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Llopiz D, Silva L, Ruiz M, Castro-Alejos C, Aparicio B, Vegas L, Infante S, Santamaria E, Sarobe P. MERTK inhibition improves therapeutic efficacy of immune checkpoint inhibitors in hepatocellular carcinoma. Oncoimmunology 2025; 14:2473165. [PMID: 40029206 PMCID: PMC11881874 DOI: 10.1080/2162402x.2025.2473165] [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] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 01/29/2025] [Accepted: 02/24/2025] [Indexed: 03/05/2025] Open
Abstract
Immunotherapy with immune checkpoint inhibitors (ICI) in hepatocellular carcinoma (HCC) patients only achieves response rates of 25%-30%, indicating the necessity of new therapies for non-responder patients. Since myeloid-related suppressive factors are associated with poor responses to ICI in a subgroup of HCC patients, modulation of these targets may improve response rates. Our aim was to characterize the expression of the efferocytosis receptor MERTK in HCC and to analyze its potential as a new therapeutic target. In HCC patients, MERTK was expressed by myeloid cells and was associated with poorer survival. In a murine HCC model with progressive myeloid cell infiltration, MERTK was detected in dendritic cells and macrophages with an activated phenotype, which overexpressed the checkpoint ligand PD-L1. Concomitant expression of PD-1 in tumor T-cells suggested the pertinence of combined PD-1/PD-L1 and MERTK blockade. In vivo experiments in mice showed that inhibition of MERTK improved the therapeutic effect promoted by anti-PD-1 or by ICI combinations currently approved for HCC. This effect was associated with enhanced tumor infiltration and superior activity of antigen presenting cells and effector lymphocytes. Our results indicate that MERTK may behave as a relevant target for immunotherapeutic combinations in those HCC patients with tumors enriched in a myeloid component.
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Affiliation(s)
- Diana Llopiz
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- CIBERehd, Pamplona, Spain
| | - Leyre Silva
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- CIBERehd, Pamplona, Spain
| | - Marta Ruiz
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- CIBERehd, Pamplona, Spain
| | - Carla Castro-Alejos
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- CIBERehd, Pamplona, Spain
| | - Belen Aparicio
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- CIBERehd, Pamplona, Spain
| | - Lucia Vegas
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
| | - Stefany Infante
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- DNA and RNA Medicine Division, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
- Facultad de Medicina Humana, Universidad de Piura, Lima, Peru
| | - Eva Santamaria
- DNA and RNA Medicine Division, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
| | - Pablo Sarobe
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- CIBERehd, Pamplona, Spain
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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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Xie D, Liu Y, Xu F, Dang Z, Li M, Zhang Q, Dang Z. Immune microenvironment and immunotherapy in hepatocellular carcinoma: mechanisms and advances. Front Immunol 2025; 16:1581098. [PMID: 40242773 PMCID: PMC12000014 DOI: 10.3389/fimmu.2025.1581098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2025] [Accepted: 03/17/2025] [Indexed: 04/18/2025] Open
Abstract
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality globally. The tumor microenvironment (TME) plays a pivotal role in HCC progression, characterized by dynamic interactions between stromal components, immune cells, and tumor cells. Key immune players, including tumor-associated macrophages (TAMs), tumor-infiltrating lymphocytes (TILs), cytotoxic T lymphocytes (CTLs), regulatory T cells (Tregs), MDSCs, dendritic cells (DCs), and natural killer (NK) cells, contribute to immune evasion and tumor progression. Recent advances in immunotherapy, such as immune checkpoint inhibitors (ICIs), cancer vaccines, adoptive cell therapy (ACT), and combination therapies, have shown promise in enhancing anti-tumor responses. Dual ICI combinations, ICIs with molecular targeted drugs, and integration with local treatments or radiotherapy have demonstrated improved outcomes in HCC patients. This review highlights the evolving understanding of the immune microenvironment and the therapeutic potential of immunotherapeutic strategies in HCC management.
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Affiliation(s)
- Dong Xie
- Diagnosis and Treatment Center for Digestive Diseases of Henan Province Hospital of Traditional Chinese Medicine, Zhengzhou, China
| | - Yang Liu
- College of Traditional Chinese Medicine, Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Fangbiao Xu
- Department of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhibo Dang
- Diagnosis and Treatment Center for Digestive Diseases of Henan Province Hospital of Traditional Chinese Medicine, Zhengzhou, China
| | - Mengge Li
- Diagnosis and Treatment Center for Digestive Diseases of Henan Province Hospital of Traditional Chinese Medicine, Zhengzhou, China
| | - Qinsheng Zhang
- Diagnosis and Treatment Center for Digestive Diseases of Henan Province Hospital of Traditional Chinese Medicine, Zhengzhou, China
| | - Zhongqin Dang
- Diagnosis and Treatment Center for Digestive Diseases of Henan Province Hospital of Traditional Chinese Medicine, Zhengzhou, China
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Gao H, Qu L, Li M, Guan X, Zhang S, Deng X, Wang J, Xing F. Unlocking the potential of chimeric antigen receptor T cell engineering immunotherapy: Long road to achieve precise targeted therapy for hepatobiliary pancreatic cancers. Int J Biol Macromol 2025; 297:139829. [PMID: 39814310 DOI: 10.1016/j.ijbiomac.2025.139829] [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: 10/27/2024] [Revised: 01/03/2025] [Accepted: 01/11/2025] [Indexed: 01/18/2025]
Abstract
Innovative therapeutic strategies are urgently needed to address the ongoing global health concern of hepatobiliary pancreatic malignancies. This review summarizes the latest and most comprehensive research of chimeric antigen receptor (CAR-T) cell engineering immunotherapy for treating hepatobiliary pancreatic cancers. Commencing with an exploration of the distinct anatomical location and the immunosuppressive, hypoxic tumor microenvironment (TME), this review critically assesses the limitations of current CAR-T therapy in hepatobiliary pancreatic cancers and proposes corresponding solutions. Various studies aim at enhancing CAR-T cell efficacy in these cancers through improving T cell persistence, enhancing antigen specificity and reducing tumor heterogeneity, also modulating the immunosuppressive and hypoxic TME. Additionally, the review examines the application of emerging nanoparticles and biotechnologies utilized in CAR-T therapy for these cancers. The results suggest that constructing optimized CAR-T cells to overcome physical barrier, manipulating the TME to relieve immunosuppression and hypoxia, designing CAR-T combination therapies, and selecting the most suitable delivery strategies, all together could collectively enhance the safety of CAR-T engineering and advance the effectiveness of adaptive cell therapy for hepatobiliary pancreatic cancers.
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Affiliation(s)
- Hongli Gao
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Lianyue Qu
- Department of Pharmacy, The First Hospital of China Medical University, Shenyang 110001, China
| | - Mu Li
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Xin Guan
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Shuang Zhang
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Xin Deng
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China.
| | - Jin Wang
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang 110001, China.
| | - Fei Xing
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang 110004, China.
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Vizioli G, Nicoletti A, Feliciani D, Funaro B, Zileri Dal Verme L, Ponziani FR, Zocco MA, Gasbarrini A, Gabrielli M. Immunotherapy and MASLD-Related HCC: Should We Reconsider the Role of Etiology in the Therapeutic Approach to HCC? APPLIED SCIENCES 2025; 15:2279. [DOI: 10.3390/app15052279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/21/2025]
Abstract
Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancers and typically arises in the context of chronic liver disease. With the increasing prevalence of metabolic disorders, metabolic dysfunction-associated steatotic liver disease (MASLD) has become the leading cause of chronic liver disease and the most rapidly increasing cause of HCC. The role of dysfunctional innate and adaptive immune responses in the development and progression of HCC is well-established, prompting numerous trials to evaluate the efficacy of immune checkpoint inhibitors (ICIs) in targeting tumor cells. These trials have yielded promising results, and ICIs, in combination with anti-vascular endothelial growth factor (VEGF) monoclonal antibodies, are now approved as first-line therapy for patients with metastatic or unresectable HCC, irrespective of the underlying liver disease. Notably, MASLD itself is characterized by immune system dysfunction, as metabolic inflammation plays a central role in its onset and progression. However, clinical studies and post-hoc analyses suggest that immunotherapy may be less effective in MASLD-associated HCC compared to viral-related HCC. This emerging evidence raises the question of whether the underlying liver disease influences the therapeutic response to ICIs in HCC. It may be time to consider tailoring therapeutic strategies for HCC based on the specific etiological, histological, and genotypical subgroups.
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Affiliation(s)
- Giuseppina Vizioli
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Alberto Nicoletti
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Daniela Feliciani
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Barbara Funaro
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Lorenzo Zileri Dal Verme
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Francesca Romana Ponziani
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Maria Assunta Zocco
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Maurizio Gabrielli
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
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Zhang M, Huang K, Yin Q, Wu X, Zhu M, Li M. Spatial heterogeneity of the hepatocellular carcinoma microenvironment determines the efficacy of immunotherapy. Discov Oncol 2025; 16:15. [PMID: 39775241 PMCID: PMC11706828 DOI: 10.1007/s12672-025-01747-5] [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: 09/01/2024] [Accepted: 01/02/2025] [Indexed: 01/11/2025] Open
Abstract
Hepatocellular carcinoma (HCC) remains a global health challenge owing to its widespread incidence and high mortality. HCC has a specific immune tolerance function because of its unique physiological structure, which limits the efficacy of chemotherapy, radiotherapy, and molecular targeting. In recent years, new immune approaches, including adoptive cell therapy, tumor vaccines, and oncolytic virus therapy, have shown great potential. As the efficacy of immunotherapy mainly depends on the spatial heterogeneity of the tumor immune microenvironment, it is necessary to elucidate the crosstalk between the composition of the liver cancer immune environment, from which potential therapeutic targets can be selected to provide more appropriate individualized treatment programs. The role of spatial heterogeneity of immune cells in the microenvironment of HCC in the progression and influence of immunotherapy on improving the treatment and prognosis of HCC were comprehensively analyzed, providing new inspiration for the subsequent clinical treatment of liver cancer.
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Affiliation(s)
- Minni Zhang
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, Haikou, 571199, Hainan, People's Republic of China
- The First Affiliated Hospital, Key Laboratory of Emergency and Trauma of Ministry of Education, Engineering Research Center for Hainan Biological Sample Resources of Major Diseases, The Hainan Branch of National Clinical Research Center for Cancer, Hainan Medical University, Haikou, 570102, Hainan, People's Republic of China
| | - Kailin Huang
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, Haikou, 571199, Hainan, People's Republic of China
| | - Qiushi Yin
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, Haikou, 571199, Hainan, People's Republic of China
| | - Xueqin Wu
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, Haikou, 571199, Hainan, People's Republic of China
| | - Mingyue Zhu
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, Haikou, 571199, Hainan, People's Republic of China.
| | - Mengsen Li
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, Haikou, 571199, Hainan, People's Republic of China.
