
Abstract
INTRODUCTION Cancer treatment underwent significant changes in the last few years with the introduction of novel treatments targeting the immune system. OBJECTIVES The objective of this review is to discuss novel anticancer drugs including kinase inhibitors, biologics and cellular therapy with CAR-T cells. METHODS Most recent research articles were extracted from PubMed using keywords such as "kinases inhibitors", "CAR-T cell therapy". RESULTS AND DISCUSSION The number of kinase inhibitors is significantly increasing due to their demonstrated effectiveness in combination with biologics. CAR-T represented a major breakthrough in the field. Also, it focused on their mechanisms of action and the rational of their use either alone or in combination in relation to their modes of action.
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Affiliation(s)
- Elia-Luna Abdo
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Imad Ajib
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Jason El Mounzer
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Mohammad Husseini
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Gharam Kalaoun
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Tatiana-Maria Matta
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Reine Mosleh
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Fidel Nasr
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Nour Richani
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Alia Khalil
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Anwar Shayya
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
- Department of Hematology-Oncology, Lebanese American University Medical Center- Rizk Hospital, Beirut, Lebanon
| | - Hady Ghanem
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
- Department of Hematology-Oncology, Lebanese American University Medical Center- Rizk Hospital, Beirut, Lebanon
| | - Wissam H Faour
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon.
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12
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Zheng J, Wang S, Xia L, Sun Z, Chan KM, Bernards R, Qin W, Chen J, Xia Q, Jin H. Hepatocellular carcinoma: signaling pathways and therapeutic advances. Signal Transduct Target Ther 2025; 10:35. [PMID: 39915447 PMCID: PMC11802921 DOI: 10.1038/s41392-024-02075-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 09/18/2024] [Accepted: 11/14/2024] [Indexed: 02/09/2025] Open
Abstract
Liver cancer represents a major global health concern, with projections indicating that the number of new cases could surpass 1 million annually by 2025. Hepatocellular carcinoma (HCC) constitutes around 90% of liver cancer cases and is primarily linked to factors incluidng aflatoxin, hepatitis B (HBV) and C (HCV), and metabolic disorders. There are no obvious symptoms in the early stage of HCC, which often leads to delays in diagnosis. Therefore, HCC patients usually present with tumors in advanced and incurable stages. Several signaling pathways are dis-regulated in HCC and cause uncontrolled cell propagation, metastasis, and recurrence of HCC. Beyond the frequently altered and therapeutically targeted receptor tyrosine kinase (RTK) pathways in HCC, pathways involved in cell differentiation, telomere regulation, epigenetic modification and stress response also provide therapeutic potential. Investigating the key signaling pathways and their inhibitors is pivotal for achieving therapeutic advancements in the management of HCC. At present, the primary therapeutic approaches for advanced HCC are tyrosine kinase inhibitors (TKI), immune checkpoint inhibitors (ICI), and combination regimens. New trials are investigating combination therapies involving ICIs and TKIs or anti-VEGF (endothelial growth factor) therapies, as well as combinations of two immunotherapy regimens. The outcomes of these trials are expected to revolutionize HCC management across all stages. Here, we provide here a comprehensive review of cellular signaling pathways, their therapeutic potential, evidence derived from late-stage clinical trials in HCC and discuss the concepts underlying earlier clinical trials, biomarker identification, and the development of more effective therapeutics for HCC.
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Affiliation(s)
- Jiaojiao Zheng
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Siying Wang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Lei Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Zhen Sun
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Kui Ming Chan
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, PR China
| | - René Bernards
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Wenxin Qin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Jinhong Chen
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, PR China.
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
| | - Haojie Jin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
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13
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Young EP, O’Neill AF, Rangaswami AA. Pediatric Hepatocellular Carcinoma: A Review of Predisposing Conditions, Molecular Mechanisms, and Clinical Considerations. Int J Mol Sci 2025; 26:1252. [PMID: 39941018 PMCID: PMC11818592 DOI: 10.3390/ijms26031252] [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: 08/31/2024] [Revised: 01/21/2025] [Accepted: 01/21/2025] [Indexed: 02/16/2025] Open
Abstract
Pediatric hepatocellular carcinoma (HCC) is a rare malignant liver tumor affecting children and adolescents and occurring either sporadically or in the context of underlying liver disease. In this review, we detail the epidemiology of pediatric HCC with a focus on predisposing factors including hepatic or systemic disease, genetic disorders, and familial cancer syndromes. We summarize existing research on the pathophysiology of pediatric HCC, including molecular mechanisms of oncogenesis, highlighting unique disease features differentiating pediatric HCC from adult HCC. We then survey the landscape of therapeutic options for pediatric HCC, including novel therapeutics. Lastly, we discuss the pathologic spectrum upon which pediatric HCC is postulated to exist, ranging from hepatoblastoma to HCC and including the hybrid entity hepatocellular neoplasm not otherwise specifed (HCN-NOS). In summary, we highlight the key clinical and molecular features of pediatric HCC that may inform future research and novel approaches to the clinical care of these patients.
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Affiliation(s)
- Elizabeth P. Young
- Department of Pediatrics, Division of Oncology, University of California San Francisco, San Francisco, CA 94158, USA;
| | - Allison F. O’Neill
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02215, USA;
| | - Arun A. Rangaswami
- Department of Pediatrics, Division of Oncology, University of California San Francisco, San Francisco, CA 94158, USA;
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14
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Nishida N. Personalized approaches to the treatment of hepatocellular carcinoma using immune checkpoint inhibitors: Editorial on "Genomic biomarkers to predict response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: Insights from the IMbrave150 trial". Clin Mol Hepatol 2025; 31:311-315. [PMID: 39228069 PMCID: PMC11791597 DOI: 10.3350/cmh.2024.0739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Accepted: 09/03/2024] [Indexed: 09/05/2024] Open
Affiliation(s)
- Naoshi Nishida
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
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15
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De Martin E, Fulgenzi CAM, Celsa C, Laurent-Bellue A, Torkpour A, Lombardi P, D'Alessio A, Pinato DJ. Immune checkpoint inhibitors and the liver: balancing therapeutic benefit and adverse events. Gut 2024:gutjnl-2024-332125. [PMID: 39658265 DOI: 10.1136/gutjnl-2024-332125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Accepted: 11/19/2024] [Indexed: 12/12/2024]
Abstract
Immune checkpoint inhibitors (ICI) have led to breakthrough improvements in the management of malignancy including hepatocellular (HCC) and biliary tract cancer, improving decades-old standards of care and increasing patient survival. In both liver tumour types, which commonly arise in the context of liver inflammation and underlying functional impairment, the lack of validated predictors of response underscores the need to balance predicted gains in survival with risk of treatment-related hepatoxicity and decompensation of underlying chronic liver disease.In addition, the liver is implicated in the toxicity associated with ICI therapy for non-liver cancers, which exhibits a high degree of variability in presentation and severity. An accurate assessment is mandatory for the diagnosis and management of ICI-induced liver injury.In this Recent Advances article, we provide an overview of the mechanisms of efficacy and toxicity of anticancer immunotherapy in liver tumours and liver toxicity in extrahepatic malignancies.We compare and contrast characteristics, management strategies and outcomes from immune-related liver injury in patients with chronic hepatitis/cirrhosis or with an underlying healthy liver and discuss the latest findings on how toxicity and decompensation may impact the outlook of patients with liver tumours and extrahepatic malignancies offering insights into the future directions of clinical research and practice in the field.
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Affiliation(s)
- Eleonora De Martin
- Centre Hepatobiliaire, Paul Brousse Hospital, Villejuif, France
- Paris-Saclay University, Faculty of Medicine, Le Kremlin-Bicetre, France
| | | | - Ciro Celsa
- Surgery & Cancer, Imperial College London, London, UK
- Department of Health Promotion, Mother & Child Care, Internal Medicine & Medical Specialties, Gastroenterology and Hepatology Unit, Palermo, Italy
| | - Astrid Laurent-Bellue
- Hôpital Kremlin Bicêtre, Anatomie & Cytologie Pathologiques, Le Kremlin Bicetre, France
| | - Aria Torkpour
- Surgery & Cancer, Imperial College London, London, UK
| | - Pasquale Lombardi
- Surgery & Cancer, Imperial College London, London, UK
- Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy
| | - Antonio D'Alessio
- Surgery & Cancer, Imperial College London, London, UK
- Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - David J Pinato
- Surgery & Cancer, Imperial College London, London, UK
- Imperial College London, University of Eastern Piedmont Amedeo Avogadro, Department of Translational Medicine, Novara, Italy
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16
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Zhang X, Tao Y, Xu Z, Jiang B, Yang X, Huang T, Tan W. Sorafenib and SIAIS361034, a novel PROTAC degrader of BCL-x L, display synergistic antitumor effects on hepatocellular carcinoma with minimal hepatotoxicity. Biochem Pharmacol 2024; 230:116542. [PMID: 39284500 DOI: 10.1016/j.bcp.2024.116542] [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: 06/11/2024] [Revised: 08/16/2024] [Accepted: 09/13/2024] [Indexed: 10/01/2024]
Abstract
The overexpression of BCL-xL is closely associated with poor prognosis in hepatocellular carcinoma (HCC). While the strategy of combination of BCL-xL and MCL-1 for treating solid tumors has been reported, it presents significant hepatotoxicity. SIAIS361034, a novel proteolysis targeting chimera (PROTAC) agent, selectively induces the ubiquitination and subsequent proteasomal degradation of BCL-xL through the CRBN-E3 ubiquitin ligase. When combined with sorafenib, SIAIS361034 showed a potent synergistic effect in inhibiting hepatocellular carcinoma development both in vitro and in vivo. Since SIAIS361034 exhibits a high degree of selectivity for degrading BCL-xL in hepatocellular carcinoma, the hepatotoxicity typically associated with the combined inhibition of BCL-xL and MCL-1 is significantly reduced, thereby greatly enhancing safety. Mechanistically, BCL-xL and MCL-1 sequester the BH3-only protein BIM on mitochondria at baseline. Treatment with SIAIS361034 and sorafenib destabilizes BIM/BCL-xL and BIM/MCL1 association, resulting in the liberation of more BIM proteins to trigger apoptosis. Additionally, we discovered a novel compensatory regulation mechanism in hepatocellular carcinoma cells. BIM can rapidly respond to changes in the balance between BCL-xL and MCL-1 through their co-transcription factor MEF2C to maintain apoptosis resistance. In summary, the combination therapy of SIAIS361034 and sorafenib represents an effective and safe approach for inhibiting hepatocellular carcinoma progression. The novel balancing mechanism may also provide insights for combination and precision therapies in the treatment of hepatocellular carcinoma.
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Affiliation(s)
- Xiaoyi Zhang
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Yachuan Tao
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Zhongli Xu
- Shanghai Institute for Advanced Immunochemical Studies, Shanghai Tech University, Shanghai 201210, China
| | - Biao Jiang
- Shanghai Institute for Advanced Immunochemical Studies, Shanghai Tech University, Shanghai 201210, China
| | - Xiaobao Yang
- Gluetacs Therapeutics (Shanghai) Co., Ltd., No. 99 Haike Road, Zhangjiang Hi-Tech Park, Shanghai 201210, China.
| | - Taomin Huang
- Department of Pharmacy, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai 200031, China.
| | - Wenfu Tan
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China.
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17
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Liu WN, Harden SL, Tan SLW, Tan RJR, Fong SY, Tan SY, Liu M, Karnik I, Shuen TWH, Toh HC, Fan Y, Lim SG, Chan JKY, Chen Q. Single-cell RNA sequencing reveals anti-tumor potency of CD56 + NK cells and CD8 + T cells in humanized mice via PD-1 and TIGIT co-targeting. Mol Ther 2024; 32:3895-3914. [PMID: 39318093 PMCID: PMC11573594 DOI: 10.1016/j.ymthe.2024.09.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 08/16/2024] [Accepted: 09/19/2024] [Indexed: 09/26/2024] Open
Abstract
In solid tumors, the exhaustion of natural killer (NK) cells and cytotoxic T cells in the immunosuppressive tumor microenvironment poses challenges for effective tumor control. Conventional humanized mouse models of hepatocellular carcinoma patient-derived xenografts (HCC-PDX) encounter limitations in NK cell infiltration, hindering studies on NK cell immunobiology. Here, we introduce an improved humanized mouse model with restored NK cell reconstitution and infiltration in HCC-PDX, coupled with single-cell RNA sequencing (scRNA-seq) to identify potential anti-HCC treatments. A single administration of adeno-associated virus carrying human interleukin-15 reinstated persistent NK cell reconstitution and infiltration in HCC-PDX in humanized mice. scRNA-seq revealed NK cell and T cell subpopulations with heightened PDCD1 and TIGIT levels. Notably, combination therapy with anti-PD-1 and anti-TIGIT antibodies alleviated HCC burden in humanized mice, demonstrating NK cell-dependent efficacy. Bulk-RNA sequencing analysis also revealed significant alterations in the tumor transcriptome that may contribute to further resistance after combination therapy, warranting further investigations. As an emerging strategy, ongoing clinical trials with anti-PD-1 and anti-TIGIT antibodies provide limited data. The improved humanized mouse HCC-PDX model not only sheds light on the pivotal role of NK cells but also serves as a robust platform for evaluating safety and anti-tumor efficacy of combination therapies and other potential regimens, complementing clinical insights.