- Department of Medical Oncology, Second Affiliated Hospital, Hainan Medical University, Haikou, 570023, Hainan, People's Republic of China.
- Key Laboratory of Tropical Translational Medicine, Ministry of Education, Hainan Medical University, Haikou, 571199, Hainan, People's Republic of China.
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Oura K, Morishita A, Tadokoro T, Fujita K, Tani J, Kobara H. Immune Microenvironment and the Effect of Vascular Endothelial Growth Factor Inhibition in Hepatocellular Carcinoma. Int J Mol Sci 2024; 25:13590. [PMID: 39769351 PMCID: PMC11679663 DOI: 10.3390/ijms252413590] [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: 11/04/2024] [Revised: 12/12/2024] [Accepted: 12/17/2024] [Indexed: 01/03/2025] Open
Abstract
Systemic therapy for unresectable hepatocellular carcinoma (HCC) has progressed with the development of multiple kinases, such as vascular endothelial growth factor (VEGF) signaling, targeting cancer growth and angiogenesis. Additionally, the efficacy of sorafenib, regorafenib, lenvatinib, ramucirumab, and cabozantinib has been demonstrated in various clinical trials, and they are now widely used in clinical practice. Furthermore, the development of effective immune checkpoint inhibitors has progressed in systemic therapy for unresectable HCC, and atezolizumab + bevacizumab (atezo/bev) therapy and durvalumab + tremelimumab therapy are now recommended as first-line treatment. Atezo/bev therapy, which combines an anti-programmed cell death 1 ligand 1 antibody with an anti-VEGF antibody, is the first cancer immunotherapy to demonstrate efficacy against unresectable HCC. With the increasing popularity of these treatments, VEGF inhibition is attracting attention from the perspective of its anti-angiogenic effects and impact on the cancer-immune cycle. In this review, we outline the role of VEGF in the tumor immune microenvironment and cancer immune cycle in HCC and outline the potential immune regulatory mechanisms of VEGF. Furthermore, we consider the potential significance of the dual inhibition of angiogenesis and immune-related molecules by VEGF, and ultimately aim to clarify the latest treatment strategies that maximizes efficacy.
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Affiliation(s)
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita 761-0793, Kagawa, Japan; (K.O.)
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Wang H, Wang T, Yan S, Tang J, Zhang Y, Wang L, Xu H, Tu C. Crosstalk of pyroptosis and cytokine in the tumor microenvironment: from mechanisms to clinical implication. Mol Cancer 2024; 23:268. [PMID: 39614288 PMCID: PMC11607834 DOI: 10.1186/s12943-024-02183-9] [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: 07/13/2024] [Accepted: 11/22/2024] [Indexed: 12/01/2024] Open
Abstract
In the realm of cancer research, the tumor microenvironment (TME) plays a crucial role in tumor initiation and progression, shaped by complex interactions between cancer cells and surrounding non-cancerous cells. Cytokines, as essential immunomodulatory agents, are secreted by various cellular constituents within the TME, including immune cells, cancer-associated fibroblasts, and cancer cells themselves. These cytokines facilitate intricate communication networks that significantly influence tumor initiation, progression, metastasis, and immune suppression. Pyroptosis contributes to TME remodeling by promoting the release of pro-inflammatory cytokines and sustaining chronic inflammation, impacting processes such as immune escape and angiogenesis. However, challenges remain due to the complex interplay among cytokines, pyroptosis, and the TME, along with the dual effects of pyroptosis on cancer progression and therapy-related complications like cytokine release syndrome. Unraveling these complexities could facilitate strategies that balance inflammatory responses while minimizing tissue damage during therapy. This review delves into the complex crosstalk between cytokines, pyroptosis, and the TME, elucidating their contribution to tumor progression and metastasis. By synthesizing emerging therapeutic targets and innovative technologies concerning TME, this review aims to provide novel insights that could enhance treatment outcomes for cancer patients.
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Affiliation(s)
- Hua Wang
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Tao Wang
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Shuxiang Yan
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Jinxin Tang
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Yibo Zhang
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Liming Wang
- School of Biomedical Sciences, Hunan University, Changsha, Hunan, 410011, China.
| | - Haodong Xu
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China.
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China.
- Center for Precision Health, McWilliams School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
| | - Chao Tu
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China.
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China.
- Shenzhen Research Institute of Central South University, Guangdong, 518063, China.
- Hunan Engineering Research Center of AI Medical Equipment, The Second Xiangya Hospital of Central, South University, Changsha, Hunan, 410011, China.
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Childs A, Aidoo-Micah G, Maini MK, Meyer T. Immunotherapy for hepatocellular carcinoma. JHEP Rep 2024; 6:101130. [PMID: 39308986 PMCID: PMC11414669 DOI: 10.1016/j.jhepr.2024.101130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 05/19/2024] [Accepted: 05/28/2024] [Indexed: 09/25/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a major global healthcare challenge, with >1 million patients predicted to be affected annually by 2025. In contrast to other cancers, both incidence and mortality rates continue to rise, and HCC is now the third leading cause of cancer-related death worldwide. Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for advanced HCC, with trials demonstrating a superior overall survival benefit compared to sorafenib in the first-line setting. Combination therapy with either atezolizumab (anti-PD-L1) and bevacizumab (anti-VEGF) or durvalumab (anti-PD-L1) and tremelimumab (anti-CTLA-4) is now recognised as standard of care for advanced HCC. More recently, two phase III studies of ICI-based combination therapy in the early and intermediate disease settings have successfully met their primary end points of improved recurrence- and progression-free survival, respectively. Despite these advances, and in contrast to other tumour types, there remain no validated predictive biomarkers of response to ICIs in HCC. Ongoing research efforts are focused on further characterising the tumour microenvironment in order to select patients most likely to benefit from ICI and identify novel therapeutic targets. Herein, we review the current understanding of the immune landscape in which HCC develops and the evidence for ICI-based therapeutic strategies in HCC. Additionally, we describe the state of biomarker development and novel immunotherapy approaches in HCC which have progressed beyond the pre-clinical stage and into early-phase trials.
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Affiliation(s)
- Alexa Childs
- Department of Medical Oncology, Royal Free Hospital, London, UK
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, UK
| | - Gloryanne Aidoo-Micah
- Department of Medical Oncology, Royal Free Hospital, London, UK
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, UK
| | - Mala K. Maini
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, UK
| | - Tim Meyer
- Department of Medical Oncology, Royal Free Hospital, London, UK
- UCL Cancer Institute, University College London, UK
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Shi J, Wen K, Mui S, Li H, Liao H, He C, Yan Y, Zhou Z, Xiao Z. Integrated analysis reveals an aspartate metabolism-related gene signature for predicting the overall survival in patients with hepatocellular carcinoma. Clin Transl Oncol 2024; 26:2181-2197. [PMID: 38472558 DOI: 10.1007/s12094-024-03431-6] [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: 01/27/2024] [Accepted: 02/28/2024] [Indexed: 03/14/2024]
Abstract
BACKGROUND Deregulating cellular metabolism is one of the prominent hallmarks of malignancy, with a critical role in tumor survival and growth. However, the role of reprogramming aspartate metabolism in hepatocellular carcinoma (HCC) are largely unknown. METHODS The multi-omics data of HCC patients were downloaded from public databases. Univariate and multivariate stepwise Cox regression were used to establish an aspartate metabolism-related gene signature (AMGS) in HCC. The Kaplan-Meier and receiver operating characteristic curve analyses were performed to evaluate the predictive ability for overall survival (OS) in HCC patients. Gene set enrichment analysis and immune infiltration analysis were operated to determine the potential mechanisms underlying the AMGS. Single-cell RNA sequencing (scRNA-seq) data of liver cancer stem cells were visualized by t-SNE algorithm. In vivo and in vitro experiments were implemented to investigate the biological function of CAD in HCC. In addition, a nomogram based on the AMGS and clinicopathologic characteristics was constructed by univariate and multivariate Cox regression analyses. RESULTS Patients in the high-AMGS subgroup exerted advanced tumor status and poor prognosis. Mechanistically, the high-AMGS subgroup patients had significantly enhanced proliferation and stemness-related pathways, increased infiltration of regulatory T cells and upregulated expression levels of suppressive immune checkpoints in the tumor immune microenvironment. Notably, scRNA-seq data revealed CAD, one of the aspartate metabolism-related gene, is significantly upregulated in liver cancer stem cells. Silencing CAD inhibited proliferative capacity and stemness properties of HCC cells in vitro and in vivo. Finally, a novel nomogram based on the AMGS showed an accurate prediction in HCC patients. CONCLUSIONS The AMGS represents a promising prognostic value for HCC patients, providing a perspective for finding novel biomarkers and therapeutic targets for HCC.
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Affiliation(s)
- Juanyi Shi
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, Guangdong, China
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, Guangdong, China
- Guangdong Province Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, Guangdong, China
| | - Kai Wen
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, Guangdong, China
- Guangdong Province Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, Guangdong, China
| | - Sintim Mui
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, Guangdong, China
- Guangdong Province Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, Guangdong, China
| | - Huoming Li
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, Guangdong, China
- Guangdong Province Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, Guangdong, China
| | - Hao Liao
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, Guangdong, China
- Guangdong Province Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, Guangdong, China
| | - Chuanchao He
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, Guangdong, China
- Guangdong Province Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, Guangdong, China
| | - Yongcong Yan
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, Guangdong, China.
- Guangdong Province Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, Guangdong, China.
| | - Zhenyu Zhou
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, Guangdong, China.
- Guangdong Province Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, Guangdong, China.
| | - Zhiyu Xiao
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, Guangdong, China.
- Guangdong Province Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, Guangdong, China.
- Shenshan Medical Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Shanwei, 516621, Guangdong, China.
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11
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Liu WF, Jiang QY, Qi ZR, Zhang F, Tang WQ, Wang HQ, Dong L. CD276 Promotes an Inhibitory Tumor Microenvironment in Hepatocellular Carcinoma and is Associated with Poor Prognosis. J Hepatocell Carcinoma 2024; 11:1357-1373. [PMID: 39011124 PMCID: PMC11247130 DOI: 10.2147/jhc.s469529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Accepted: 06/19/2024] [Indexed: 07/17/2024] Open
Abstract
Background CD276 is an emerging immune checkpoint molecule that has been implicated in various cancers. However, its specific role in hepatocellular carcinoma (HCC) remains unclear. This study examined the impact of CD276 on patient prognosis and the tumor microenvironment (TME). Methods The Cancer Genome Atlas (TCGA) database was utilized to evaluate CD276 expression in HCC and the association between CD276 and immune indicators was also analyzed. The signaling pathways correlated with CD276 expression were identified by gene set enrichment analysis (GSEA). Different algorithms were used to assess immune cell infiltration. The effect of CD276 knockdown on HCC cell phenotypes and its relationship with macrophage polarization was examined using the cell counting kit 8 (CCK-8) assay and co-culture system. Results CD276 was upregulated in HCC and associated with unfavorable clinical outcomes. Hgh CD276 expression was associated with enrichment of the G2/M checkpoint, E2F targets, and mitotic spindles. CD276 expression was correlated with the infiltration of immune cells, including high level of tumor-associated macrophages and low levels of CD8+ T cells. Knockdown of CD276 decreased HCC cell proliferation and increased apoptosis. CD276 silencing in HCC cells and co-culture with THP-1-derived macrophages had a regulatory effect on macrophage polarization and macrophage-mediated cell proliferation and migration. Conclusion CD276 expression in HCC is associated with unfavorable clinical outcomes and may contribute to the development of an immunosuppressive microenvironment. Specifically, CD276 was associated with alterations in immune cell infiltration, immune marker expression, and macrophage polarization during HCC progression, suggesting its potential as a prognostic indicator and promising target for immunotherapeutic intervention in HCC.
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Affiliation(s)
- Wen-Feng Liu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
- Shanghai Institute of Liver Disease, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Qiu-Yu Jiang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
- Shanghai Institute of Liver Disease, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Zhuo-Ran Qi
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
- Shanghai Institute of Liver Disease, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Feng Zhang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
- Shanghai Institute of Liver Disease, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Wen-Qing Tang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
- Shanghai Institute of Liver Disease, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Hao-Qi Wang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
- Shanghai Institute of Liver Disease, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Ling Dong
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
- Shanghai Institute of Liver Disease, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
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12
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Rahmat JN, Liu J, Chen T, Li Z, Zhang Y. Engineered biological nanoparticles as nanotherapeutics for tumor immunomodulation. Chem Soc Rev 2024; 53:5862-5903. [PMID: 38716589 DOI: 10.1039/d3cs00602f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/05/2024]
Abstract
Biological nanoparticles, or bionanoparticles, are small molecules manufactured in living systems with complex production and assembly machinery. The products of the assembly systems can be further engineered to generate functionalities for specific purposes. These bionanoparticles have demonstrated advantages such as immune system evasion, minimal toxicity, biocompatibility, and biological clearance. Hence, bionanoparticles are considered the new paradigm in nanoscience research for fabricating safe and effective nanoformulations for therapeutic purposes. Harnessing the power of the immune system to recognize and eradicate malignancies is a viable strategy to achieve better therapeutic outcomes with long-term protection from disease recurrence. However, cancerous tissues have evolved to become invisible to immune recognition and to transform the tumor microenvironment into an immunosuppressive dwelling, thwarting the immune defense systems and creating a hospitable atmosphere for cancer growth and progression. Thus, it is pertinent that efforts in fabricating nanoformulations for immunomodulation are mindful of the tumor-induced immune aberrations that could render cancer nanotherapy inoperable. This review systematically categorizes the immunosuppression mechanisms, the regulatory immunosuppressive cellular players, and critical suppressive molecules currently targeted as breakthrough therapies in the clinic. Finally, this review will summarize the engineering strategies for affording immune moderating functions to bionanoparticles that tip the tumor microenvironment (TME) balance toward cancer elimination, a field still in the nascent stage.
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Affiliation(s)
- Juwita N Rahmat
- Department of Biomedical Engineering, College of Design and Engineering, National University of Singapore, Singapore 117585, Singapore
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore
| | - Jiayi Liu
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Taili Chen
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - ZhiHong Li
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha 410011, China
| | - Yong Zhang
- Department of Biomedical Engineering, College of Engineering, The City University of Hong Kong, Hong Kong SAR.
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13
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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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14
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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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15
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Llovet JM, Pinyol R, Yarchoan M, Singal AG, Marron TU, Schwartz M, Pikarsky E, Kudo M, Finn RS. Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma. Nat Rev Clin Oncol 2024; 21:294-311. [PMID: 38424197 PMCID: PMC11984461 DOI: 10.1038/s41571-024-00868-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/02/2024] [Indexed: 03/02/2024]
Abstract
Liver cancer, specifically hepatocellular carcinoma (HCC), is the sixth most common cancer and the third leading cause of cancer mortality worldwide. The development of effective systemic therapies, particularly those involving immune-checkpoint inhibitors (ICIs), has substantially improved the outcomes of patients with advanced-stage HCC. Approximately 30% of patients are diagnosed with early stage disease and currently receive potentially curative therapies, such as resection, liver transplantation or local ablation, which result in median overall survival durations beyond 60 months. Nonetheless, up to 70% of these patients will have disease recurrence within 5 years of resection or local ablation. To date, the results of randomized clinical trials testing adjuvant therapy in patients with HCC have been negative. This major unmet need has been addressed with the IMbrave 050 trial, demonstrating a recurrence-free survival benefit in patients with a high risk of relapse after resection or local ablation who received adjuvant atezolizumab plus bevacizumab. In parallel, studies testing neoadjuvant ICIs alone or in combination in patients with early stage disease have also reported efficacy. In this Review, we provide a comprehensive overview of the current approaches to manage patients with early stage HCC. We also describe the tumour immune microenvironment and the mechanisms of action of ICIs and cancer vaccines in this setting. Finally, we summarize the available evidence from phase II/III trials of neoadjuvant and adjuvant approaches and discuss emerging clinical trials, identification of biomarkers and clinical trial design considerations for future studies.
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Affiliation(s)
- Josep M Llovet
- Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.
- Mount Sinai Liver Cancer Program, Divisions of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.
| | - Roser Pinyol
- Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
| | - Mark Yarchoan
- Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Amit G Singal
- Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Thomas U Marron
- Mount Sinai Liver Cancer Program, Divisions of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Myron Schwartz
- Department of Liver Surgery, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Eli Pikarsky
- The Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel-Canada (IMRIC), Hebrew University-Hadassah Medical School, Jerusalem, Israel
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Richard S Finn
- Department of Medicine, Division of Hematology/Oncology, Geffen School of Medicine at UCLA, Los Angeles, CA, USA
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16
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Hou K, Xu X, Ge X, Jiang J, Ouyang F. Blockade of PD-1 and CTLA-4: A potent immunotherapeutic approach for hepatocellular carcinoma. Biofactors 2024; 50:250-265. [PMID: 37921427 DOI: 10.1002/biof.2012] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 09/07/2023] [Indexed: 11/04/2023]
Abstract
Immune checkpoints (ICPs) can promote tumor growth and prevent immunity-induced cancer cell apoptosis. Fortunately, targeting ICPs, such as programmed cell death 1 (PD-1) or cytotoxic T lymphocyte associated protein 4 (CTLA-4), has achieved great success in the past few years and has gradually become an effective treatment for cancers, including hepatocellular carcinoma (HCC). However, many patients do not respond to ICP therapy due to acquired resistance and recurrence. Therefore, clarifying the specific mechanisms of ICP in the development of HCC is very important for enhancing the efficacy of anti-PD-1 and anti-CTLA-4 therapy. In particular, antigen presentation and interferon-γ (IFN-γ) signaling were reported to be involved in the development of resistance. In this review, we have explained the role and regulatory mechanisms of ICP therapy in HCC pathology. Moreover, we have also elaborated on combinations of ICP inhibitors and other treatments to enhance the antitumor effect. Collectively, recent advances in the pharmacological targeting of ICPs provide insights for the development of a novel alternative treatment for HCC.
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Affiliation(s)
- Kai Hou
- Clinical Research Center of the Second Affiliated Hospital, University of South China, Hengyang, Hunan, PR China
| | - Xiaohui Xu
- Department of Medicine of the Second Affiliated Hospital, University of South China, Hengyang, Hunan, PR China
| | - Xin Ge
- Clinical Research Center of the Second Affiliated Hospital, University of South China, Hengyang, Hunan, PR China
| | - Jiacen Jiang
- Department of Medicine of the Second Affiliated Hospital, University of South China, Hengyang, Hunan, PR China
| | - Fan Ouyang
- Department of Cardiology, Zhuzhou Hospital, the Affiliated Hospital of Xiangya Medical College of Central South University, Zhuzhou, Hunan, PR China
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17
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Yu X, Yang F, Shen Z, Zhang Y, Sun J, Qiu C, Zheng Y, Zhao W, Yuan S, Zeng D, Zhang S, Long J, Zhu M, Zhang X, Wu J, Ma Z, Zhu H, Su M, Xu J, Li B, Mao R, Su Z, Zhang J. BTLA contributes to acute-on-chronic liver failure infection and mortality through CD4 + T-cell exhaustion. Nat Commun 2024; 15:1835. [PMID: 38418488 PMCID: PMC10901893 DOI: 10.1038/s41467-024-46047-8] [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: 11/27/2022] [Accepted: 02/08/2024] [Indexed: 03/01/2024] Open
Abstract
B- and T-lymphocyte attenuator (BTLA) levels are increased in patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). This condition is characterized by susceptibility to infection and T-cell immune exhaustion. However, whether BTLA can induce T-cell immune exhaustion and increase the risk of infection remains unclear. Here, we report that BTLA levels are significantly increased in the circulating and intrahepatic CD4+ T cells from patients with HBV-ACLF, and are positively correlated with disease severity, prognosis, and infection complications. BTLA levels were upregulated by the IL-6 and TNF signaling pathways. Antibody crosslinking of BTLA activated the PI3K-Akt pathway to inhibit the activation, proliferation, and cytokine production of CD4+ T cells while promoting their apoptosis. In contrast, BTLA knockdown promoted their activation and proliferation. BTLA-/- ACLF mice exhibited increased cytokine secretion, and reduced mortality and bacterial burden. The administration of a neutralizing anti-BTLA antibody reduced Klebsiella pneumoniae load and mortality in mice with ACLF. These data may help elucidate HBV-ACLF pathogenesis and aid in identifying novel drug targets.