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MESH Headings
- Animals
- Killer Cells, Natural/immunology
- Killer Cells, Natural/metabolism
- Humans
- Mice
- Programmed Cell Death 1 Receptor/antagonists & inhibitors
- Programmed Cell Death 1 Receptor/metabolism
- Receptors, Immunologic/metabolism
- Receptors, Immunologic/genetics
- CD56 Antigen/metabolism
- CD56 Antigen/genetics
- Carcinoma, Hepatocellular/therapy
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Liver Neoplasms/therapy
- Liver Neoplasms/immunology
- Liver Neoplasms/genetics
- CD8-Positive T-Lymphocytes/immunology
- CD8-Positive T-Lymphocytes/metabolism
- Interleukin-15/metabolism
- Interleukin-15/genetics
- Xenograft Model Antitumor Assays
- Single-Cell Analysis/methods
- Tumor Microenvironment/immunology
- Disease Models, Animal
- Cell Line, Tumor
- Sequence Analysis, RNA/methods
- Dependovirus/genetics
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Affiliation(s)
- Wai Nam Liu
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Republic of Singapore
| | - Sarah L Harden
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Republic of Singapore
| | - Shawn Lu Wen Tan
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Republic of Singapore
| | - Rachel Jun Rou Tan
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Republic of Singapore
| | - Shin Yie Fong
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Republic of Singapore
| | - Sue Yee Tan
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Republic of Singapore
| | - Min Liu
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Republic of Singapore
| | - Isha Karnik
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Republic of Singapore
| | - Timothy Wai Ho Shuen
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore 168583, Republic of Singapore
| | - Han Chong Toh
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore 168583, Republic of Singapore
| | - Yong Fan
- Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Seng Gee Lim
- Division of Gastroenterology and Hepatology, National University Hospital, Singapore 119228, Republic of Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Republic of Singapore
| | - Jerry Kok Yen Chan
- Department of Reproductive Medicine, KK Women's and Children's Hospital, Singapore 229899, Republic of Singapore; Experimental Fetal Medicine Group, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Republic of Singapore
| | - Qingfeng Chen
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Republic of Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Republic of Singapore; Singapore Immunology Network (SIgN), A∗STAR, 8A Biomedical Grove, Immunos, Singapore 138648, Republic of Singapore.
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18
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Ijaz M, Ullah Z, Aslam B, Khurshid M, Chen P, Guo B. From promise to progress: the dynamic landscape of glioblastoma immunotherapy. Drug Discov Today 2024; 29:104188. [PMID: 39307298 DOI: 10.1016/j.drudis.2024.104188] [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: 03/21/2024] [Revised: 09/09/2024] [Accepted: 09/17/2024] [Indexed: 09/29/2024]
Abstract
Glioblastoma multiforme (GBM) is the most common CNS cancer, it has dismal survival rates despite several effective mediators: intensified cytotoxic therapy, chimeric antigen receptor (CAR)-T cell therapy, viral therapy, adoptive cell therapy, immune checkpoint blockade therapy, radiation therapy and vaccine therapy. This review examines the basic concepts underlying immune targeting and examines products such as checkpoint blockade drugs, CAR-T cells, oncolytic viruses, combinatory multimodal immunotherapy and cancer vaccines. New approaches to overcoming current constraints and challenges in GBM therapy are discussed, based on recent studies into these tactics, findings from ongoing clinical trials, as well as previous trial results.
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Affiliation(s)
- Muhammad Ijaz
- School of Science, Shenzhen Key Laboratory of Flexible Printed Electronics Technology, Shenzhen Key Laboratory of Advanced Functional Carbon Materials Research and Comprehensive Application, Harbin Institute of Technology, Shenzhen 518055, China; Institute of Microbiology, Government College University Faisalabad, Pakistan
| | - Zia Ullah
- School of Science, Shenzhen Key Laboratory of Flexible Printed Electronics Technology, Shenzhen Key Laboratory of Advanced Functional Carbon Materials Research and Comprehensive Application, Harbin Institute of Technology, Shenzhen 518055, China
| | - Bilal Aslam
- Institute of Microbiology, Government College University Faisalabad, Pakistan
| | - Mohsin Khurshid
- Institute of Microbiology, Government College University Faisalabad, Pakistan
| | - Pengfei Chen
- Department of Traumatic Orthopedics, Shenzhen Longhua District Central Hospital, Shenzhen, China.
| | - Bing Guo
- School of Science, Shenzhen Key Laboratory of Flexible Printed Electronics Technology, Shenzhen Key Laboratory of Advanced Functional Carbon Materials Research and Comprehensive Application, Harbin Institute of Technology, Shenzhen 518055, China.
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Kuo LF, Liu WC, Li MF, Huang FH, Chou CK, Chen TH, Tsai YT, Hsu PI, Li CJ, Wu IT, Tsai KF. Prognostic Evaluation of Conversion Therapy following Hepatic Arterial Infusion Chemotherapy or Immunotherapy in Patients with Advanced or Transarterial Chemoembolization Unsuitable Intermediate-Stage Hepatocellular Carcinoma: A Retrospective Cohort Study. Oncology 2024:1-13. [PMID: 39467524 DOI: 10.1159/000542291] [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: 08/12/2024] [Accepted: 10/21/2024] [Indexed: 10/30/2024]
Abstract
INTRODUCTION Patients with advanced-stage or intermediate-stage hepatocellular carcinoma (HCC) unsuitable for transarterial chemoembolization (TACE) had poor prognoses. Recent advancements in hepatic arterial infusion chemotherapy (HAIC) and immune checkpoint inhibitors (ICIs) have demonstrated higher tumor response rates, which improved overall survival (OS). HAIC achieves an OS rate of approximately 14.5-15.3 months with a 39.1-42.5% tumor response rate. In comparison, ICIs have a 12-14 month OS rate with a 26-33% tumor response rate. Given these promising responses, this study evaluates the efficacy of conversion therapy with curative intent following HAIC or ICIs, focusing on survival outcomes. METHODS We retrospectively analyzed 80 patients with advanced or TACE-unsuitable intermediate HCC. Patients completed two HAIC or four ICI cycles, followed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria imaging. Based on demographics, cirrhosis status, Barcelona Clinic Liver Cancer classification (BCLC) stage, treatment responses, and treatment modality, survival impacts were analyzed. OS was compared between HAIC and immunotherapy groups. The effect of conversion therapy with curative intent on survival outcomes was analyzed using a Cox regression model. RESULTS Among the 80 patients, 26 achieved positive response (CR/PR) with HAIC or ICIs, and 9 of them subsequently underwent conversion therapy with curative intent. Key prognostic factors included Child-Pugh stage B versus A (HR = 2.21, p = 0.041), BCLC stage C versus B (HR = 4.38, p = 0.011), and elevated alpha-fetoprotein levels (HR = 5.02, p < 0.001). Positive responders saw substantial survival benefits (HR = 0.26, p = 0.001). Patients undergoing conversion therapy exhibited significantly enhanced survival. Median OS was 13.58 months with standard therapy, while the curative intent surgery group did not reach the median OS (p = 0.002). For CR/PR patients, 48-month survival was 75.0% for the curative surgery group versus 38.0% for standard treatment. CONCLUSION Conversion therapy with curative intent following HAIC or ICIs might enhance survival in patients with advanced or TACE-unsuitable intermediate-stage HCC.
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Affiliation(s)
- Li-Fu Kuo
- Gastroenterology and Hepatology Section, Department of Internal Medicine, An Nan Hospital, China Medical University, Tainan, Taiwan
| | - Wen-Chun Liu
- Department of Nursing, National Tainan Junior College of Nursing, Tainan, Taiwan
| | - Ming-Feng Li
- Department of Radiology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- Department of Medical Imaging and Radiology, Shu-Zen Junior College of Medicine and Management, Kaohsiung, Taiwan
| | - Fu-Huan Huang
- Division of Pediatric Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei, Taiwan
| | - Chu-Kuang Chou
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan
- Obesity Center, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan
- Department of Medical Quality, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan
| | - Tsung-Hsien Chen
- Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan
| | - Yi-Tseng Tsai
- Department of Nursing, An Nan Hospital, China Medical University, Tainan, Taiwan
| | - Ping-I Hsu
- Gastroenterology and Hepatology Section, Department of Internal Medicine, An Nan Hospital, China Medical University, Tainan, Taiwan
| | - Chao-Jen Li
- General and Gastroenterological Surgery Section, Department of Surgery, An Nan Hospital, China Medical University, Tainan, Taiwan
| | - I-Ting Wu
- Gastroenterology and Hepatology Section, Department of Internal Medicine, An Nan Hospital, China Medical University, Tainan, Taiwan
| | - Kun-Feng Tsai
- Gastroenterology and Hepatology Section, Department of Internal Medicine, An Nan Hospital, China Medical University, Tainan, Taiwan
- Department of Medical Sciences Industry, Chang Jung Christian University, Tainan, Taiwan
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20
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Cao WH, Zhang YQ, Li XX, Zhang ZY, Li MH. Advances in immunotherapy for hepatitis B virus associated hepatocellular carcinoma patients. World J Hepatol 2024; 16:1158-1168. [PMID: 39474576 PMCID: PMC11514615 DOI: 10.4254/wjh.v16.i10.1158] [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: 06/18/2024] [Revised: 08/28/2024] [Accepted: 09/19/2024] [Indexed: 10/21/2024] Open
Abstract
Hepatitis B virus (HBV) infection plays an important role in the occurrence and development of hepatocellular carcinoma (HCC), and the rate of HBV infection in liver cancer patients in China is as high as 92.05%. Due to long-term exposure to chronic antigens from the gut, the liver needs to maintain a certain level of immune tolerance, both to avoid severe inflammation caused by non-pathogenic antigens and to maintain the possibility of rapid and violent responses to infection and tumors. Therefore, HBV infection interacts with the tumor microenvironment (TME) through a highly complex and intertwined signaling pathway, which results in a special TME in HCC. Due to changes in the TME, tumor cells can evade immune surveillance by inhibiting tumor-specific T cell function through cytotoxic T-lymphocy-associated protein-4 (CTLA-4) and programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1). Interferons, as a class of immune factors with strong biological activity, can improve the TME of HBV-HCC through various pathways. In recent years, the systematic treatment of HCC has gradually come out of the dilemma. In addition to the continuous emergence of new multi-target anti-vascular tyrosine kinase inhibitor drugs, immune checkpoint inhibitors have opened up a new avenue for the systematic treatment of HCC. At present, immunotherapy based on PD-1/L1 inhibitors has gradually become a new direction of systematic treatment for HCC, and the disease characteristics of patients included in global clinical studies are different from those of Chinese patients. Therefore, whether a group of HCC patients with HBV background and poor prognosis in China can also benefit from immunotherapy is an issue of wide concern. This review aims to elucidate the advances of immunotherapy for HBV related HCC patients with regard to: (1) Immunotherapy based on interferons; (2) Immunotherapy based on PD-1/L1 inhibitors; (3) Immunotherapy based on CTLA4 inhibitors; (4) Adoptive cell transfer; (5) Combination immunotherapy strategy; and (6) Shortcomings of immunotherapy.
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Affiliation(s)
- Wei-Hua Cao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Ya-Qin Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Xin-Xin Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Zi-Yu Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Ming-Hui Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Peking University Ditan Teaching Hospital, Beijing 100015, China
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21
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Cao WH, Zhang YQ, Li XX, Zhang ZY, Li MH. Advances in immunotherapy for hepatitis B virus associated hepatocellular carcinoma patients. World J Hepatol 2024; 16:1338-1348. [DOI: 10.4254/wjh.v16.i10.1338] [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: 06/18/2024] [Revised: 08/28/2024] [Accepted: 09/19/2024] [Indexed: 11/22/2024] Open
Abstract
Hepatitis B virus (HBV) infection plays an important role in the occurrence and development of hepatocellular carcinoma (HCC), and the rate of HBV infection in liver cancer patients in China is as high as 92.05%. Due to long-term exposure to chronic antigens from the gut, the liver needs to maintain a certain level of immune tolerance, both to avoid severe inflammation caused by non-pathogenic antigens and to maintain the possibility of rapid and violent responses to infection and tumors. Therefore, HBV infection interacts with the tumor microenvironment (TME) through a highly complex and intertwined signaling pathway, which results in a special TME in HCC. Due to changes in the TME, tumor cells can evade immune surveillance by inhibiting tumor-specific T cell function through cytotoxic T-lymphocy-associated protein-4 (CTLA-4) and programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1). Interferons, as a class of immune factors with strong biological activity, can improve the TME of HBV-HCC through various pathways. In recent years, the systematic treatment of HCC has gradually come out of the dilemma. In addition to the continuous emergence of new multi-target anti-vascular tyrosine kinase inhibitor drugs, immune checkpoint inhibitors have opened up a new avenue for the systematic treatment of HCC. At present, immunotherapy based on PD-1/L1 inhibitors has gradually become a new direction of systematic treatment for HCC, and the disease characteristics of patients included in global clinical studies are different from those of Chinese patients. Therefore, whether a group of HCC patients with HBV background and poor prognosis in China can also benefit from immunotherapy is an issue of wide concern. This review aims to elucidate the advances of immunotherapy for HBV related HCC patients with regard to: (1) Immunotherapy based on interferons; (2) Immunotherapy based on PD-1/L1 inhibitors; (3) Immunotherapy based on CTLA4 inhibitors; (4) Adoptive cell transfer; (5) Combination immunotherapy strategy; and (6) Shortcomings of immunotherapy.
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Affiliation(s)
- Wei-Hua Cao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Ya-Qin Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Xin-Xin Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Zi-Yu Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Ming-Hui Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Peking University Ditan Teaching Hospital, Beijing 100015, China
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Gong Q, Zhang L, Guo J, Zhao W, Zhou B, Yang C, Jiang N. FBXO family genes promotes hepatocellular carcinoma via ubiquitination of p53. J Cancer Res Clin Oncol 2024; 150:458. [PMID: 39397119 PMCID: PMC11471714 DOI: 10.1007/s00432-024-05948-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Accepted: 09/10/2024] [Indexed: 10/15/2024]
Abstract
FBXO protein family plays an essential role in the ubiquitination process acting as E3 ligases, which may contribute to the progression of cancers. However, the molecular functions of FBXOs in hepatocellular carcinoma (HCC) remain incompletely understood. Here, we investigated the overlapping genes between the FBXOs and differentially expressed genes (DEGs) of HCC identified by utilizing The Cancer Genome Atlas (TCGA) dataset, then, a prognostic model with effective predictive capacity was constructed based on the uni-cox and LASSO regression analyses. To elucidate the underlying mechanism of the FBXO model genes, KEGG analysis was carried out. Drug metabolism-cytochrome P450 and retinol metabolism were revealed as the potential pathway, which Increased the credibility of subsequent drug prediction research. Meanwhile, patients divided by the prognostic model showed a different immune infiltrating status and we also found FBXO model genes may ubiquitinate P53, inducing TP53 more prone to mutations, thereby promoting the occurrence and development of tumors. Consistent with these findings, the result of immunohistochemistry (IHC) validated an elevated expression of these model genes in HCC tissues than in the adjacent tissues. The primary aim of this investigation is to formulate a prognostic model while exploring the underlying mechanisms associated with FBXO genes in HCC. These findings offer initial research perspectives on the involvement of FBXO genes in HCC and contribute to the discovery of dependable biomarkers for the management, prognostication, and early detection of HCC in patients.
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Affiliation(s)
- Qingge Gong
- Chongqing Medical University, Chongqing, China
| | - La Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jiao Guo
- School of Basic Medical Science, Chongqing Medical University, Chongqing, China
| | - Wei Zhao
- School of Basic Medical Science, Chongqing Medical University, Chongqing, China
| | - Baoyong Zhou
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Changhong Yang
- Department of Bioinformatics, Chongqing Medical University, Chongqing, People's Republic of China.
| | - Ning Jiang
- Department of Pathology, Chongqing Medical University, Chongqing, China.
- Molecular Medicine Diagnostic and Testing Center, Chongqing Medical University, Chongqing, China.
- Department of Pathology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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23
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Xin Y, Peng G, Song W, Zhou X, Huang X, Cao X. Gut microbiota as a prognostic biomarker for unresectable hepatocellular carcinoma treated with anti-PD-1 therapy. Front Genet 2024; 15:1366131. [PMID: 39421302 PMCID: PMC11484251 DOI: 10.3389/fgene.2024.1366131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 09/18/2024] [Indexed: 10/19/2024] Open
Abstract
Objective To investigate the relationship between the gut microbiome and the response to anti-PD-1-based combination therapy in unresectable hepatocellular carcinoma (HCC). We aimed to identify potential non-invasive biomarkers and new strategies to modulate immunotherapy in HCC. Methods In this study, fresh stool samples and clinical data were collected from unresectable HCC patients treated with anti-PD-1-based combination therapy at the Cancer Hospital of the Chinese Academy of Medical Sciences between January 2020 and December 2021. The patients were divided into two groups based on their response to treatment: the treatment responder group (R group) and the treatment non-responder group (NR group). The composition and diversity of the gut microbiome were bioinformatically analyzed by using the Whole Genome Shotgun strategy, including taxonomic composition analysis, Alpha diversity analysis, Beta diversity analysis, and differentially enriched bacterial taxa analysis. Differentially enriched bacterial taxa between R and NR groups were identified based on the magnitude of the linear discriminant analysis effect size (LEfSe) and analyzed for their impact on the survival of the patient. Results A total of 45 eligible patients with unresectable HCC treated with anti-PD-1-based combination therapy participated in this study. The gut microbiological composition and Alpha diversity of patients were not statistically different, but there was a statistically significant difference in Beta diversity between the R and NR groups. (PERMANOVA tests, P = 0.006). We further identified 56 enriched bacterial taxa in the R group and 44 enriched bacterial taxa in the NR group based on the LEfSe analysis (LDA >2.66, P< 0.05). Patients with a high abundance of Collinsella genus, Ruminococcus_AM4211, and Ruminococcus_AF25_28AC had a longer median PFS and median OS compared to those with low abundance (P < 0.05). On the contrary, the median PFS and OS of patients with a high abundance of Bacteroides_AF20_13LB and Veillonella_atypica were significantly shorter than those of patients with low abundance (P < 0.05). The multivariate analysis showed that the abundance of Bacteroides_AF20_13LB and Ruminococcus_ AF25_28AC was independent related factors for PFS, and the abundance of Bacteroides_AF20_13LB was an independent related factor of OS. Conclusion The enrichment of specific gut microbiota affected clinical efficacy and survival benefits in HCC treated with anti-PD-1 therapy and may be a promising non-invasive gut microbial biomarker and a new strategy for modulating immunotherapy in HCC.
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Affiliation(s)
- Yujing Xin
- Department of Minimally Invasive Comprehensive Treatment of Cancer, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Gang Peng
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wei Song
- Department of Minimally Invasive Comprehensive Treatment of Cancer, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Xiang Zhou
- Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaoyu Huang
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaojing Cao
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Yim SY, Lee SH, Baek SW, Sohn B, Jeong YS, Kang SH, Park K, Park H, Lee SS, Kaseb AO, Park YN, Leem SH, Curran MA, Kim JH, Lee JS. Genomic biomarkers to predict response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: Insights from the IMbrave150 trial. Clin Mol Hepatol 2024; 30:807-823. [PMID: 39038962 PMCID: PMC11540371 DOI: 10.3350/cmh.2024.0333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Revised: 07/14/2024] [Accepted: 07/21/2024] [Indexed: 07/24/2024] Open
Abstract
BACKGROUND/AIMS Combination immunotherapy, exemplified by atezolizumab plus bevacizumab, has become the standard of care for inoperable hepatocellular carcinoma (HCC). However, the lack of predictive biomarkers and limited understanding of response mechanisms remain a challenge. METHODS Using data from the IMbrave150plus cohort, we applied an immune signature score (ISS) predictor to stratify HCC patients treated with atezolizumab plus bevacizumab or with sorafenib alone into potential high and low response groups. By applying multiple statistical approaches including a Bayesian covariate prediction algorithm, we refined the signature to 10 key genes (ISS10) for clinical use while maintaining similar predictive power to the full model. We further validated ISS10 in an independent HCC cohort treated with nivolumab plus ipilimumab. RESULTS The study identified a significant association between the ISS and treatment response. Among patients classified as high responders, those treated with the atezolizumab plus bevacizumab combination exhibited improved overall and progression-free survival as well as better objective response rate compared to those treated with sorafenib. We also observed a significant correlation between ISS10 and response to nivolumab plus ipilimumab treatment. Analysis of immune cell subpopulations revealed distinct characteristics associated with ISS subtypes. In particular, the ISS10 high subtype displayed a more favorable immune environment with higher proportions of antitumor macrophages and activated T-cells, potentially explaining its better response. CONCLUSION Our study suggests that ISS and ISS10 are promising predictive biomarkers for enhanced therapeutic outcomes in HCC patients undergoing combination immunotherapy. These markers are crucial for refining patient stratification and personalized treatment approaches to advance the effectiveness of standard-of-care regimens.
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Affiliation(s)
- Sun Young Yim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Sung Hwan Lee
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Seung-Woo Baek
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
| | - Bohwa Sohn
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yun Seong Jeong
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sang-Hee Kang
- Department of Surgery, Korea University Guro Hospital, Seoul, Korea
| | - Kena Park
- Department of Obstetrics and Gynecology, Kyung Hee University Hospital at Gangdong, Seoul, Korea
- Department of Medicine, Graduate School, Kyung Hee University, Seoul, Korea
| | - Hyewon Park
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sunyoung S. Lee
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ahmed O. Kaseb
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Young Nyun Park
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
| | - Sun-Hee Leem
- Department of Biomedical Sciences, Dong-A University, Busan, Korea
- Department of Health Sciences, The Graduate School of Dong-A University, Busan, Korea
| | - Michael A. Curran
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ji Hoon Kim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Ju-Seog Lee
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Zhou MT, Zhang P, Mao Q, Wei XQ, Yang L, Zhang XM. Current research status of transarterial therapies for hepatocellular carcinoma. World J Gastrointest Oncol 2024; 16:3752-3760. [PMID: 39350995 PMCID: PMC11438772 DOI: 10.4251/wjgo.v16.i9.3752] [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: 03/11/2024] [Revised: 05/22/2024] [Accepted: 05/30/2024] [Indexed: 09/09/2024] Open
Abstract
With continuous advancements in interventional radiology, considerable progress has been made in transarterial therapies for hepatocellular carcinoma (HCC) in recent years, and an increasing number of research papers on transarterial therapies for HCC have been published. In this editorial, we comment on the article by Ma et al published in the recent issue of the World Journal of Gastro intestinal Oncology: "Efficacy and predictive factors of transarterial chemoembolization combined with lenvatinib plus programmed cell death protein-1 inhibition for unresectable HCC". We focus specifically on the current research status and future directions of transarterial therapies. In the future, more studies are needed to determine the optimal transarterial local treatment for HCC. With the emergence of checkpoint immunotherapy modalities, it is expected that the results of trials of transarterial local therapy combined with systemic therapy will bring new hope to HCC patients.
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Affiliation(s)
- Mao-Ting Zhou
- Department of Radiology, Interventional Medical Center, Science and Technology Innovation Center, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Peng Zhang
- Department of Radiology, Interventional Medical Center, Science and Technology Innovation Center, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Qi Mao
- Department of Radiology, Interventional Medical Center, Science and Technology Innovation Center, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Xiao-Qin Wei
- School of Medical Imaging, North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Lin Yang
- Department of Radiology, Interventional Medical Center, Science and Technology Innovation Center, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Xiao-Ming Zhang
- Department of Radiology, Interventional Medical Center, Science and Technology Innovation Center, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
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Abstract
ABSTRACT Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. Its high recurrence rate and lack of effective control drugs result in a 5-year survival rate of only about 10%. HCC is a tumor regulated by the immune system. Significant breakthroughs have occurred in treating solid tumors with immunotherapy in recent years. Various immunotherapies, such as immune checkpoint inhibitors (ICIs), including combination therapies, have demonstrated promising therapeutic effects in both clinical applications and research. Other immunotherapies, such as adoptive cell therapies and oncolytic viruses, are also emerging, offering hope for addressing long-term survival issues in HCC. This article reviews current commonly used immunotherapy strategies and the latest research findings for reference.