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Affiliation(s)
- Xueping Yu
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, 200040, Shanghai, China.
- Department of Infectious Diseases, First Hospital of Quanzhou Affiliated to Fujian Medical University, 362000, Quanzhou, China.
| | - Feifei Yang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, 200040, Shanghai, China
| | - Zhongliang Shen
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, 200040, Shanghai, China
| | - Yao Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, 200040, Shanghai, China
| | - Jian Sun
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, 200040, Shanghai, China
| | - Chao Qiu
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, 200040, Shanghai, China
| | - Yijuan Zheng
- Department of Infectious Diseases, First Hospital of Quanzhou Affiliated to Fujian Medical University, 362000, Quanzhou, China
| | - Weidong Zhao
- Department of Laboratory Medicine, Clinical Medicine College, Dali University, 671000, Dali, China
| | - Songhua Yuan
- Shanghai Public Health Clinical Center and Institutes of Biomedical Science, Shanghai Medical College, Fudan University, 200040, Shanghai, China
| | - Dawu Zeng
- Department of Hepatology, the First Affiliated Hospital, Fujian Medical University, 350000, Fuzhou, China
| | - Shenyan Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, 200040, Shanghai, China
| | - Jianfei Long
- Department of Pharmacy, Huashan Hospital, Fudan University, 200040, Shanghai, China
| | - Mengqi Zhu
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, 200040, Shanghai, China
| | - Xueyun Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, 200040, Shanghai, China
| | - Jingwen Wu
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, 200040, Shanghai, China
| | - Zhenxuan Ma
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, 200040, Shanghai, China
| | - Haoxiang Zhu
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, 200040, Shanghai, China
| | - Milong Su
- Department of Infectious Diseases, First Hospital of Quanzhou Affiliated to Fujian Medical University, 362000, Quanzhou, China
| | - Jianqing Xu
- Shanghai Public Health Clinical Center and Institutes of Biomedical Science, Shanghai Medical College, Fudan University, 200040, Shanghai, China
| | - Bin Li
- Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, 200040, Shanghai, China
| | - Richeng Mao
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, 200040, Shanghai, China.
| | - Zhijun Su
- Department of Infectious Diseases, First Hospital of Quanzhou Affiliated to Fujian Medical University, 362000, Quanzhou, China.
| | - Jiming Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, 200040, Shanghai, China.
- Key Laboratory of Medical Molecular Virology (MOE/MOH), Shanghai Medical College, Fudan University, 200040, Shanghai, China.
- Department of Infectious Diseases, Jing'An Branch of Huashan Hospital, Fudan University, 200040, Shanghai, China.
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18
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Pan D, Liu HN, Qu PF, Ma X, Ma LY, Chen XX, Wang YQ, Qin XB, Han ZX. Progress in the treatment of advanced hepatocellular carcinoma with immune combination therapy. World J Gastrointest Oncol 2024; 16:273-286. [PMID: 38425407 PMCID: PMC10900147 DOI: 10.4251/wjgo.v16.i2.273] [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: 10/06/2023] [Revised: 12/13/2023] [Accepted: 01/08/2024] [Indexed: 02/02/2024] Open
Abstract
Advanced hepatocellular carcinoma (HCC) is a severe malignancy that poses a serious threat to human health. Owing to challenges in early diagnosis, most patients lose the opportunity for radical treatment when diagnosed. Nonetheless, recent advancements in cancer immunotherapy provide new directions for the treatment of HCC. For instance, monoclonal antibodies against immune checkpoint inhibitors (ICIs) such as programmed cell death protein 1/death ligand-1 inhibitors and cytotoxic t-lymphocyte associated antigen-4 significantly improved the prognosis of patients with HCC. However, tumor cells can evade the immune system through various mechanisms. With the rapid development of genetic engineering and molecular biology, various new immunotherapies have been used to treat HCC, including ICIs, chimeric antigen receptor T cells, engineered cytokines, and certain cancer vaccines. This review summarizes the current status, research progress, and future directions of different immunotherapy strategies in the treatment of HCC.
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Affiliation(s)
- Di Pan
- Department of Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, Jiangsu Province, China
| | - Hao-Nan Liu
- Department of Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, Jiangsu Province, China
| | - Peng-Fei Qu
- Department of Gastroenterology, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, Jiangsu Province, China
| | - Xiao Ma
- Department of Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, Jiangsu Province, China
| | - Lu-Yao Ma
- Department of Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, Jiangsu Province, China
| | - Xiao-Xiao Chen
- Department of Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, Jiangsu Province, China
| | - Yu-Qin Wang
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, Jiangsu Province, China
| | - Xiao-Bing Qin
- Department of Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, Jiangsu Province, China
| | - Zheng-Xiang Han
- Department of Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, Jiangsu Province, China
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19
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Liu S, Jia M, Dai R. Deciphering the tumour immune microenvironment of hepatocellular carcinoma. Scand J Immunol 2023; 98:e13327. [PMID: 38441331 DOI: 10.1111/sji.13327] [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: 06/06/2023] [Revised: 08/13/2023] [Accepted: 08/28/2023] [Indexed: 03/07/2024]
Abstract
Current treatments for hepatocellular carcinoma (HCC) are less effective and prone to recurrence after surgery, so it's needed to seek new ideas for its therapy. Tumour immune microenvironment (TME) is crucial for the pathogenesis, development and metastasis of HCC. Interactions between immune cells and tumour cells significantly impact responses to immunotherapies and patient prognosis. In recent years, immunotherapies for HCC have shown promising potential, but the response rate is still unsatisfactory. Understanding their cross-talks is helpful for selecting potential therapeutic targets, predicting immunotherapy responses, determining immunotherapy efficacy, identifying prognostic markers and selecting individualized treatment options. In this paper, we reviewed the research advances on the roles of immune cells and multi-omic research associated with HCC pathogenesis and therapy, and future perspectives on TME.
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Affiliation(s)
- Sha Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
- Department of Pain, Daping Hospital, Army Medical University, Chongqing, China
| | - Man Jia
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Rongyang Dai
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
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20
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Schrodt MV, Behan-Bush RM, Liszewski JN, Humpal-Pash ME, Boland LK, Scroggins SM, Santillan DA, Ankrum JA. Efferocytosis of viable versus heat-inactivated MSC induces human monocytes to distinct immunosuppressive phenotypes. Stem Cell Res Ther 2023; 14:206. [PMID: 37592321 PMCID: PMC10433682 DOI: 10.1186/s13287-023-03443-z] [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: 02/23/2023] [Accepted: 08/07/2023] [Indexed: 08/19/2023] Open
Abstract
BACKGROUND Immunomodulation by mesenchymal stromal cells (MSCs) can occur through trophic factor mechanisms, however, intravenously infused MSCs are rapidly cleared from the body yet a potent immunotherapeutic response is still observed. Recent work suggests that monocytes contribute to the clearance of MSCs via efferocytosis, the body's natural mechanism for clearing dead and dying cells in a non-inflammatory manner. This begs the questions of how variations in MSC quality affect monocyte phenotype and if viable MSCs are even needed to elicit an immunosuppressive response. METHODS Herein, we sought to dissect MSC's trophic mechanism from their efferocytic mechanisms and determine if the viability of MSCs prior to efferocytosis influences the resultant phenotype of monocytes. We cultured viable or heat-inactivated human umbilical cord MSCs with human peripheral blood mononuclear cells for 24 h and observed changes in monocyte surface marker expression and secretion profile. To isolate the effect of efferocytosis from MSC trophic factors, we used cell separation techniques to remove non-efferocytosed MSCs before challenging monocytes to suppress T-cells or respond to inflammatory stimuli. For all experiments, viable and heat-inactivated efferocytic-licensing of monocytes were compared to non-efferocytic-licensing control. RESULTS We found that monocytes efferocytose viable and heat-inactivated MSCs equally, but only viable MSC-licensed monocytes suppress activated T-cells and suppression occurred even after depletion of residual MSCs. This provides direct evidence that monocytes that efferocytose viable MSCs are immunosuppressive. Further characterization of monocytes after efferocytosis showed that uptake of viable-but not heat inactivated-MSC resulted in monocytes secreting IL-10 and producing kynurenine. When monocytes were challenged with LPS, IL-2, and IFN-γ to simulate sepsis, monocytes that had efferocytosed viable MSC had higher levels of IDO while monocytes that efferocytosed heat inactivated-MSCs produced the lowest levels of TNF-α. CONCLUSION Collectively, these studies show that the quality of MSCs efferocytosed by monocytes polarize monocytes toward distinctive immunosuppressive phenotypes and highlights the need to tailor MSC therapies for specific indications.
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Affiliation(s)
- Michael V Schrodt
- Roy J. Carver Department of Biomedical Engineering, University of Iowa, Iowa City, IA, 52245, USA
- Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA, 52245, USA
| | - Riley M Behan-Bush
- Roy J. Carver Department of Biomedical Engineering, University of Iowa, Iowa City, IA, 52245, USA
- Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA, 52245, USA
| | - Jesse N Liszewski
- Roy J. Carver Department of Biomedical Engineering, University of Iowa, Iowa City, IA, 52245, USA
- Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA, 52245, USA
| | - Madeleine E Humpal-Pash
- Roy J. Carver Department of Biomedical Engineering, University of Iowa, Iowa City, IA, 52245, USA
- Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA, 52245, USA
| | - Lauren K Boland
- Roy J. Carver Department of Biomedical Engineering, University of Iowa, Iowa City, IA, 52245, USA
- Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA, 52245, USA
| | - Sabrina M Scroggins
- Department of Obstetrics and Gynecology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
- Center for Immunology and Immune Based Diseases, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
- Department of Biomedical Sciences, Center for Immunology, Center for Clinical and Translational Science, University of Minnesota School of Medicine, Duluth, MN, USA
| | - Donna A Santillan
- Department of Obstetrics and Gynecology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
- Center for Immunology and Immune Based Diseases, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
- Department of Biomedical Sciences, Center for Immunology, Center for Clinical and Translational Science, University of Minnesota School of Medicine, Duluth, MN, USA
| | - James A Ankrum
- Roy J. Carver Department of Biomedical Engineering, University of Iowa, Iowa City, IA, 52245, USA.
- Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA, 52245, USA.
- , 103 S. Capitol St., 5621 SC, Iowa City, IA, 52242, USA.