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Affiliation(s)
- Xiaoxia Wang
- Department of Medical Oncology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
- Laboratory for Clinical Medicine, Capital Medical University
| | - Jun Lu
- Department of Medical Oncology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
- Laboratory for Clinical Medicine, Capital Medical University
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Sun LL, Zhao LN, Sun J, Yuan HF, Wang YF, Hou CY, Lv P, Zhang HH, Yang G, Zhang NN, Zhang XD, Lu W. Inhibition of USP7 enhances CD8 + T cell activity in liver cancer by suppressing PRDM1-mediated FGL1 upregulation. Acta Pharmacol Sin 2024; 45:1686-1700. [PMID: 38589688 PMCID: PMC11272784 DOI: 10.1038/s41401-024-01263-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 03/07/2024] [Indexed: 04/10/2024]
Abstract
Lymphocyte activation gene 3 (LAG3), an immune checkpoint molecule expressed on activated T cells, functions as a negative regulator of immune responses. Persistent antigen exposure in the tumor microenvironment results in sustained LAG3 expression on T cells, contributing to T cell dysfunction. Fibrinogen-like protein 1 (FGL1) has been identified as a major ligand of LAG3, and FGL1/LAG3 interaction forms a novel immune checkpoint pathway that results in tumor immune evasion. In addition, ubiquitin-specific peptidase 7 (USP7) plays a crucial role in cancer development. In this study we investigated the role of USP7 in modulation of FGL1-mediated liver cancer immune evasion. We showed that knockdown of USP7 or treatment with USP7 inhibitor P5091 suppressed liver cancer growth by promoting CD8+ T cell activity in Hepa1-6 xenograft mice and in HepG2 or Huh7 cells co-cultured with T cells, whereas USP7 overexpression produced the opposite effect. We found that USP7 upregulated FGL1 in HepG2 and Huh7 cells by deubiquitination of transcriptional factor PR domain zinc finger protein 1 (PRDM1), which transcriptionally activated FGL1, and attenuated the CD8+ T cell activity, leading to the liver cancer growth. Interestingly, USP7 could be transcriptionally stimulated by PRDM1 as well in a positive feedback loop. P5091, an inhibitor of USP7, was able to downregulate FGL1 expression, thus enhancing CD8+ T cell activity. In an immunocompetent liver cancer mouse model, the dual blockade of USP7 and LAG3 resulted in a superior antitumor activity compared with anti-LAG3 therapy alone. We conclude that USP7 diminishes CD8+ T cell activity by a USP7/PRDM1 positive feedback loop on FGL1 production in liver cancer; USP7 might be a promising target for liver cancer immunotherapy.
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Affiliation(s)
- Lin-Lin Sun
- Department of Hepatobiliary Oncology, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University, Tianjin, 300060, China
| | - Li-Na Zhao
- National Key Laboratory of Drug ability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer / Department of Gastrointestinal Cancer Biology, Tianjin Cancer Institute, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Jiao Sun
- Department of Hepatobiliary Oncology, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University, Tianjin, 300060, China
| | - Hong-Feng Yuan
- National Key Laboratory of Drug ability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer / Department of Gastrointestinal Cancer Biology, Tianjin Cancer Institute, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Yu-Fei Wang
- National Key Laboratory of Drug ability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer / Department of Gastrointestinal Cancer Biology, Tianjin Cancer Institute, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Chun-Yu Hou
- National Key Laboratory of Drug ability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer / Department of Gastrointestinal Cancer Biology, Tianjin Cancer Institute, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Pan Lv
- National Key Laboratory of Drug ability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer / Department of Gastrointestinal Cancer Biology, Tianjin Cancer Institute, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Hui-Hui Zhang
- National Key Laboratory of Drug ability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer / Department of Gastrointestinal Cancer Biology, Tianjin Cancer Institute, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Guang Yang
- National Key Laboratory of Drug ability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer / Department of Gastrointestinal Cancer Biology, Tianjin Cancer Institute, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China.
| | - Ning-Ning Zhang
- Department of Hepatobiliary Oncology, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University, Tianjin, 300060, China.
| | - Xiao-Dong Zhang
- National Key Laboratory of Drug ability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer / Department of Gastrointestinal Cancer Biology, Tianjin Cancer Institute, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China.
| | - Wei Lu
- Department of Hepatobiliary Oncology, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University, Tianjin, 300060, China.
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Liu X, Lu Y, Zhou W, Peng T, Zhou J, Bi H, Xia F, Chen X. Chinese Multidisciplinary Expert Consensus on Immune Checkpoint Inhibitor-Based Combination Therapy for Hepatocellular Carcinoma (2023 Edition). Liver Cancer 2024; 13:355-375. [PMID: 39114757 PMCID: PMC11305662 DOI: 10.1159/000535496] [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: 06/25/2023] [Accepted: 11/10/2023] [Indexed: 08/10/2024] Open
Abstract
Background Immune checkpoint inhibitor (ICI)-based combination therapy modalities for hepatocellular carcinoma (HCC) have achieved significant efficacy in clinical research and practice and have become the mainstay for the treatment of unresectable HCC. Summary To better help clinicians use combination immunotherapy drugs and regimens rationally, effectively, and safely, the editorial board facilitated a discussion with multidisciplinary experts in the field, adopted the "Delphi" consensus formation method, and finally revised and completed the "Chinese Multidisciplinary Expert Consensus on the Immune Checkpoint Inhibitors (ICIs)-Based Combination Therapy for Hepatocellular Carcinoma (2023 Edition)" on the basis of the 2021 edition. Key Messages This consensus primarily focuses on the principles and methods of clinical practice of combination therapy based on ICIs, aiming to summarize the recommendations for clinical application based on the latest research and expert experience and provide application guidance for clinicians.
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Affiliation(s)
- Xiufeng Liu
- Department of Medical Oncology of PLA Cancer Center, Jinling Hospital, Nanjing, China
| | - Yinying Lu
- Comprehensive Liver Cancer Center, 5th Medical Center of PLA General Hospital, Beijing, China
| | - Weiping Zhou
- Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Tao Peng
- Hepatobiliary Surgery Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jie Zhou
- Division of Hepatobiliopancreatic Surgery and Liver Transplantation, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Huaqiang Bi
- Department of Hepatobiliary Surgery, The First Hospital Affiliated to Army Medical University, Chongqing, China
| | - Feng Xia
- Department of Hepatobiliary Surgery, The First Hospital Affiliated to Army Medical University, Chongqing, China
| | - Xiaoping Chen
- Department of Hepatobiliary Surgery, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
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Tong LW, Hu YS, Yu SJ, Li CL, Shao JW. Current application and future perspective of CRISPR/cas9 gene editing system mediated immune checkpoint for liver cancer treatment. NANOTECHNOLOGY 2024; 35:402002. [PMID: 38964289 DOI: 10.1088/1361-6528/ad5f33] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 07/04/2024] [Indexed: 07/06/2024]
Abstract
Liver cancer, which is well-known to us as one of human most prevalent malignancies across the globe, poses a significant risk to live condition and life safety of individuals in every region of the planet. It has been shown that immune checkpoint treatment may enhance survival benefits and make a significant contribution to patient prognosis, which makes it a promising and popular therapeutic option for treating liver cancer at the current time. However, there are only a very few numbers of patients who can benefit from the treatment and there also exist adverse events such as toxic effects and so on, which is still required further research and discussion. Fortunately, the clustered regularly interspaced short palindromic repeat/CRISPR-associated nuclease 9 (CRISPR/Cas9) provides a potential strategy for immunotherapy and immune checkpoint therapy of liver cancer. In this review, we focus on elucidating the fundamentals of the recently developed CRISPR/Cas9 technology as well as the present-day landscape of immune checkpoint treatment which pertains to liver cancer. What's more, we aim to explore the molecular mechanism of immune checkpoint treatment in liver cancer based on CRISPR/Cas9 technology. At last, its encouraging and powerful potential in the future application of the clinic is discussed, along with the issues that already exist and the difficulties that must be overcome. To sum up, our ultimate goal is to create a fresh knowledge that we can utilize this new CRISPR/Cas9 technology for the current popular immune checkpoint therapy to overcome the treatment issues of liver cancer.
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Affiliation(s)
- Ling-Wu Tong
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, College of Chemistry, Fuzhou University, Fuzhou 350108, People's Republic of China
| | - Yong-Shan Hu
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, College of Chemistry, Fuzhou University, Fuzhou 350108, People's Republic of China
| | - Shi-Jing Yu
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, College of Chemistry, Fuzhou University, Fuzhou 350108, People's Republic of China
| | - Cheng-Lei Li
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, College of Chemistry, Fuzhou University, Fuzhou 350108, People's Republic of China
| | - Jing-Wei Shao
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, College of Chemistry, Fuzhou University, Fuzhou 350108, People's Republic of China
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Fu J, Mao L, Jiao Y, Mei D, Chen Y. Elucidating CTLA-4's role in tumor immunity: a comprehensive overview of targeted antibody therapies and clinical developments. Mol Divers 2024:10.1007/s11030-024-10917-6. [PMID: 38985379 DOI: 10.1007/s11030-024-10917-6] [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: 04/17/2024] [Accepted: 06/11/2024] [Indexed: 07/11/2024]
Abstract
Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) emerges as a key single-chain transmembrane glycoprotein predominantly expressed in effector T cells and regulatory T cells. It plays a crucial role in tumor immunity by modulating T cell responses. Specifically, CTLA-4 dampens T cell activation and proliferation while bolstering the survival of regulatory T cell through its competitive interaction with B7 family molecules, thereby aiding tumor cells in eluding immune detection. Given CTLA-4's significant influence on tumor immune dynamics, an array of anti-CTLA-4 antibody therapeutics have been clinically developed to combat various malignancies, including melanoma, renal cell carcinoma, colorectal carcinoma, hepatocellular carcinoma, non-small cell lung carcinoma, and pleural mesothelioma, demonstrating notable clinical therapeutic effects. This paper aims to delve into CTLA-4's integral role in tumor immunity and to encapsulate the latest advancements in the clinical research of anti-CTLA-4 antibody.
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Affiliation(s)
- Juan Fu
- Suzhou Guo Kuang Pharmaceutical Technology Co, Sichuan, China
- College of Science, China Pharmaceutical University, Nanjing, China
| | - Lin Mao
- College of Science, China Pharmaceutical University, Nanjing, China
| | - Yu Jiao
- College of Science, China Pharmaceutical University, Nanjing, China
| | - Desheng Mei
- Suzhou Guo Kuang Pharmaceutical Technology Co, Sichuan, China.
| | - Yadong Chen
- College of Science, China Pharmaceutical University, Nanjing, China.
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Mardi A, Alizadeh M, Abdolalizadeh AS, Baghbanzadeh A, Baradaran B, Aghebaqti-Maleki A, Sandoghchian Shotorbani S, Movloudi M, Aghebati-Maleki L. CTLA-4 silencing could promote anti-tumor effects in hepatocellular. Med Oncol 2024; 41:193. [PMID: 38955918 DOI: 10.1007/s12032-024-02361-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Accepted: 03/19/2024] [Indexed: 07/04/2024]
Abstract
Preclinical and clinical research showed that immune checkpoint blockade provides beneficial effects for many patients with liver cancer. This study aimed to assess the effect of CTLA-4-specific siRNA on the proliferation, cell cycle, migration, and apoptosis of HePG2 cells. Transfection of siRNA was performed by electroporation. The viability of cells was determined through MTT assay. Flow cytometry was performed to investigate the cell cycle and apoptosis rate, and the wound-healing assay was used to determine HepG2 cells migration. The expression levels of CTLA-4, c-Myc, Ki-67, BCL-2, BAX, caspase-9 (CAS9), and MMP-2,9,13 were measured by qRT-PCR. Transfection of specific CTLA-4-siRNA significantly inhibited the expression of the CTLA-4 gene. Also, our results revealed that CTLA-4 silencing diminished the proliferation and migration as well as induced the apoptosis of HePG2 cells. CTLA-4-siRNA transfection induced the cell cycle arrest in G2 phase. Moreover, CTLA-4-siRNA transfection reduced the expression levels of c-Myc, Ki-67, BCL-2, MMP-2,9,13, and elevated the expression levels of BAX and caspase-9. Our results suggest that silencing CTLA-4 through specific siRNA may be a promising strategy for future therapeutic interventions for treating liver cancer.
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Affiliation(s)
- Amirhossein Mardi
- Student Research Committee, Tabriz University of Medical Science, Tabriz, Iran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran
| | - Mahsan Alizadeh
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Tabriz Medical Sciences, Islamic Azad University, Tabriz, Iran
| | - Amir Shahabaddin Abdolalizadeh
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Tabriz Medical Sciences, Islamic Azad University, Tabriz, Iran
| | - Amir Baghbanzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Aghebaqti-Maleki
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Mohammad Movloudi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Pourbagheri-Sigaroodi A, Momeny M, Rezaei N, Fallah F, Bashash D. Immune landscape of hepatocellular carcinoma: From dysregulation of the immune responses to the potential immunotherapies. Cell Biochem Funct 2024; 42:e4098. [PMID: 39034646 DOI: 10.1002/cbf.4098] [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: 05/25/2024] [Revised: 07/03/2024] [Accepted: 07/10/2024] [Indexed: 07/23/2024]
Abstract
Hepatocellular carcinoma (HCC) presents a considerable global health burden due to its late diagnosis and high morbidity. The liver's specific anatomical and physiological features expose it to various antigens, requiring precise immune regulation. To the best of our knowledge, this is the first time that a comprehensive overview of the interactions between the immune system and gut microbiota in the development of HCC, as well as the relevant therapeutic approaches are discussed. Dysregulation of immune compartments within the liver microenvironment drives HCC pathogenesis, characterized by elevated regulatory cells such as regulatory T cells (Tregs), myeloid-derived suppressor cells, and M2 macrophages as well as suppressive molecules, alongside reduced number of effector cells like T cells, natural killer cells, and M1 macrophages. Dysbiosis of gut microbiota also contributes to HCC by disrupting intestinal barrier integrity and triggering overactivated immune responses. Immunotherapy approaches, particularly immune checkpoint inhibitors, have exhibited promise in HCC management, yet adoptive cell therapy and cancer vaccination research are in the early steps with relatively less favorable outcomes. Further understanding of immune dysregulation, gut microbiota involvement, and therapeutic combination strategies are essential for advancing precision immunotherapy in HCC.