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21
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Zhang GP, Xie ZL, Jiang J, Zhao YT, Lei K, Lin ZL, Chen SL, Su TH, Tan L, Peng S, Wang J, Liu C, Kuang M. Mechanical confinement promotes heat resistance of hepatocellular carcinoma via SP1/IL4I1/AHR axis. Cell Rep Med 2023; 4:101128. [PMID: 37478857 PMCID: PMC10439175 DOI: 10.1016/j.xcrm.2023.101128] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 03/10/2023] [Accepted: 06/23/2023] [Indexed: 07/23/2023]
Abstract
Mechanical stress can modulate the fate of cells in both physiological and extreme conditions. Recurrence of tumors after thermal ablation, a radical therapy for many cancers, indicates that some tumor cells can endure temperatures far beyond physiological ones. This unusual heat resistance with unknown mechanisms remains a key obstacle to fully realizing the clinical potential of thermal ablation. By developing a 3D bioprinting-based thermal ablation system, we demonstrate that hepatocellular carcinoma (HCC) cells in this 3D model exhibit enhanced heat resistance as compared with cells on plates. Mechanistically, the activation of transcription factor SP1 under mechanical confinement enhances the transcription of Interleukin-4-Induced-1, which catalyzes tryptophan metabolites to activate the aryl hydrocarbon receptor (AHR), leading to heat resistance. Encouragingly, the AHR inhibitor prevents HCC recurrence after thermal ablation. These findings reveal a previously unknown role of mechanical confinement in heat resistance and provide a rationale for AHR inhibitors as neoadjuvant therapy.
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Affiliation(s)
- Guo-Pei Zhang
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
| | - Zong-Lin Xie
- Department of Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
| | - Juan Jiang
- Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
| | - Yu-Tong Zhao
- Department of Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
| | - Kai Lei
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
| | - Zhi-Long Lin
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
| | - Shu-Ling Chen
- Division of Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Tian-Hong Su
- Department of Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
| | - Li Tan
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
| | - Sui Peng
- Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; Clinical Trials Unit, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
| | - Ji Wang
- Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.
| | - Chun Liu
- Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Guangzhou 510080, China.
| | - Ming Kuang
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.
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22
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Guerra P, Martini A, Pontisso P, Angeli P. Novel Molecular Targets for Immune Surveillance of Hepatocellular Carcinoma. Cancers (Basel) 2023; 15:3629. [PMID: 37509293 PMCID: PMC10377787 DOI: 10.3390/cancers15143629] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 07/06/2023] [Accepted: 07/11/2023] [Indexed: 07/30/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a common and aggressive cancer with a high mortality rate. The incidence of HCC is increasing worldwide, and the lack of effective screening programs often results in delayed diagnosis, making it a challenging disease to manage. Immunotherapy has emerged as a promising treatment option for different kinds of cancers, with the potential to stimulate the immune system to target cancer cells. However, the current immunotherapeutic approaches for HCC have shown limited efficacy. Since HCC arises within a complex tumour microenvironment (TME) characterized by the presence of various immune and stromal cell types, the understanding of this interaction is crucial for the identification of effective therapy. In this review, we highlight recent advances in our understanding of the TME of HCC and the immune cells involved in anti-tumour responses, including the identification of new possible targets for immunotherapy. We illustrate a possible classification of HCC based on the tumour immune infiltration and give evidence about the role of SerpinB3, a serine protease inhibitor involved in the regulation of the immune response in different cancers.
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Affiliation(s)
- Pietro Guerra
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine (DIMED), University of Padova, 35122 Padova, Italy
| | - Andrea Martini
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine (DIMED), University of Padova, 35122 Padova, Italy
| | - Patrizia Pontisso
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine (DIMED), University of Padova, 35122 Padova, Italy
| | - Paolo Angeli
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine (DIMED), University of Padova, 35122 Padova, Italy
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23
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Jiang D, Ma X, Zhang X, Cheng B, Wang R, Liu Y, Zhang X. New techniques: a roadmap for the development of HCC immunotherapy. Front Immunol 2023; 14:1121162. [PMID: 37426674 PMCID: PMC10323423 DOI: 10.3389/fimmu.2023.1121162] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Accepted: 06/09/2023] [Indexed: 07/11/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. The absence of effective early diagnostic methods and the limitations of conventional therapies have led to a growing interest in immunotherapy as a novel treatment approach for HCC. The liver serves as an immune organ and a recipient of antigens from the digestive tract, creating a distinctive immune microenvironment. Key immune cells, including Kupffer cells and cytotoxic T lymphocytes, play a crucial role in HCC development, thus offering ample research opportunities for HCC immunotherapy. The emergence of advanced technologies such as clustered regularly interspaced short palindromic repeats (CRISPR) and single-cell ribonucleic acid sequencing has introduced new biomarkers and therapeutic targets, facilitating early diagnosis and treatment of HCC. These advancements have not only propelled the progress of HCC immunotherapy based on existing studies but have also generated new ideas for clinical research on HCC therapy. Furthermore, this review analysed and summarised the combination of current therapies for HCC and the improvement of CRISPR technology for chimeric antigen receptor T cell therapy, instilling renewed hope for HCC treatment. This review comprehensively explores the advancements in immunotherapy for HCC, focusing on the use of new techniques.
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24
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Brandi N, Renzulli M. The Synergistic Effect of Interventional Locoregional Treatments and Immunotherapy for the Treatment of Hepatocellular Carcinoma. Int J Mol Sci 2023; 24:ijms24108598. [PMID: 37239941 DOI: 10.3390/ijms24108598] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 05/05/2023] [Accepted: 05/08/2023] [Indexed: 05/28/2023] Open
Abstract
Immunotherapy has remarkably revolutionized the management of advanced HCC and prompted clinical trials, with therapeutic agents being used to selectively target immune cells rather than cancer cells. Currently, there is great interest in the possibility of combining locoregional treatments with immunotherapy for HCC, as this combination is emerging as an effective and synergistic tool for enhancing immunity. On the one hand, immunotherapy could amplify and prolong the antitumoral immune response of locoregional treatments, improving patients' outcomes and reducing recurrence rates. On the other hand, locoregional therapies have been shown to positively alter the tumor immune microenvironment and could therefore enhance the efficacy of immunotherapy. Despite the encouraging results, many unanswered questions still remain, including which immunotherapy and locoregional treatment can guarantee the best survival and clinical outcomes; the most effective timing and sequence to obtain the most effective therapeutic response; and which biological and/or genetic biomarkers can be used to identify patients likely to benefit from this combined approach. Based on the current reported evidence and ongoing trials, the present review summarizes the current application of immunotherapy in combination with locoregional therapies for the treatment of HCC, and provides a critical evaluation of the current status and future directions.
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Affiliation(s)
- Nicolò Brandi
- Department of Radiology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, 40138 Bologna, Italy
| | - Matteo Renzulli
- Department of Radiology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, 40138 Bologna, Italy
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25
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Nikoo M, Hassan ZF, Mardasi M, Rostamnezhad E, Roozbahani F, Rahimi S, Mohammadi J. Hepatocellular carcinoma (HCC) immunotherapy by anti-PD-1 monoclonal antibodies: A rapidly evolving strategy. Pathol Res Pract 2023; 247:154473. [PMID: 37207558 DOI: 10.1016/j.prp.2023.154473] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 04/16/2023] [Accepted: 04/18/2023] [Indexed: 05/21/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the deadliest cancers in the world, with a high relapse rate. Delayed symptom onset observed in 70-80% of patients leads to diagnosis in advanced stages commonly associated with chronic liver disease. Programmed cell death protein 1 (PD-1) blockade therapy has recently emerged as a promising therapeutic option in the clinical management of several advanced malignancies, including HCC, due to the activation of exhausted tumor-infiltrating lymphocytes and improved outcomes of T-cell function. However, many people with HCC do not respond to PD-1 blockade therapy, and the diversity of immune-related adverse events (irAEs) restricts their clinical utility. Therefore, numerous effective combinatory strategies, including combinations with anti-PD-1 antibodies and other therapeutic methods ranging from chemotherapy to targeted therapies, are evolving to improve therapeutic outcomes and evoke synergistic anti-tumor impressions in patients with advanced HCC. Unfortunately, combined therapy may have more side effects than single-agent treatment. Nonetheless, identifying appropriate predictive biomarkers can aid in managing potential immune-related adverse events by distinguishing patients who respond best to PD-1 inhibitors as single agents or in combination strategies. In the present review, we summarize the therapeutic potential of PD-1 blockade therapy for advanced HCC patients. Besides, a glimpse of the pivotal predictive biomarkers influencing a patient's response to anti-PD-1 antibodies will be provided.
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Affiliation(s)
- Marzieh Nikoo
- Department of Immunology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | | | - Mahsa Mardasi
- Biotechnology Department, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University G. C., Evin, Tehran, Iran
| | - Elmira Rostamnezhad
- Department of Molecular Genetics, Faculty of Advanced Science and Technology, Tehran Medical Science, Islamic Azad University, Tehran, Iran
| | - Fatemeh Roozbahani
- Department of Microbiology and Virology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Sahel Rahimi
- Industrial and Environmental Biotechnology Department, National Institute of Genetic Engineering and Biotechnology(NIGEB), Tehran, Iran
| | - Javad Mohammadi
- Department of Life Science Engineering, Faculty of New Sciences and Technologies, University of Tehran, Tehran, Iran.
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26
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Ozer M, Goksu SY, Akagunduz B, George A, Sahin I. Adoptive Cell Therapy in Hepatocellular Carcinoma: A Review of Clinical Trials. Cancers (Basel) 2023; 15:1808. [PMID: 36980692 PMCID: PMC10046758 DOI: 10.3390/cancers15061808] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 03/10/2023] [Accepted: 03/15/2023] [Indexed: 03/19/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Immune checkpoint inhibitors (ICIs) have become the new reference standard in first-line HCC treatment, replacing tyrosine kinase inhibitors (TKIs) such as sorafenib. Many clinical trials with different combinations are already in development to validate novel immunotherapies for the treatment of patients with HCC. Adoptive cell therapy (ACT), also known as cellular immunotherapy, with chimeric antigen receptors (CAR) or gene-modified T cells expressing novel T cell receptors (TCR) may represent a promising alternative approach to modify the immune system to recognize tumor cells with better clinical outcomes. In this review, we briefly discuss the overview of ACT as a promising treatment modality in HCC, along with recent updates of ongoing clinical trials.