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Affiliation(s)
- Atieh Pourbagheri-Sigaroodi
- Pediatric Infections Research Center, Research Institute for Children's Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Majid Momeny
- Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Fallah
- Pediatric Infections Research Center, Research Institute for Children's Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Yue B, Gao Y, Hu Y, Zhan M, Wu Y, Lu L. Harnessing CD8 + T cell dynamics in hepatitis B virus-associated liver diseases: Insights, therapies and future directions. Clin Transl Med 2024; 14:e1731. [PMID: 38935536 PMCID: PMC11210506 DOI: 10.1002/ctm2.1731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 05/16/2024] [Accepted: 05/21/2024] [Indexed: 06/29/2024] Open
Abstract
Hepatitis B virus (HBV) infection playsa significant role in the etiology and progression of liver-relatedpathologies, encompassing chronic hepatitis, fibrosis, cirrhosis, and eventual hepatocellularcarcinoma (HCC). Notably, HBV infection stands as the primary etiologicalfactor driving the development of HCC. Given the significant contribution ofHBV infection to liver diseases, a comprehensive understanding of immunedynamics in the liver microenvironment, spanning chronic HBV infection,fibrosis, cirrhosis, and HCC, is essential. In this review, we focused on thefunctional alterations of CD8+ T cells within the pathogenic livermicroenvironment from HBV infection to HCC. We thoroughly reviewed the roles ofhypoxia, acidic pH, metabolic reprogramming, amino acid deficiency, inhibitory checkpointmolecules, immunosuppressive cytokines, and the gut-liver communication in shapingthe dysfunction of CD8+ T cells in the liver microenvironment. Thesefactors significantly impact the clinical prognosis. Furthermore, we comprehensivelyreviewed CD8+ T cell-based therapy strategies for liver diseases,encompassing HBV infection, fibrosis, cirrhosis, and HCC. Strategies includeimmune checkpoint blockades, metabolic T-cell targeting therapy, therapeuticT-cell vaccination, and adoptive transfer of genetically engineered CD8+ T cells, along with the combined usage of programmed cell death protein-1/programmeddeath ligand-1 (PD-1/PD-L1) inhibitors with mitochondria-targeted antioxidants.Given that targeting CD8+ T cells at various stages of hepatitis Bvirus-induced hepatocellular carcinoma (HBV + HCC) shows promise, we reviewedthe ongoing need for research to elucidate the complex interplay between CD8+ T cells and the liver microenvironment in the progression of HBV infection toHCC. We also discussed personalized treatment regimens, combining therapeuticstrategies and harnessing gut microbiota modulation, which holds potential forenhanced clinical benefits. In conclusion, this review delves into the immunedynamics of CD8+ T cells, microenvironment changes, and therapeuticstrategies within the liver during chronic HBV infection, HCC progression, andrelated liver diseases.
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Affiliation(s)
- Bing Yue
- Guangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and TreatmentZhuhai Institute of Translational MedicineZhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Jinan UniversityZhuhaiGuangdongChina
| | - Yuxia Gao
- Guangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and TreatmentZhuhai Institute of Translational MedicineZhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Jinan UniversityZhuhaiGuangdongChina
| | - Yi Hu
- Microbiology and Immunology DepartmentSchool of MedicineFaculty of Medical ScienceJinan UniversityGuangzhouGuangdongChina
| | - Meixiao Zhan
- Guangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and TreatmentZhuhai Institute of Translational MedicineZhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Jinan UniversityZhuhaiGuangdongChina
| | - Yangzhe Wu
- Guangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and TreatmentZhuhai Institute of Translational MedicineZhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Jinan UniversityZhuhaiGuangdongChina
| | - Ligong Lu
- Guangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and TreatmentZhuhai Institute of Translational MedicineZhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Jinan UniversityZhuhaiGuangdongChina
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Zarlashat Y, Mushtaq H, Pham L, Abbas W, Sato K. Advancements in Immunotherapeutic Treatments for Hepatocellular Carcinoma: Potential of Combination Therapies. Int J Mol Sci 2024; 25:6830. [PMID: 38999940 PMCID: PMC11241106 DOI: 10.3390/ijms25136830] [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: 05/25/2024] [Revised: 06/16/2024] [Accepted: 06/17/2024] [Indexed: 07/14/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and a significant global health burden, with increasing incidence rates and limited treatment options. Immunotherapy has become a promising approach due to its ability to affect the immune microenvironment and promote antitumor responses. The immune microenvironment performs an essential role in both the progression and the development of HCC, with different characteristics based on specific immune cells and etiological factors. Immune checkpoint inhibitors, including programmed death-1/programmed death-ligand 1 inhibitors (pembrolizumab, nivolumab, and durvalumab) and cytotoxic T lymphocyte antigen-4 inhibitors (tremelimumab and ipilimumab), have the potential to treat advanced HCC and overcome adverse effects, such as liver failure and chemoresistance. Phase II and phase III clinical trials highlight the efficacy of pembrolizumab and nivolumab, respectively, in advanced HCC patients, as demonstrated by their positive effects on overall survival and progression-free survival. Tremelimumab has exhibited modest response rates, though it does possess antiviral activity. Thus, it is still being investigated in ongoing clinical trials. Combination therapies with multiple drugs have demonstrated potential benefits in terms of survival and tumor response rates, improving patient outcomes compared to monotherapy, especially for advanced-stage HCC. This review addresses the clinical trials of immunotherapies for early-, intermediate-, and advanced-stage HCC. Additionally, it highlights how combination therapy can significantly enhance overall survival, progression-free survival, and objective response rate in advanced-stage HCC, where treatment options are limited.
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Affiliation(s)
- Yusra Zarlashat
- Department of Biochemistry, Government College University Faisalabad, Faisalabad 38000, Pakistan
| | - Hassan Mushtaq
- Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering-C (NIBGE), Faisalabad 38000, Pakistan
- Pakistan Institute of Engineering and Applied Sciences (PIEAS), Islamabad 45650, Pakistan
| | - Linh Pham
- Department of Science and Mathematics, Texas A&M University-Central Texas, Killeen, TX 76549, USA
| | - Wasim Abbas
- Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering-C (NIBGE), Faisalabad 38000, Pakistan
- Pakistan Institute of Engineering and Applied Sciences (PIEAS), Islamabad 45650, Pakistan
| | - Keisaku Sato
- Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Chen G, Zhang G, Zhu Y, Wu A, Fang J, Yin Z, Chen H, Cao K. Identifying disulfidptosis subtypes in hepatocellular carcinoma through machine learning and preliminary exploration of its connection with immunotherapy. Cancer Cell Int 2024; 24:194. [PMID: 38831301 PMCID: PMC11149214 DOI: 10.1186/s12935-024-03387-1] [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: 12/26/2023] [Accepted: 05/25/2024] [Indexed: 06/05/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a highly prevalent and deadly cancer, with limited treatment options for advanced-stage patients. Disulfidptosis is a recently identified mechanism of programmed cell death that occurs in SLC7A11 high-expressing cells due to glucose starvation-induced disintegration of the cellular disulfide skeleton. We aimed to explore the potential of disulfidptosis, as a prognostic and therapeutic marker in HCC. METHODS We classified HCC patients into two disulfidptosis subtypes (C1 and C2) based on the transcriptional profiles of 31 disulfrgs using a non-negative matrix factorization (NMF) algorithm. Further, five genes (NEIL3, MMP1, STC2, ADH4 and CFHR3) were screened by Cox regression analysis and machine learning algorithm to construct a disulfidptosis scoring system (disulfS). Cell proliferation assay, F-actin staining and PBMC co-culture model were used to validate that disulfidptosis occurs in HCC and correlates with immunotherapy response. RESULTS Our results suggests that the low disulfidptosis subtype (C2) demonstrated better overall survival (OS) and progression-free survival (PFS) prognosis, along with lower levels of immunosuppressive cell infiltration and activation of the glycine/serine/threonine metabolic pathway. Additionally, the low disulfidptosis group showed better responses to immunotherapy and potential antagonism with sorafenib treatment. As a total survival risk factor, disulfS demonstrated high predictive efficacy in multiple validation cohorts. We demonstrated the presence of disulfidptosis in HCC cells and its possible relevance to immunotherapeutic sensitization. CONCLUSION The present study indicates that novel biomarkers related to disulfidptosis may serve as useful clinical diagnostic indicators for liver cancer, enabling the prediction of prognosis and identification of potential treatment targets.
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Affiliation(s)
- Guanjun Chen
- Department of Oncology, Third Xiangya Hospital of Central South University, Changsha, 410013, China
| | - Ganghua Zhang
- Department of Oncology, Third Xiangya Hospital of Central South University, Changsha, 410013, China
| | - Yuxing Zhu
- Department of Oncology, Third Xiangya Hospital of Central South University, Changsha, 410013, China
| | - Anshan Wu
- Department of Oncology,, Zhuzhou Hospital Xiangya School of Medicine, Zhuzhou, 412000, China
| | - Jianing Fang
- Department of Oncology, Third Xiangya Hospital of Central South University, Changsha, 410013, China
| | - Zhijing Yin
- Department of Oncology, Third Xiangya Hospital of Central South University, Changsha, 410013, China
| | - Haotian Chen
- Department of Oncology, Third Xiangya Hospital of Central South University, Changsha, 410013, China
| | - Ke Cao
- Department of Oncology, Third Xiangya Hospital of Central South University, Changsha, 410013, China.
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Liu H, Fu L, Jin S, Ye X, Chen Y, Pu S, Xue Y. Cardiovascular toxicity with CTLA-4 inhibitors in cancer patients: A meta-analysis. CANCER INNOVATION 2024; 3:e116. [PMID: 38947758 PMCID: PMC11212283 DOI: 10.1002/cai2.116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 12/04/2023] [Accepted: 12/25/2023] [Indexed: 07/02/2024]
Abstract
Background With the emergence of cytotoxic T lymphocyte-associated protein-4 (CTLA-4) inhibitors, the outcomes of patients with malignant tumors have improved significantly. However, the incidence of cardiovascular adverse events has also increased, which can affect tumor treatment. In this study, we evaluated the incidence and severity of adverse cardiovascular events caused by CTLA-4 inhibitors by analyzing reported trials that involved CTLA-4 inhibitor therapy. Methods Randomized clinical trials published in English from January 1, 2013, to November 30, 2022, were searched using the Cochrane Library and PubMed databases. All included trials examined all grade and grades 3-5 cardiac and vascular adverse events. These involved comparisons of CTLA-4 inhibitors to placebo, CTLA-4 inhibitors plus chemotherapy to chemotherapy alone, CTLA-4 inhibitors combined with PD-1/PD-L1 inhibitors to PD-1/PD-L1 inhibitors alone, and CTLA-4 inhibitors plus target agent to PD-1/PD-L1 inhibitors plus target agent. The odds ratio (OR) and corresponding 95% confidence intervals (CIs) were calculated using the Mantel-Haenszel method. Results Overall, 20 trials were included. CTLA-4 inhibitors significantly increased the incidence of all-grade cardiovascular toxicity (OR = 1.33, 95% CI: 1.00-1.75, p = 0.05). The incidence of all-grade cardiovascular toxicity increased in malignant tumor patients who received single-agent CTLA-4 inhibitors (OR = 1.73, 95% CI: 1.13-2.65, p = 0.01), as well as the incidence rate of grades 3-5 cardiovascular adverse events (OR = 2.00, 95% CI: 1.08-3.70, p = 0.03). Compared with the non-CTLA-4 inhibitor group, CTLA-4 inhibitors plus chemotherapy, PD-1/PD-L1 inhibitors, or target agent did not significantly affect the incidence of cardiac and vascular toxicity. The incidence of grades 3-5 cardiac failure, hypertension, pericardial effusion, myocarditis, and atrial fibrillation were much higher among patients exposed to CTLA-4 inhibitor, but the data were not statistically significant. Conclusion Our findings suggest that the incidence rate of all cardiovascular toxicity and severe cardiovascular toxicity increased in patients who were administered CTLA-4 inhibitors. In addition, the risk of serious cardiovascular toxic events was independent of the type of adverse event. From these results, physicians should assess the benefits and risks of CTLA-4 inhibitors when treating malignancies.
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Affiliation(s)
- Huiyi Liu
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhouGuangdongChina
| | - Lu Fu
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhouGuangdongChina
| | - Shuyu Jin
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhouGuangdongChina
- The Second School of Clinical MedicineSouthern Medical UniversityGuangzhouGuangdongChina
| | - Xingdong Ye
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhouGuangdongChina
| | - Yanlin Chen
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhouGuangdongChina
| | - Sijia Pu
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhouGuangdongChina
- School of MedicineSouth China University of TechnologyGuangzhouGuangdongChina
| | - Yumei Xue
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhouGuangdongChina
- Guangdong Provincial Key Laboratory of Clinical Pharmacology, Research Center of Medical Sciences, Guangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhouGuangdongChina
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Rossari F, Foti S, Camera S, Persano M, Casadei-Gardini A, Rimini M. Treatment options for advanced hepatocellular carcinoma: the potential of biologics. Expert Opin Biol Ther 2024; 24:455-470. [PMID: 38913107 DOI: 10.1080/14712598.2024.2363234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Accepted: 05/30/2024] [Indexed: 06/25/2024]
Abstract
INTRODUCTION Advanced hepatocellular carcinoma (HCC) represents a significant global health burden, whose treatment has been recently revolutionized by the advent of biologic treatments. Despite that, innovative therapeutic regimens and approaches, especially immune-based, remain to be explored aiming at extending the therapeutic benefits to a wider population of patients. AREAS COVERED This review comprehensively discusses the evolving landscape of biological treatment modalities for advanced HCC, including immune checkpoint inhibitors, antiangiogenic monoclonal antibodies, tumor-targeting monoclonal antibodies either naked or drug-conjugated, therapeutic vaccines, oncolytic viruses, adoptive cell therapies, and cytokine-based therapies. Key clinical trials and preclinical studies are examined, highlighting the actual or potential impact of these interventions in reshaping treatment paradigms for HCC. EXPERT OPINION Tailored and rational combination strategies, leveraging the synergistic effects of different modalities, represent a promising approach to maximize treatment efficacy in advanced HCC, which should aim at conversion endpoints to increase the fraction of patients eligible for curative approaches. The identification of predictive biomarkers holds the key to optimizing patient selection and improving therapeutic outcomes.
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Affiliation(s)
- Federico Rossari
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
- San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Silvia Foti
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Silvia Camera
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Mara Persano
- Medical Oncology, University and University Hospital of Cagliari, Cagliari, Italy
| | - Andrea Casadei-Gardini
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Margherita Rimini
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
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Chiang CL, Lee FAS, Chan KSK, Lee VWY, Chiu KWH, Ho RLM, Fong JKS, Wong NSM, Yip WWL, Yeung CSY, Lau VWH, Man K, Kong FMS, Chan ACY. Survival Outcome Analysis of Stereotactic Body Radiotherapy and Immunotherapy (SBRT-IO) versus SBRT-Alone in Unresectable Hepatocellular Carcinoma. Liver Cancer 2024; 13:265-276. [PMID: 38756147 PMCID: PMC11095610 DOI: 10.1159/000533425] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 08/02/2023] [Indexed: 05/18/2024] Open
Abstract
Introduction While combination of stereotactic body radiotherapy (SBRT) and immunotherapy are promising, their efficacy and safety have not been compared with SBRT-alone in patients with unresectable hepatocellular carcinoma (HCC). Methods This retrospective study included 100 patients with nonmetastatic, unresectable HCC in two hospitals. Eligible patients had tumor nodules ≤3 and Child-Pugh liver function score of A5 to B7. Seventy patients received SBRT-alone, and 30 patients underwent combined SBRT and immunotherapy (SBRT-IO). Overall survival (OS), time to progression (TTP), overall response rate (ORR), and toxicity were analyzed. We adjusted for the potential confounding factors using propensity score matching. Results The median tumor size was 7.3 cm (range, 2.6-18 cm). Twenty-five (25%) of patients had vascular invasion. Before propensity score matching, the 1-year and 3-year OS rate was 89.9% and 59.8% in the SBRT-IO group and 75.7% and 42.3% in SBRT-alone group (p = 0.039). After propensity score matching (1:2), 25 and 50 patients were selected from the SBRT-IO and SBRT-alone group. The 1-year and 3-year OS was 92.0% and 63.9% in the SBRT-IO group versus 74.0% and 43.3% in the SBRT-alone group (p = 0.034). The 1-year and 3-year TTP was better in SBRT-IO group (1-year: 68.9% vs. 58.9% and 3-year: 61.3% vs. 32.5%, p = 0.057). The ORR of 88% (complete response [CR]: 56%, partial response [PR]: 22%) in SBRT-IO arm was significantly better than 50% (CR: 20%, PR: 30%) in the SBRT-alone arm (p = 0.006). Three patients (12%) developed ≥grade 3 immune-related treatment adverse events (n = 2 hepatitis, n = 1 dermatitis) leading to permanent treatment discontinuation. Conclusion Adding immunotherapy to SBRT resulted in better survival with manageable toxicities. Prospective randomized trial is warranted.
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Affiliation(s)
- Chi Leung Chiang
- Department of Clinical Oncology, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR
| | | | - Kenneth Sik Kwan Chan
- Department of Clinical Oncology, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR
| | - Venus Wan Yan Lee
- Medical Physics Unit, Department of Clinical Oncology, Tuen Mun Hospital, Hong Kong, Hong Kong SAR
| | - Keith Wan Hang Chiu
- Department of Diagnostic Radiology, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR
- Department of Radiology and Imaging, Queen Elizabeth Hospital, Hong Kong, Hong Kong SAR
| | - Ryan Lok Man Ho
- Radiotherapy and Oncology Department, Gleneagles Hospital, Hong Kong, Hong Kong SAR
| | - John Ka Shun Fong
- Department of Clinical Oncology, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR
| | | | | | - Cynthia Sin Yu Yeung
- Department of Clinical Oncology, Tuen Mun Hospital, Hong Kong, Hong Kong SAR
- Union Oncology Center, Union Hospital, Hong Kong, Hong Kong SAR
| | - Vince Wing Hang Lau
- Department of Diagnostic Radiology, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR
- Department of Radiology, Gleneagles Hospital, Hong Kong, Hong Kong SAR
| | - Kwan Man
- Department of Surgery, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR
| | - Feng Ming Spring Kong
- Department of Clinical Oncology, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR
| | - Albert Chi Yan Chan
- Department of Surgery, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR
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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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Ruli TM, Pollack ED, Lodh A, Evers CD, Price CA, Shoreibah M. Immune Checkpoint Inhibitors in Hepatocellular Carcinoma and Their Hepatic-Related Side Effects: A Review. Cancers (Basel) 2024; 16:2042. [PMID: 38893164 PMCID: PMC11171072 DOI: 10.3390/cancers16112042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 05/24/2024] [Accepted: 05/27/2024] [Indexed: 06/21/2024] Open
Abstract
Primary liver cancer is one of the leading causes of cancer mortality worldwide, with hepatocellular carcinoma (HCC) being the most prevalent type of liver cancer. The prognosis of patients with advanced, unresectable HCC has historically been poor. However, with the emergence of immunotherapy, specifically immune checkpoint inhibitors (ICIs), there is reason for optimism. Nevertheless, ICIs do not come without risk, especially when administered in patients with HCC, given their potential underlying poor hepatic reserve. Given their novelty in the management of HCC, there are few studies to date specifically investigating ICI-related side effects on the liver in patients with underlying HCC. This review will serve as a guide for clinicians on ICIs' role in the management of HCC and their potential side effect profile. There will be a discussion on ICI-related hepatotoxicity, the potential for hepatitis B and C reactivation with ICI use, the potential for the development of autoimmune hepatitis with ICI use, and the risk of gastrointestinal bleeding with ICI use. As ICIs become more commonplace as a treatment option in patients with advanced HCC, it is imperative that clinicians not only understand the mechanism of action of such agents but also understand and are able to identify hepatic-related side effects.
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Affiliation(s)
- Thomas M. Ruli
- Internal Medicine Residency Program, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (E.D.P.); (A.L.); (C.A.P.)
| | - Ethan D. Pollack
- Internal Medicine Residency Program, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (E.D.P.); (A.L.); (C.A.P.)
| | - Atul Lodh
- Internal Medicine Residency Program, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (E.D.P.); (A.L.); (C.A.P.)
| | - Charles D. Evers
- Internal Medicine Residency Program, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (E.D.P.); (A.L.); (C.A.P.)
| | - Christopher A. Price
- Internal Medicine Residency Program, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (E.D.P.); (A.L.); (C.A.P.)
| | - Mohamed Shoreibah
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, USA;
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He K, Xie MY, Gao XJ, Wang H, Li JD. The Correlation of Centromere Protein Q with Diagnosis and Prognosis in Hepatocellular Carcinoma. Pharmgenomics Pers Med 2024; 17:271-288. [PMID: 38827182 PMCID: PMC11141762 DOI: 10.2147/pgpm.s456965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Accepted: 05/18/2024] [Indexed: 06/04/2024] Open
Abstract
Introduction Hepatocellular carcinoma (HCC) is one of the major types of liver cancer. Previous studies have shown that the centromere protein family is associated with malignant biological behaviors such as HCC proliferation. As a member of the centromere protein family, centromere protein Q (CENPQ) is closely associated with immunotherapy and immune cell infiltration in various tumors. However, the role and mechanism of CENPQ in HCC remain unclear. Methods Multiple public databases and RT-qPCR were used to study the expression of CENPQ in HCC. Based on TCGA data, the correlation between CENPQ and clinicopathological characteristics and prognosis of HCC patients was analyzed, and its diagnostic value was evaluated. The potential biological functions of CENPQ in HCC were explored by functional enrichment analysis of differentially expressed genes. The distribution of tumor-infiltrating immune cell types was assessed using single-sample GSEA, and immune checkpoint gene expression was analyzed using Spearman correlation. Subsequently, loss-of-function experiments were performed to determine the function of CENPQ on the cell cycle and proliferation of HCC cells in vitro. Results CENPQ was found highly expressed in HCC and correlated with weight, BMI, age, AFP, T stage, pathologic stage, histologic grade, and prothrombin time (all p < 0.05). ROC and Kaplan-Meier analyses indicated that CENPQ may be potentially used as a diagnostic marker for HCC (AUC = 0.881), and its upregulation is associated with decreased OS (p = 0.002), DSS (p < 0.001), and PFI (p = 0.002). Functional enrichment analysis revealed an association of CENPQ with biological processes such as immune cell infiltration, cell cycle, and hippo-merlin signaling deregulation in HCC. Furthermore, knockdown of CENPQ manifested in HCC cells with G0/1 phase cycle arrest and decreased proliferative capacity. Conclusion CENPQ expression was higher in HCC tissues than in normal liver tissues. It was significantly associated with poor prognosis, immune cell infiltration, cell cycle, and proliferation. Therefore, CENPQ may become a promising prognostic biomarker for HCC patients.
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Affiliation(s)
- Kun He
- Institute of Hepatobiliary, Pancreatic and Intestinal Diseases, North Sichuan Medical College, Nanchong, Sichuan, People’s Republic of China
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, People’s Republic of China
| | - Meng-yi Xie
- Institute of Hepatobiliary, Pancreatic and Intestinal Diseases, North Sichuan Medical College, Nanchong, Sichuan, People’s Republic of China
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, People’s Republic of China
| | - Xiao-jin Gao
- Institute of Hepatobiliary, Pancreatic and Intestinal Diseases, North Sichuan Medical College, Nanchong, Sichuan, People’s Republic of China
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, People’s Republic of China
| | - Hao Wang
- Institute of Hepatobiliary, Pancreatic and Intestinal Diseases, North Sichuan Medical College, Nanchong, Sichuan, People’s Republic of China
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, People’s Republic of China
| | - Jing-dong Li
- Institute of Hepatobiliary, Pancreatic and Intestinal Diseases, North Sichuan Medical College, Nanchong, Sichuan, People’s Republic of China
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, People’s Republic of China
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Galasso L, Cerrito L, Maccauro V, Termite F, Ainora ME, Gasbarrini A, Zocco MA. Hepatocellular Carcinoma and the Multifaceted Relationship with Its Microenvironment: Attacking the Hepatocellular Carcinoma Defensive Fortress. Cancers (Basel) 2024; 16:1837. [PMID: 38791916 PMCID: PMC11119751 DOI: 10.3390/cancers16101837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 04/30/2024] [Accepted: 05/07/2024] [Indexed: 05/26/2024] Open
Abstract
Hepatocellular carcinoma is a malignant tumor that originates from hepatocytes in an inflammatory substrate due to different degrees of liver fibrosis up to cirrhosis. In recent years, there has been growing interest in the role played by the complex interrelationship between hepatocellular carcinoma and its microenvironment, capable of influencing tumourigenesis, neoplastic growth, and its progression or even inhibition. The microenvironment is made up of an intricate network of mesenchymal cells, immune system cells, extracellular matrix, and growth factors, as well as proinflammatory cytokines and translocated bacterial products coming from the intestinal microenvironment via the enterohepatic circulation. The aim of this paper is to review the role of the HCC microenvironment and describe the possible implications in the choice of the most appropriate therapeutic scheme in the prediction of tumor response or resistance to currently applied treatments and in the possible development of future therapeutic perspectives, in order to circumvent resistance and break down the tumor's defensive fort.