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Affiliation(s)
- Muhammet Ozer
- Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Suleyman Yasin Goksu
- Division of Hematology and Oncology, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Baran Akagunduz
- Department of Medical Oncology, School of Medicine, Erzincan Binali Yildirim University, Erzincan 24100, Turkey
| | - Andrew George
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University, Providence, RI 02915, USA
- Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI 02915, USA
- Legorreta Cancer Center, The Warren Alpert Medical School, Brown University, Providence, RI 02915, USA
| | - Ilyas Sahin
- Division of Hematology and Oncology, Department of Medicine, University of Florida, Gainesville, FL 32608, USA
- University of Florida Health Cancer Center, Gainesville, FL 32608, USA
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27
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Luo YZ, Zhu H. Immunotherapy for advanced or recurrent hepatocellular carcinoma. World J Gastrointest Oncol 2023; 15:405-424. [PMID: 37009314 PMCID: PMC10052663 DOI: 10.4251/wjgo.v15.i3.405] [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: 09/18/2022] [Revised: 02/11/2023] [Accepted: 02/28/2023] [Indexed: 03/14/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is associated with high morbidity and mortality, and is prone to intra- and extrahepatic metastasis due to the anatomical and functional characteristics of the liver. Due to the complexity and high relapse rate associated with radical surgery or radiofrequency ablation, immune checkpoint inhibitors (ICIs) are increasingly being used to treat HCC. Several immunotherapeutic agents, along with their combinations, have been clinically approved to treat advanced or recurrent HCC. This review discusses the leading ICIs in practice and those currently undergoing randomized phase 1–3 trials as monotherapy or combination therapy. Furthermore, we summarize the rapidly developing alternative strategies such as chimeric antigen receptor-engineered T cell therapy and tumor vaccines. Combination therapy is a promising potential treatment option. These immunotherapies are also summarized in this review, which provides insights into the advantages, limitations, and novel angles for future research in establishing viable and alternative therapies against HCC.
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Affiliation(s)
- Ying-Zhe Luo
- Department of Medical Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610075, Sichuan Province, China
| | - Hong Zhu
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
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28
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Zhang J, Hu C, Xie X, Qi L, Li C, Li S. Immune Checkpoint Inhibitors in HBV-Caused Hepatocellular Carcinoma Therapy. Vaccines (Basel) 2023; 11:vaccines11030614. [PMID: 36992198 DOI: 10.3390/vaccines11030614] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 02/28/2023] [Accepted: 03/06/2023] [Indexed: 03/11/2023] Open
Abstract
Hepatitis B virus (HBV) infection is the main risk factor for the development of hepatocellular carcinoma (HCC), the most common type of liver cancer, with high incidence and mortality worldwide. Surgery, liver transplantation, and ablation therapies have been used to treat early HBV-caused HCC (HBV-HCC); meanwhile, in the advanced stage, chemoradiotherapy and drug-targeted therapy are regularly considered, but with limited efficacy. Recently, immunotherapies, such as tumor vaccine therapy, adoptive cell transfer therapy, and immune checkpoint inhibitor therapy, have demonstrated promising efficacy in cancer treatment. In particular, immune checkpoint inhibitors can successfully prevent tumors from achieving immune escape and promote an anti-tumor response, thereby boosting the therapeutic effect in HBV-HCC. However, the advantages of immune checkpoint inhibitors in the treatment of HBV-HCC remain to be exploited. Here, we describe the basic characteristics and development of HBV-HCC and introduce current treatment strategies for HBV-HCC. Of note, we review the principles of immune checkpoint molecules, such as programmed cell death protein 1(PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) in HBV-HCC, as well as related inhibitors being considered in the clinic. We also discuss the benefits of immune checkpoint inhibitors in the treatment of HBV-HCC and the efficacy of those inhibitors in HCC with various etiologies, aiming to provide insights into the use of immune checkpoint inhibitors for the treatment of HBV-HCC.
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Affiliation(s)
- Jin Zhang
- School of Medicine, Chongqing University, Chongqing 400044, China
| | - Changwei Hu
- School of Medicine, Chongqing University, Chongqing 400044, China
| | - Xiaoxiao Xie
- School of Medicine, Chongqing University, Chongqing 400044, China
| | - Linzhi Qi
- School of Medicine, Chongqing University, Chongqing 400044, China
| | - Chuanzhou Li
- Department of Medical Genetics, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Shangze Li
- School of Medicine, Chongqing University, Chongqing 400044, China
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29
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Chen C, Wang Z, Ding Y, Qin Y. Tumor microenvironment-mediated immune evasion in hepatocellular carcinoma. Front Immunol 2023; 14:1133308. [PMID: 36845131 PMCID: PMC9950271 DOI: 10.3389/fimmu.2023.1133308] [Citation(s) in RCA: 97] [Impact Index Per Article: 48.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 02/02/2023] [Indexed: 02/12/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is the third leading cause of tumor-related mortality worldwide. In recent years, the emergency of immune checkpoint inhibitor (ICI) has revolutionized the management of HCC. Especially, the combination of atezolizumab (anti-PD1) and bevacizumab (anti-VEGF) has been approved by the FDA as the first-line treatment for advanced HCC. Despite great breakthrough in systemic therapy, HCC continues to portend a poor prognosis owing to drug resistance and frequent recurrence. The tumor microenvironment (TME) of HCC is a complex and structured mixture characterized by abnormal angiogenesis, chronic inflammation, and dysregulated extracellular matrix (ECM) remodeling, collectively contributing to the immunosuppressive milieu that in turn prompts HCC proliferation, invasion, and metastasis. The tumor microenvironment coexists and interacts with various immune cells to maintain the development of HCC. It is widely accepted that a dysfunctional tumor-immune ecosystem can lead to the failure of immune surveillance. The immunosuppressive TME is an external cause for immune evasion in HCC consisting of 1) immunosuppressive cells; 2) co-inhibitory signals; 3) soluble cytokines and signaling cascades; 4) metabolically hostile tumor microenvironment; 5) the gut microbiota that affects the immune microenvironment. Importantly, the effectiveness of immunotherapy largely depends on the tumor immune microenvironment (TIME). Also, the gut microbiota and metabolism profoundly affect the immune microenvironment. Understanding how TME affects HCC development and progression will contribute to better preventing HCC-specific immune evasion and overcoming resistance to already developed therapies. In this review, we mainly introduce immune evasion of HCC underlying the role of immune microenvironment, describe the dynamic interaction of immune microenvironment with dysfunctional metabolism and the gut microbiome, and propose therapeutic strategies to manipulate the TME in favor of more effective immunotherapy.
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Affiliation(s)
| | | | | | - Yanru Qin
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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30
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Moudi B, Mohades MR, Mahmoudzadeh-Sagheb H, Heidari Z. Immunohistochemical expression of CB1 receptors in the liver of patients with HBV related-HCC. Arab J Gastroenterol 2023; 24:34-39. [PMID: 36379858 DOI: 10.1016/j.ajg.2022.10.002] [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: 05/12/2021] [Revised: 08/20/2022] [Accepted: 10/14/2022] [Indexed: 11/15/2022]
Abstract
BACKGROUND AND AIMS The most common cause of hepatocellular carcinoma (HCC), which has a high death rate, is hepatitis B virus (HBV) infection. This study aimed to examine immunoexpression of CB1 receptors in the livers of patients with HBV-related HCC in comparison with HCC and chronic HBV as well as healthy people. Patients and methods Participants in this case-controlled study were patients with only HBV (HBV; 40), only HCC (HCC; 41), and HBV-related HCC (HBV + HCC; 40) and a healthy control group (C; 30). Tissue expression of CB1 at the protein level was studied using immunohistochemical methods. RESULTS All groups were significantly different in terms of expression of CB1 protein (P < 0.001). The expression levels of CB1 in the liver tissue of the HBV and C groups were not significantly different (P = 0.072). The expression levels of CB1 in the liver tissue of the HBV-related HCC and HCC groups had a statistically significant increase compared to the C and HBV groups (P < 0.001). Also, the CB1 expression levels in the liver tissues of HBV-related HCC and HCC groups were significantly different (P = 0.008). The sensitivity and specificity of immunohistochemistry tests in the diagnosis of HCC using CB1 were 63.4 and 91.2, respectively. Positive and negative predictive values were 90.0 % and 65.1 %, respectively. There was no relationship between the expression of CB1and other clinicopathological variables (P < 0.05). CONCLUSION The present findings revealed a tumor promoting function of the CB1 receptor in HCC. CB1 is also a pathological valuable factor for identifying the pathway of inflammation during infection.
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Affiliation(s)
- Bita Moudi
- Infectious Disease and Tropical Medicine Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran; Department of Histology, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Mohammad-Reza Mohades
- Department of Histology, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Hamidreza Mahmoudzadeh-Sagheb
- Infectious Disease and Tropical Medicine Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran; Department of Histology, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Zahra Heidari
- Infectious Disease and Tropical Medicine Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran; Department of Histology, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran.
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31
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Mirza S, Penny C, Jain NK, Rawal RM. Curcumin mediated dendritic cell maturation by modulating cancer associated fibroblasts-derived exosomal miRNA-146a. J Cancer Res Ther 2023; 19:S649-S657. [PMID: 38384034 DOI: 10.4103/jcrt.jcrt_1286_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 07/20/2022] [Indexed: 02/23/2024]
Abstract
BACKGROUND Though cancer associated fibroblasts (CAFs), being a main component of tumor microenvironment (TME), are known to modulate immune response through secretion of various growth hormones, exosomes carrying miRNAs and cytokines; their effect on dendritic cells (DCs) are yet to be elucidated. Thus, aim of this study was to assess the effect of miRNAs and cytokines released by lung-CAFs and to evaluate immunomodulatory potential of curcumin on DC maturation through modulating their TME. MATERIAL AND METHODS To check the effect of CAFs derived exosomes on DC maturation, we cultured imDCs in the presence of CAFs derived conditioned media (CAFs-CM) and characterized by the presence of maturation markers CD80, CD83, CD86 and CTLA4 using qRT-PCR. Additionally, expression of miR-221, miR-222, miR-155, miR-142-3p and miR-146a was assessed to evaluate the role of epigenetic regulators on DC maturation. Likewise, cytokine profiling of CAFs-CM as well as CAFs-CM treated with curcumin was also conducted using ELISA. RESULTS Results revealed the generation of regulatory DCs which were characterized by decreased expression of maturation markers in the presence of CAFs-CM. In addition, such DCs showed higher expression of epigenetic regulator miR-146a which was positively correlated with increased expression of anti-inflammatory cytokines like IL-6, IL-10, TGF-β and decreased expression of TNF-α (pro-inflammatory). Moreover, curcumin had the potential to convert regulatory DCs generated by CAFs into mDCs, which were characterized by high expression of co-stimulatory molecules, low expression of CTLA4, lower levels of immune suppressive cytokines production and lower levels of miR-146a. CONCLUSION Collectively, these findings provide insight into understanding the immunomodulatory role of curcumin in targeting CAFs and modulating TME, thus enhancing antitumor immune response in DC based therapy.