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Affiliation(s)
- Linda Galasso
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy (L.C.); (V.M.); (A.G.)
| | - Lucia Cerrito
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy (L.C.); (V.M.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Valeria Maccauro
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy (L.C.); (V.M.); (A.G.)
| | - Fabrizio Termite
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy (L.C.); (V.M.); (A.G.)
| | - Maria Elena Ainora
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy (L.C.); (V.M.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy (L.C.); (V.M.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Maria Assunta Zocco
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy (L.C.); (V.M.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
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Shen KY, Zhu Y, Xie SZ, Qin LX. Immunosuppressive tumor microenvironment and immunotherapy of hepatocellular carcinoma: current status and prospectives. J Hematol Oncol 2024; 17:25. [PMID: 38679698 PMCID: PMC11057182 DOI: 10.1186/s13045-024-01549-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Accepted: 04/23/2024] [Indexed: 05/01/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a major health concern worldwide, with limited therapeutic options and poor prognosis. In recent years, immunotherapies such as immune checkpoint inhibitors (ICIs) have made great progress in the systemic treatment of HCC. The combination treatments based on ICIs have been the major trend in this area. Recently, dual immune checkpoint blockade with durvalumab plus tremelimumab has also emerged as an effective treatment for advanced HCC. However, the majority of HCC patients obtain limited benefits. Understanding the immunological rationale and exploring novel ways to improve the efficacy of immunotherapy has drawn much attention. In this review, we summarize the latest progress in this area, the ongoing clinical trials of immune-based combination therapies, as well as novel immunotherapy strategies such as chimeric antigen receptor T cells, personalized neoantigen vaccines, oncolytic viruses, and bispecific antibodies.
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Affiliation(s)
- Ke-Yu Shen
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
- Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Ying Zhu
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
- Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Sun-Zhe Xie
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
- Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Lun-Xiu Qin
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China.
- Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
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Wei H, Dong C, Li X. Treatment Options for Hepatocellular Carcinoma Using Immunotherapy: Present and Future. J Clin Transl Hepatol 2024; 12:389-405. [PMID: 38638377 PMCID: PMC11022065 DOI: 10.14218/jcth.2023.00462] [Citation(s) in RCA: 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: 10/16/2023] [Revised: 01/22/2024] [Accepted: 01/25/2024] [Indexed: 04/20/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a common cancer, and the body's immune responses greatly affect its progression and the prognosis of patients. Immunological suppression and the maintenance of self-tolerance in the tumor microenvironment are essential responses, and these form part of the theoretical foundations of immunotherapy. In this review, we first discuss the tumor microenvironment of HCC, describe immunosuppression in HCC, and review the major biomarkers used to track HCC progression and response to treatment. We then examine antibody-based therapies, with a focus on immune checkpoint inhibitors (ICIs), monoclonal antibodies that target key proteins in the immune response (programmed cell death protein 1, anti-cytotoxic T-lymphocyte associated protein 4, and programmed death-ligand 1) which have transformed the treatment of HCC and other cancers. ICIs may be used alone or in conjunction with various targeted therapies for patients with advanced HCC who are receiving first-line treatments or subsequent treatments. We also discuss the use of different cellular immunotherapies, including T cell receptor (TCR) T cell therapy and chimeric antigen receptor (CAR) T cell therapy. We then review the use of HCC vaccines, adjuvant immunotherapy, and oncolytic virotherapy, and describe the goals of future research in the development of treatments for HCC.
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Affiliation(s)
- Hongbin Wei
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China
- The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Chunlu Dong
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China
- The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Xun Li
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China
- The First Hospital of Lanzhou University, Lanzhou, Gansu, China
- Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, Gansu, China
- Cancer Prevention and Treatment Center of Lanzhou University School of Medicine, Lanzhou, Gansu, China
- Hepatopancreatobiliary Surgery Institute of Gansu Province, Lanzhou, Gansu, China
- Clinical Research Center for General Surgery of Gansu Province, Lanzhou, Gansu, China
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Akbulut Z, Aru B, Aydın F, Yanıkkaya Demirel G. Immune checkpoint inhibitors in the treatment of hepatocellular carcinoma. Front Immunol 2024; 15:1379622. [PMID: 38638433 PMCID: PMC11024234 DOI: 10.3389/fimmu.2024.1379622] [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: 01/31/2024] [Accepted: 03/18/2024] [Indexed: 04/20/2024] Open
Abstract
Despite advances in cancer treatment, hepatocellular carcinoma (HCC), the most common form of liver cancer, remains a major public health problem worldwide. The immune microenvironment plays a critical role in regulating tumor progression and resistance to therapy, and in HCC, the tumor microenvironment (TME) is characterized by an abundance of immunosuppressive cells and signals that facilitate immune evasion and metastasis. Recently, anti-cancer immunotherapies, therapeutic interventions designed to modulate the immune system to recognize and eliminate cancer, have become an important cornerstone of cancer therapy. Immunotherapy has demonstrated the ability to improve survival and provide durable cancer control in certain groups of HCC patients, while reducing adverse side effects. These findings represent a significant step toward improving cancer treatment outcomes. As demonstrated in clinical trials, the administration of immune checkpoint inhibitors (ICIs), particularly in combination with anti-angiogenic agents and tyrosine kinase inhibitors, has prolonged survival in a subset of patients with HCC, providing an alternative for patients who progress on first-line therapy. In this review, we aimed to provide an overview of HCC and the role of the immune system in its development, and to summarize the findings of clinical trials involving ICIs, either as monotherapies or in combination with other agents in the treatment of the disease. Challenges and considerations regarding the administration of ICIs in the treatment of HCC are also outlined.
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Affiliation(s)
- Zeynep Akbulut
- Cancer and Stem Cell Research Center, Maltepe University, Istanbul, Türkiye
- Department of Medical Biology and Genetics, Faculty of Medicine, Maltepe University, Istanbul, Türkiye
| | - Başak Aru
- Department of Immunology, Faculty of Medicine, Yeditepe University, Istanbul, Türkiye
| | - Furkan Aydın
- Department of Immunology, Faculty of Medicine, Yeditepe University, Istanbul, Türkiye
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Qian H, Yang X, Zhang T, Zou P, Zhang Y, Tian W, Mao Z, Wei J. Improving the safety of CAR-T-cell therapy: The risk and prevention of viral infection for patients with relapsed or refractory B-cell lymphoma undergoing CAR-T-cell therapy. Am J Hematol 2024; 99:662-678. [PMID: 38197307 DOI: 10.1002/ajh.27198] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 12/05/2023] [Accepted: 12/15/2023] [Indexed: 01/11/2024]
Abstract
Chimeric antigen receptor (CAR) T-cell therapy, an innovative immunotherapeutic against relapsed/refractory B-cell lymphoma, faces challenges due to frequent viral infections. Despite this, a comprehensive review addressing risk assessment, surveillance, and treatment management is notably absent. This review elucidates immune response compromises during viral infections in CAR-T recipients, collates susceptibility risk factors, and deliberates on preventive strategies. In the post-pandemic era, marked by the Omicron variant, new and severe threats to CAR-T therapy emerge, necessitating exploration of preventive and treatment measures for COVID-19. Overall, the review provides recommendations for viral infection prophylaxis and management, enhancing CAR-T product safety and recipient survival.
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Affiliation(s)
- Hu Qian
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xingcheng Yang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tingting Zhang
- Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
- Department of Hematology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
- Sino-German Joint Oncological Research Laboratory, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Taiyuan, China
| | - Ping Zou
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yicheng Zhang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Weiwei Tian
- Department of Hematology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
- Sino-German Joint Oncological Research Laboratory, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Taiyuan, China
| | - Zekai Mao
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jia Wei
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Hematology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
- Sino-German Joint Oncological Research Laboratory, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Taiyuan, China
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Chen W, Hu Z, Li G, Zhang L, Li T. The State of Systematic Therapies in Clinic for Hepatobiliary Cancers. J Hepatocell Carcinoma 2024; 11:629-649. [PMID: 38559555 PMCID: PMC10981875 DOI: 10.2147/jhc.s454666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 03/16/2024] [Indexed: 04/04/2024] Open
Abstract
Hepatobiliary cancer (HBC) includes hepatocellular carcinoma and biliary tract carcinoma (cholangiocarcinoma and gallbladder carcinoma), and its morbidity and mortality are significantly correlated with disease stage. Surgery is the cornerstone of curative therapy for early stage of HBC. However, a large proportion of patients with HBC are diagnosed with advanced stage and can only receive systemic treatment. According to the results of clinical trials, the first-line and second-line treatment programs are constantly updated with the improvement of therapeutic effectiveness. In order to improve the therapeutic effect, reduce the occurrence of drug resistance, and reduce the adverse reactions of patients, the treatment of HBC has gradually developed from single-agent therapy to combination. The traditional therapeutic philosophy proposed that patients with advanced HBC are only amenable to systematic therapies. With some encouraging clinical trial results, the treatment concept has been revolutionized, and patients with advanced HBC who receive novel systemic combination therapies with multi-modality treatment (including surgery, transplant, TACE, HAIC, RT) have significantly improved survival time. This review summarizes the treatment options and the latest clinical advances of HBC in each stage and discusses future direction, in order to inform the development of more effective treatments for HBC.
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Affiliation(s)
- Weixun Chen
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of China
| | - Zhengnan Hu
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of China
| | - Ganxun Li
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of China
| | - Lei Zhang
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of China
| | - Tao Li
- Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, People’s Republic of China
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Celsa C, Cabibbo G, Fulgenzi CAM, Scheiner B, D'Alessio A, Manfredi GF, Nishida N, Ang C, Marron TU, Saeed A, Wietharn B, Pinter M, Cheon J, Huang YH, Lee PC, Phen S, Gampa A, Pillai A, Vivaldi C, Salani F, Masi G, Roehlen N, Thimme R, Vogel A, Schönlein M, von Felden J, Schulze K, Wege H, Galle PR, Kudo M, Rimassa L, Singal AG, El Tomb P, Ulahannan S, Parisi A, Chon HJ, Hsu WF, Stefanini B, Verzoni E, Giusti R, Veccia A, Catino A, Aprile G, Guglielmini PF, Di Napoli M, Ermacora P, Antonuzzo L, Rossi E, Verderame F, Zustovich F, Ficorella C, Di Pietro FR, Battelli N, Negrini G, Grossi F, Bordonaro R, Pipitone S, Banzi M, Ricciardi S, Laera L, Russo A, De Giorgi U, Cavanna L, Sorarù M, Montesarchio V, Bordi P, Brunetti L, Pinto C, Bersanelli M, Cammà C, Cortellini A, Pinato DJ. Characteristics and outcomes of immunotherapy-related liver injury in patients with hepatocellular carcinoma versus other advanced solid tumours. J Hepatol 2024; 80:431-442. [PMID: 37972660 DOI: 10.1016/j.jhep.2023.10.040] [Citation(s) in RCA: 20] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 10/26/2023] [Accepted: 10/30/2023] [Indexed: 11/19/2023]
Abstract
BACKGROUND & AIMS Immune-related liver injury (irLI) is commonly observed in patients with cancer treated with immune checkpoint inhibitors (ICIs). We aimed to compare the incidence, clinical characteristics, and outcomes of irLI between patients receiving ICIs for hepatocellular carcinoma (HCC) vs. other solid tumours. METHODS Two separate cohorts were included: 375 patients with advanced/unresectable HCC, Child-Pugh A class treated with first-line atezolizumab+bevacizumab from the AB-real study, and a non-HCC cohort including 459 patients treated with first-line ICI therapy from the INVIDIa-2 multicentre study. IrLI was defined as a treatment-related increase of aminotransferase levels after exclusion of alternative aetiologies of liver injury. The incidence of irLI was adjusted for the duration of treatment exposure. RESULTS In patients with HCC, the incidence of any grade irLI was 11.4% over a median treatment exposure of 4.4 months (95% CI 3.7-5.2) vs. 2.6% in the INVIDIa-2 cohort over a median treatment exposure of 12.4 months (95% CI 11.1-14.0). Exposure-adjusted-incidence of any grade irLI was 22.1 per 100-patient-years in patients with HCC and 2.1 per 100-patient-years in patients with other solid tumours (p <0.001), with median time-to-irLI of 1.4 and 4.7 months, respectively. Among patients who developed irLI, systemic corticosteroids were administered in 16.3% of patients with HCC and 75.0% of those without HCC (p <0.001), and irLI resolution was observed in 72.1% and 58.3%, respectively (p = 0.362). In patients with HCC, rates of hepatic decompensation and treatment discontinuation due to irLI were 7%. Grade 1-2 irLI was associated with improved overall survival only in patients with HCC (hazard ratio 0.53, 95% CI 0.29-0.96). CONCLUSIONS Despite higher incidence and earlier onset, irLI in patients with HCC is characterised by higher rates of remission and lower requirement for corticosteroid therapy (vs. irLI in other solid tumours), low risk of hepatic decompensation and treatment discontinuation, not negatively affecting oncological outcomes. IMPACT AND IMPLICATIONS Immune-related liver injury (irLI) is common in patients with cancer receiving immune checkpoint inhibitors (ICIs), but whether irLI is more frequent or it is associated with a worse clinical course in patients with hepatocellular carcinoma (HCC), compared to other tumours, is not known. Herein, we compared characteristics and outcomes of irLI in two prospective cohorts including patients treated with ICIs for HCC or for other oncological indications. irLI is significantly more common and it occurs earlier in patients with HCC, also after adjustment for duration of treatment exposure. However, outcomes of patients with HCC who developed irLI are not negatively affected in terms of requirement for corticosteroid therapy, hepatic decompensation, treatment discontinuation and overall survival.