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Affiliation(s)
- Sheefa Mirza
- Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
- Department of Life Science, School of Sciences, Gujarat University, Ahmedabad, Gujarat, India
- Division of Medicinal Chemistry and Pharmacogenomics, Department of Cancer Biology, The Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India
| | - Clement Penny
- Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Nayan K Jain
- Department of Life Science, School of Sciences, Gujarat University, Ahmedabad, Gujarat, India
| | - Rakesh M Rawal
- Department of Life Science, School of Sciences, Gujarat University, Ahmedabad, Gujarat, India
- Division of Medicinal Chemistry and Pharmacogenomics, Department of Cancer Biology, The Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India
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Zulaziz N, Chai SJ, Lim KP. The origins, roles and therapies of cancer associated fibroblast in liver cancer. Front Oncol 2023; 13:1151373. [PMID: 37035187 PMCID: PMC10076538 DOI: 10.3389/fonc.2023.1151373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 03/03/2023] [Indexed: 04/11/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common form of liver cancer. It is often preceded by chronic inflammation such as liver fibrosis and cirrhosis. Different cell types are believed to give rise to liver-specific cancer associated fibroblast (CAF), these include resident fibroblast, hepatic stellate cell, liver cancer cell, hepatic sinusoidal endothelial cell and mesenchymal stromal cell. The abundance of fibroblasts has contributed to the cancer progression, immune modulation and treatment resistance in HCC. In this review, we discussed the origins, subtypes and roles of cancer associated fibroblasts in HCC. Their specific roles in shaping the tumor microenvironment, facilitating cancer growth, and modulating different immune cell types to confer a permissive environment for cancer growth. CAF is now an attractive therapeutic target for cancer treatment, however specific therapeutic development in HCC is still lacking. Hence, we have included preclinical and clinical development of CAF-specific interventions for other cancer types in this review. However, most CAF-specific therapies have resulted in disappointing clinical outcomes, likely due to the difficulties in differentiating CAF from normal fibroblast. A thorough understanding of the characteristics and functionalities of CAF is warranted to further improve the therapeutic efficacy of anti-CAF therapies.
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Pourhamzeh M, Asadian S, Mirzaei H, Minaei A, Shahriari E, Shpichka A, Es HA, Timashev P, Hassan M, Vosough M. Novel antigens for targeted radioimmunotherapy in hepatocellular carcinoma. Mol Cell Biochem 2023; 478:23-37. [PMID: 35708866 DOI: 10.1007/s11010-022-04483-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 05/18/2022] [Indexed: 01/17/2023]
Abstract
Liver cancer is the sixth common cancer and forth cause of cancer-related death worldwide. Based on usually advanced stages of hepatocellular carcinoma (HCC) at the time of diagnosis, therapeutic options are limited and, in many cases, not effective, and typically result in the tumor recurrence with a poor prognosis. Radioimmunotherapy (RIT) offers a selective internal radiation therapy approach using beta or alpha emitting radionuclides conjugated with tumor-specific monoclonal antibodies (mAbs), or specific selective peptides. When compared to chemotherapy or radiotherapy, radiolabeled mAbs against cancer-associated antigens could provide a high therapeutic and exclusive radiation dose for cancerous cells while decreasing the exposure-induced side effects to healthy tissues. The recent advances in cancer immunotherapy, such as blockade of immune-checkpoint inhibitors (ICIs), has changed the landscape of cancer therapy, and the efficacy of different classes of immunotherapy has been tested in many clinical trials. Taking into account the use of ICIs in the liver tumor microenvironment, combined therapies with different approaches may enhance the outcome in the future clinical studies. With the development of novel immunotherapy treatment options in the recent years, there has been a great deal of information about combining the diverse treatment modalities to boost the effectiveness of immunomodulatory drugs. In this opinion review, we will discuss the recent advancements in RIT. The current status of immunotherapy and internal radiotherapy will be updated, and we will propose novel approaches for the combination of both techniques. Potential target antigens for radioimmunotherapy in Hepatocellular carcinoma (HCC). HCC radioimmunotherapy target antigens are the most specific and commonly accessible antigens on the surface of HCC cells. CTLA-4 ligand and receptor, TAMs, PD-1/PD-L, TIM-3, specific IEXs/TEXs, ROBO1, and cluster of differentiation antigens CD105, CD147 could all be used in HCC radioimmunotherapy. Abbreviations: TAMs, tumor-associated macrophages; CTLA-4, cytotoxic T-lymphocyte associated antigen-4; PD-1, Programmed cell death protein 1; PD-L, programmed death-ligand1; TIM-3, T-cell immunoglobulin (Ig) and mucin-domain containing protein-3; IEXs, immune cell-derived exosomes; TEXs, tumor-derived exosomes.
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Affiliation(s)
- Mahsa Pourhamzeh
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.,Departments of Pathology and Medicine, UC San Diego, La Jolla, CA, USA
| | - Samieh Asadian
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Azita Minaei
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Diseases, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Elahe Shahriari
- Departments of Pathology and Medicine, UC San Diego, La Jolla, CA, USA
| | - Anastasia Shpichka
- World-Class Research Center "Digital Biodesign and Personalized Healthcare", Sechenov First Moscow State Medical University, Moscow, Russia.,Institute for Regenerative Medicine, Sechenov First Moscow State Medical University, Moscow, Russia.,Chemistry Department, Lomonosov Moscow State University, Moscow, Russia
| | | | - Peter Timashev
- World-Class Research Center "Digital Biodesign and Personalized Healthcare", Sechenov First Moscow State Medical University, Moscow, Russia. .,Institute for Regenerative Medicine, Sechenov First Moscow State Medical University, Moscow, Russia. .,Chemistry Department, Lomonosov Moscow State University, Moscow, Russia.
| | - Moustapha Hassan
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran. .,Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.
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Khanam A, Kottilil S. New Therapeutics for HCC: Does Tumor Immune Microenvironment Matter? Int J Mol Sci 2022; 24:ijms24010437. [PMID: 36613878 PMCID: PMC9820509 DOI: 10.3390/ijms24010437] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 12/21/2022] [Accepted: 12/22/2022] [Indexed: 12/28/2022] Open
Abstract
The incidence of liver cancer is continuously rising where hepatocellular carcinoma (HCC) remains the most common form of liver cancer accounting for approximately 80-90% of the cases. HCC is strongly prejudiced by the tumor microenvironment and being an inflammation-associated condition, the contribution of various immune mechanisms is critical in its development, progression, and metastasis. The tumor immune microenvironment is initially inflammatory which is subsequently replenished by the immunosuppressive cells contributing to tumor immune escape. Regardless of substantial advancement in systemic therapy, HCC has poor prognosis and outcomes attributed to the drug resistance, recurrence, and its metastatic behavior. Therefore, currently, new immunotherapeutic strategies are extensively targeted in preclinical and clinical settings in order to elicit robust HCC-specific immune responses and appear to be quite effective, extending current treatment alternatives. Understanding the complex interplay between the tumor and the immune cells and its microenvironment will provide new insights into designing novel immunotherapeutics to overcome existing treatment hurdles. In this review, we have provided a recent update on immunological mechanisms associated with HCC and discussed potential advancement in immunotherapies for HCC treatment.
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Li Q, Han J, Yang Y, Chen Y. PD-1/PD-L1 checkpoint inhibitors in advanced hepatocellular carcinoma immunotherapy. Front Immunol 2022; 13:1070961. [PMID: 36601120 PMCID: PMC9806143 DOI: 10.3389/fimmu.2022.1070961] [Citation(s) in RCA: 105] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Accepted: 12/06/2022] [Indexed: 12/23/2022] Open
Abstract
Hepatocellular carcinoma (HCC) has a high prevalence and mortality rate worldwide. Sorafenib monotherapy has been the standard of first-line treatment for advanced HCC for a long time, but there are still many shortcomings. In recent years, with the deepening of research on tumor immune microenvironment, researchers have begun to explore new approaches in immunotherapy, and the introduction of immune checkpoint inhibitors has brought fundamental changes to the treatment of HCC. Programmed cell death protein 1 (PD-1) is an immune checkpoint molecule that plays an important role in down-regulating immune system function and promoting tolerance. Programmed cell death ligand 1 (PDL-1) is involved in tumor immune evasion by binding to PD-1, resulting in failure of treatment. Currently, immunotherapy targeting the PD-1/PD-L1 axis has achieved unprecedented success in HCC, but it also faces great challenges, with its low remission rate still to be solved. For most patients with HCC, the PD-1/PD-L1 pathway is not the only rate limiting factor of antitumor immunity, and blocking only the PD-1/PD-L1 axis is not enough to stimulate an effective antitumor immune response; thus, combination therapy may be a better option. In this study, changes in the immune microenvironment of HCC patients were reviewed to clarify the feasibility of anti-PD-1/PD-L1 therapy, and a series of monotherapy and combination therapy clinical trials were summarized to verify the safety and efficacy of this newly developed treatment in patients with advanced HCC. Furthermore, we focused on hyperprogressive disease and drug resistance to gain a better understanding of PD-1/PD-L1 blockade as a promising treatment.
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Affiliation(s)
- Qian Li
- Department of Anesthesiology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jingjing Han
- Department of Anesthesiology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yonglin Yang
- Department of Infectious Diseases, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, China
| | - Yu Chen
- Department of Anesthesiology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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36
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Prognostic potential and mechanism of
SORT1
and its co‐expressed genes in hepatocellular carcinoma based on integrative analysis of multiple database. PRECISION MEDICAL SCIENCES 2022. [DOI: 10.1002/prm2.12084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
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37
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de la Torre M, Sangro P, D Avola D, Sangro B. Immunotherapy in hepatocellular carcinoma. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2022; 114:663-670. [PMID: 35704367 DOI: 10.17235/reed.2022.8876/2022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Hepatocellular carcinoma is a highly prevalent tumor worldwide and when it reaches an advanced stage, few systemic treatments are available to improve the survival of these patients. However, greater knowledge about the tumor microenvironment and the role of the immune system in the control of tumor progression has allowed the development of treatments targeting immune checkpoints, which result in encouraging tumor response rates and prolonged survival. Although most of these treatments are well tolerated, up to 20 % of patients may experience side effects derived from non-specific stimulation of the immune system. In the cirrhotic patient, the early diagnosis and treatment of such adverse events is particularly challenging. Therefore, the ongoing investigation on the use of these new therapies will allow us to better understand the profile of the patients who will benefit most.