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Affiliation(s)
- Ciro Celsa
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, W120HS London, UK; Gastroenterology and Hepatology Unit, Department of Health Promotion, Mother & Child Care, Internal Medicine & Medical Specialties, University of Palermo, Italy
| | - Giuseppe Cabibbo
- Gastroenterology and Hepatology Unit, Department of Health Promotion, Mother & Child Care, Internal Medicine & Medical Specialties, University of Palermo, Italy
| | - Claudia A M Fulgenzi
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, W120HS London, UK; Operative Research Unit of Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200 - 00128 Roma, Italy
| | - Bernhard Scheiner
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, W120HS London, UK; Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Antonio D'Alessio
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, W120HS London, UK; Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Giulia F Manfredi
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, W120HS London, UK; Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Naoshi Nishida
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Celina Ang
- Department of Medicine, Division of Hematology/Oncology, Tisch Cancer Institute, Mount Sinai Hospital, New York, NY, USA
| | - Thomas U Marron
- Department of Medicine, Division of Hematology/Oncology, Tisch Cancer Institute, Mount Sinai Hospital, New York, NY, USA
| | - Anwaar Saeed
- Department of Medicine, Division of Hematology & Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Brooke Wietharn
- Department of Medicine, Division of Medical Oncology, Kansas University Cancer Center, Kansas City, Kansas, USA
| | - Matthias Pinter
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Jaekyung Cheon
- Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, South Korea
| | - Yi-Hsiang Huang
- Healthcare and Services Center, Taipei Veterans General Hospital, Taipei, Taiwan; Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Pei-Chang Lee
- Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Samuel Phen
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Anuhya Gampa
- Section of Gastroenterology, Hepatology & Nutrition, the University of Chicago Medicine 5841 S. Maryland Ave, 60637 Chicago, IL, USA
| | - Anjana Pillai
- Unit of Medical Oncology 2, Azienda Ospedaliero- Universitaria Pisana, Pisa, Italy
| | - Caterina Vivaldi
- Scuola Superiore Sant'Anna Pisa, interdisciplinary research center "Health Science", Pisa, Italy
| | - Francesca Salani
- Unit of Medical Oncology 2, Azienda Ospedaliero- Universitaria Pisana, Pisa, Italy; Scuola Superiore Sant'Anna Pisa, interdisciplinary research center "Health Science", Pisa, Italy
| | - Gianluca Masi
- Unit of Medical Oncology 2, Azienda Ospedaliero- Universitaria Pisana, Pisa, Italy
| | - Natascha Roehlen
- Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases), Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Robert Thimme
- Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases), Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Arndt Vogel
- Hannover Medical School, Hannover, Germany; Longo Family Chair in Liver Cancer Research, Division of Gastroenterology and Hepatology, Toronto General Hospital, Medical Oncology, Princess Margaret Cancer Centre, Schwartz Reisman Liver Research Centre, Toronto, Canada
| | - Martin Schönlein
- Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Johann von Felden
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Kornelius Schulze
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Henning Wege
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Peter R Galle
- University Medical Center Mainz, Department of Internal Medicine I, Mainz, Germany
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan, Italy; Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Amit G Singal
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Paul El Tomb
- Medical Oncology/TSET Phase 1 Program, Stephenson Cancer Center, University of Oklahoma, Oklahoma City
| | - Susanna Ulahannan
- Medical Oncology/TSET Phase 1 Program, Stephenson Cancer Center, University of Oklahoma, Oklahoma City
| | - Alessandro Parisi
- Department of Oncology, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria delle Marche, 60126 Ancona, Italy
| | - Hong Jae Chon
- Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, South Korea
| | - Wei-Fan Hsu
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Bernardo Stefanini
- Department of Medical and Surgical Sciences, University of Bologna, Italy
| | - Elena Verzoni
- SS. Oncologia Genitourinaria, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | | | | | - Annamaria Catino
- Medical Thoracic Oncology Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - Giuseppe Aprile
- Department of Oncology, San Bortolo General Hospital, Vicenza, Italy
| | | | - Marilena Di Napoli
- UC Oncologia Medica Uro-Ginecologica, Istituto Nazionale Tumori "Fondazione G. Pascale", IRCCS, Napoli, Italy
| | - Paola Ermacora
- Dipartimento di Oncologia, Presidio Ospedaliero Universitario Santa Maria della Misericordia, Azienda sanitaria universitaria Integrata Friuli Centrale, Udine, Italy
| | | | - Ernesto Rossi
- Medical Oncology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | | | - Fable Zustovich
- UOC Oncologia di Belluno, Dipartimento di Oncologia Clinica, AULSS 1 Dolomiti, Ospedale S.Martino, Belluno, Italy
| | - Corrado Ficorella
- Department of Biotechnological and Applied Clinical Sciences, St Salvatore Hospital, University of L'Aquila, L'Aquila, Italy
| | | | - Nicola Battelli
- UOC Oncologia, Ospedale Generale Provinciale di Macerata, ASUR Marche Area Vasta 3, Macerata, Italy
| | - Giorgia Negrini
- Medical Oncology Unit, Papa Giovanni XXIII Hospital, Bergamo, Italy
| | - Francesco Grossi
- Medical Oncology Department, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | | | - Stefania Pipitone
- Medical Oncology Unit, University Hospital of Modena e Reggio Emilia, Italy
| | - Maria Banzi
- Medical Oncology Unit, AUSL-IRCCS of Reggio Emilia, Reggio Emilia, Italy
| | | | - Letizia Laera
- Medical Oncology, Ospedale Generale Regionale F Miulli, Acquaviva delle Fonti, Puglia, Italy
| | - Antonio Russo
- Dipartimento di Discipline Chirurgiche, Oncologiche e Stomatologiche, Università degli Studi di Palermo, Palermo, Italy
| | - Ugo De Giorgi
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | | | - Mariella Sorarù
- Medical Oncology, Camposampiero Hospital, AULSS 6 Euganea, Padova, Italy
| | - Vincenzo Montesarchio
- UOC Oncologia, Ospedale Monaldi, Azienda Ospedaliera Specialistica dei Colli, Napoli, Italy
| | - Paola Bordi
- Medical Oncology Unit, Medicine and Surgery Department, University of Parma, Parma, Italy
| | - Leonardo Brunetti
- Operative Research Unit of Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200 - 00128 Roma, Italy
| | - Carmine Pinto
- Medical Oncology Unit, AUSL-IRCCS of Reggio Emilia, Reggio Emilia, Italy
| | - Melissa Bersanelli
- Medical Oncology Unit, Medicine and Surgery Department, University of Parma, Parma, Italy
| | - Calogero Cammà
- Gastroenterology and Hepatology Unit, Department of Health Promotion, Mother & Child Care, Internal Medicine & Medical Specialties, University of Palermo, Italy
| | - Alessio Cortellini
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, W120HS London, UK; Operative Research Unit of Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200 - 00128 Roma, Italy
| | - David J Pinato
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, W120HS London, UK; Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.
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Zhang Q, Zhu B, Yang H, Li F, Qu Y, Lu L, Zhang Q. Exploration of YBX1 role in the prognostic value and immune characteristics by single-cell and bulk sequencing analysis for liver hepatocellular carcinoma. J Gene Med 2024; 26:e3680. [PMID: 38448368 DOI: 10.1002/jgm.3680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 02/01/2024] [Accepted: 02/05/2024] [Indexed: 03/08/2024] Open
Abstract
BACKGROUND Y-box binding protein 1 (YBX1) plays a variety of roles in progression of multiple tumors. However, the role of YBX1 in prognostic value and immune regulation for liver hepatocellular carcinoma (LIHC) remains unclear. The present study aimed to examine the effect of YBX1 on the regulation of tumor immunity and survival prediction in LIHC patients. METHODS YBX1-related expression profiles and single-cell and bulk sequencing analysis were performed using online databases. YBX1 expression was validated by a quantitative real-time PCR (qRT-PCR), western blotting and immunohistochemistry. Univariate/multivariate Cox regression analysis was performed to determine independent predictors of overall survival (OS). The ESTIMATE (i.e., Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data) algorithm and Tumor Immune Dysfunction and Exclusion (TIDE) analysis were used to assess the relationships between YBX1 and LIHC immunity. RESULTS YBX1 was over-expressed in LIHC tissues and cell lines. High YBX1 expression was significantly associated with poor OS. Univariate/multivariate Cox regression analysis revealed that YBX1 was an independent prognostic factor for LIHC. Gene set enrichment analysis revealed that YBX1 was associated with multiple signaling pathways correlated to LIHC. Additionally, YBX1 was expressed in multiple immune cells and was significantly correlated with immune cells, immune checkpoint markers and tumor immune microenvironment. The TIDE analysis demonstrated that LIHC patients with high YBX1 expression showed a higher T-cell dysfunction score and a higher exclusion score, as well as poorer immunotherapy response. CONCLUSIONS YBX1 plays crucial oncogenic roles in LIHC and is closely associated with the immune defense system. YBX1 inhibition may serve as a potential treatment for LIHC.
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Affiliation(s)
- Qingqing Zhang
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bingye Zhu
- Department of Urology, Affiliated Nantong Hospital of Shanghai University, The Sixth People's Hospital of Nantong, Nantong, Jiangsu Province, China
| | - Hongyan Yang
- Nursing Department, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fei Li
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ying Qu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lungen Lu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qidi Zhang
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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50
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Ebrahimi N, Abdulwahid AHRR, Mansouri A, Karimi N, Bostani RJ, Beiranvand S, Adelian S, Khorram R, Vafadar R, Hamblin MR, Aref AR. Targeting the NF-κB pathway as a potential regulator of immune checkpoints in cancer immunotherapy. Cell Mol Life Sci 2024; 81:106. [PMID: 38418707 PMCID: PMC10902086 DOI: 10.1007/s00018-023-05098-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Revised: 10/01/2023] [Accepted: 10/29/2023] [Indexed: 03/02/2024]
Abstract
Advances in cancer immunotherapy over the last decade have led to the development of several agents that affect immune checkpoints. Inhibitory receptors expressed on T cells that negatively regulate the immune response include cytotoxic T‑lymphocyte antigen 4 (CTLA4) and programmed cell death protein 1 (PD1), which have been studied more than similar receptors. Inhibition of these proteins and other immune checkpoints can stimulate the immune system to attack cancer cells, and prevent the tumor from escaping the immune response. However, the administration of anti-PD1 and anti-CTLA4 antibodies has been associated with adverse inflammatory responses similar to autoimmune diseases. The current review discussed the role of the NF-κB pathway as a tumor promoter, and how it can govern inflammatory responses and affect various immune checkpoints. More precise knowledge about the communication between immune checkpoints and NF-κB pathways could increase the effectiveness of immunotherapy and reduce the adverse effects of checkpoint inhibitor therapy.
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Affiliation(s)
- Nasim Ebrahimi
- Genetics Division, Department of Cell and Molecular Biology and Microbiology, Faculty of Science and Technology, University of Isfahan, Isfahan, Iran
| | | | - Atena Mansouri
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Nasrin Karimi
- Department of Biology, Faculty of Basic Science, Islamic Azad University Damghan Branch, Damghan, Iran
| | | | - Sheida Beiranvand
- Department of Biology, Faculty of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Samaneh Adelian
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Roya Khorram
- Bone and Joint Diseases Research Center, Department of Orthopedic Surgery, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Vafadar
- Department of Orthopeadic Surgery, Kerman University of Medical Sciences, Kerman, Iran
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein, 2028, South Africa.
- Radiation Biology Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Amir Reza Aref
- Xsphera Biosciences, Translational Medicine Group, 6 Tide Street, Boston, MA, 02210, USA.
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA.
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