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Affiliation(s)
| | | | | | - Bruno Sangro
- Hepatología, Clinica Universidad de Navarra, España
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38
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Harkus U, Wankell M, Palamuthusingam P, McFarlane C, Hebbard L. Immune checkpoint inhibitors in HCC: Cellular, molecular and systemic data. Semin Cancer Biol 2022; 86:799-815. [PMID: 35065242 DOI: 10.1016/j.semcancer.2022.01.005] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/12/2022] [Accepted: 01/17/2022] [Indexed: 01/27/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related deaths in the world, and for patients with advanced disease there are few therapeutic options available. The complex immunological microenvironment of HCC and the success of immunotherapy in several types of tumours, has raised the prospect of potential benefit for immune based therapies, such as immune checkpoint inhibitors (ICIs), in HCC. This has led to significant breakthrough research, numerous clinical trials and the rapid approval of multiple systemic drugs for HCC by regulatory bodies worldwide. Although some patients responded well to ICIs, many have failed to achieve significant benefit, while others showed unexpected and paradoxical deterioration. The aim of this review is to discuss the pathophysiology of HCC, the tumour microenvironment, key clinical trials evaluating ICIs in HCC, various resistance mechanisms to ICIs, and possible ways to overcome these impediments to improve patient outcomes.
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Affiliation(s)
- Uasim Harkus
- Townsville University Hospital, Townsville, Queensland 4811, Australia
| | - Miriam Wankell
- Department of Molecular and Cell Biology, College of Public Health, Medical and Veterinary Sciences, Australian Institute of Tropical Medicine and Health, James Cook University, Townsville, Queensland 4811, Australia
| | - Pranavan Palamuthusingam
- College of Medicine and Dentistry, James Cook University, Townsville, Queensland 4811, Australia; Townsville University Hospital, Townsville, Queensland 4811, Australia; Mater Hospital, Townsville, Queensland 4811, Australia
| | - Craig McFarlane
- Department of Molecular and Cell Biology, College of Public Health, Medical and Veterinary Sciences, Australian Institute of Tropical Medicine and Health, James Cook University, Townsville, Queensland 4811, Australia
| | - Lionel Hebbard
- Department of Molecular and Cell Biology, College of Public Health, Medical and Veterinary Sciences, Australian Institute of Tropical Medicine and Health, James Cook University, Townsville, Queensland 4811, Australia; Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, New South Wales 2145, Australia.
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Gaikwad S, Agrawal MY, Kaushik I, Ramachandran S, Srivastava SK. Immune checkpoint proteins: Signaling mechanisms and molecular interactions in cancer immunotherapy. Semin Cancer Biol 2022; 86:137-150. [PMID: 35341913 DOI: 10.1016/j.semcancer.2022.03.014] [Citation(s) in RCA: 90] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 03/17/2022] [Accepted: 03/18/2022] [Indexed: 02/06/2023]
Abstract
Immune checkpoint proteins (ICP) are currently one of the most novel and promising areas of immune-oncology research. This novel way of targeting tumor cells has shown favorable success over the past few years with some FDA approvals such as Ipilimumab, Nivolumab, Pembrolizumab etc. Currently, more than 3000 clinical trials of immunotherapeutic agents are ongoing with majority being ICPs. However, as the number of trials increase so do the challenges. Some challenges such as adverse side effects, non-specific binding on healthy tissues and absence of response in some subset populations are critical obstacles. For a safe and effective further therapeutic development of molecules targeting ICPs, understanding their mechanism at molecular level is crucial. Since ICPs are mostly membrane bound receptors, a number of downstream signaling pathways divaricate following ligand-receptor binding. Most ICPs are expressed on more than one type of immune cell populations. Further, the expression varies within a cell type. This naturally varied expression pattern adds to the difficulty of targeting specific effector immune cell types against cancer. Hence, understanding the expression pattern and cellular mechanism helps lay out the possible effect of any immunotherapy. In this review, we discuss the signaling mechanism, expression pattern among various immune cells and molecular interactions derived using interaction database analysis (BioGRID).
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Affiliation(s)
- Shreyas Gaikwad
- Department of Immunotherapeutics and Biotechnology, and Center for Tumor Immunology and Targeted Cancer Therapy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA
| | - Manas Yogendra Agrawal
- Department of Immunotherapeutics and Biotechnology, and Center for Tumor Immunology and Targeted Cancer Therapy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA
| | - Itishree Kaushik
- Department of Immunotherapeutics and Biotechnology, and Center for Tumor Immunology and Targeted Cancer Therapy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA
| | - Sharavan Ramachandran
- Department of Immunotherapeutics and Biotechnology, and Center for Tumor Immunology and Targeted Cancer Therapy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA
| | - Sanjay K Srivastava
- Department of Immunotherapeutics and Biotechnology, and Center for Tumor Immunology and Targeted Cancer Therapy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA.
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Feng H, Zhuo Y, Zhang X, Li Y, Li Y, Duan X, Shi J, Xu C, Gao Y, Yu Z. Tumor Microenvironment in Hepatocellular Carcinoma: Key Players for Immunotherapy. J Hepatocell Carcinoma 2022; 9:1109-1125. [PMID: 36320666 PMCID: PMC9618253 DOI: 10.2147/jhc.s381764] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 10/19/2022] [Indexed: 11/06/2022] Open
Abstract
Hepatocellular carcinoma (HCC) remains a serious medical therapeutic challenge as conventional curative avenues such as surgery and chemotherapy only benefit for few patients with limited tumor burden. Immunotherapy achieves clinical progress in the treatment of this prevalent malignant disease by virtue of the development of tumor immunology; however, most patients have experienced minimal or no clinical benefit in terms of overall survival. The complexity and diversity of tumor microenvironment (TME) built by immune and stromal cell subsets has been considered to be responsible for the insufficiency of immunotherapy. The advance of bioanalytical technology boosts the exploration of the composition and differentiation of these infiltrated cells, which reflect the immune state of the TME and impact the efficacy of the antitumor immune response. Targeting these cells to remodel the TME is one of the important immunotherapeutic approaches to improve HCC treatment. In this review, we focused on the role of these non-cancerous cells in the tumor progression, and elaborated their function on cancer immunotherapy when manipulating them as potential targets.
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Affiliation(s)
- Hai Feng
- Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Yunhui Zhuo
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Xuemei Zhang
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Yuyao Li
- Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Yue Li
- Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Xiangjuan Duan
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Jia Shi
- Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Chengbin Xu
- Department of Informatics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Yueqiu Gao
- Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China,Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China,Correspondence: Yueqiu Gao, Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China, Tel +86 21 20256507, Fax +86 21 20256699, Email
| | - Zhuo Yu
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China,Zhuo Yu, Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China, Tel +86 21 20256507, Fax +86 21 20256699, Email
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Ince V, Sahin TT, Akbulut S, Yilmaz S. Liver transplantation for hepatocellular carcinoma: Historical evolution of transplantation criteria. World J Clin Cases 2022; 10:10413-10427. [PMID: 36312504 PMCID: PMC9602233 DOI: 10.12998/wjcc.v10.i29.10413] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 07/27/2022] [Accepted: 08/25/2022] [Indexed: 02/05/2023] Open
Abstract
Liver transplantation (LT) for hepatocellular carcinoma is still a hot topic, and the main factor that is associated with the success of treatment is to determine the patients who will benefit from LT. Milan criteria have been defined 25 years ago and still is being used for patient selection for LT. However, in living donor LT, the Milan criteria is being extended. Current criteria for patient selection do not only consider morphologic characteristics such as tumor size and number of tumor nodules but also biologic markers that show tumor aggressiveness is also being considered. In the present review article, we have summarized all the criteria and scoring systems regarding LT for hepatocellular carcinoma. All criteria have 5-year overall survival rates that were comparable to the Milan Criteria and ranged between 60%-85%. On the other hand, it was seen that the recurrence rates had increased as the Milan criteria were exceeded; the 5-year recurrence rates ranged between 4.9% to 39.9%. Treatment of hepatocellular carcinoma needs a multidisciplinary approach. Ideal selection criteria are yet to be discovered. The same is true for treatment modalities. The goal will be achieved by a harmonic interplay between basic science researchers and clinicians.
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Affiliation(s)
- Volkan Ince
- Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya 44280, Turkey
| | - Tevfik Tolga Sahin
- Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya 44280, Turkey
| | - Sami Akbulut
- Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya 44280, Turkey
- Biostatistics and Medical Informatics, Inonu University Faculty of Medicine, Malatya 44280, Turkey
| | - Sezai Yilmaz
- Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya 44280, Turkey
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42
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Zhu Y, Qin LX. Strategies for improving the efficacy of immunotherapy in hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int 2022; 21:420-429. [PMID: 35977874 DOI: 10.1016/j.hbpd.2022.08.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 08/02/2022] [Indexed: 02/05/2023]
Abstract
Primary liver cancer, mainly hepatocellular carcinoma (HCC), is the sixth most diagnosed cancer and third leading cause of cancer-related death globally. Recently, immunotherapies such as immune checkpoint inhibitors (ICIs) have made great progress in the systemic treatment of HCC. However, anti-PD-1 therapy with pembrolizumab or nivolumab as a single agent did not meet their predefined end points of overall survival in the KEYNOTE-240 and CheckMate 459 trials. It is urgent to understand the immunological rationale and explore novel ways to improve the efficacy of immunotherapy. The combination of ICIs with other therapies, such as tyrosine kinase inhibitors (TKIs), monoclonal antibodies, or local therapy, has been demonstrated to improve overall response rate and survival. In addition, modulating tumor microenvironment is a potential way to overcome the primary and secondary resistance to immunotherapies. In this review, we summarized the latest findings in the immune microenvironment, the mechanisms of their synergistic effects when combined with anti-VEGF agents or TKIs, as well as other kinds of immune treatment.
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Affiliation(s)
- Ying Zhu
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai 200040, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Lun-Xiu Qin
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai 200040, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
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43
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Liu Z, Zhou Z, Dang Q, Xu H, Lv J, Li H, Han X. Immunosuppression in tumor immune microenvironment and its optimization from CAR-T cell therapy. Am J Cancer Res 2022; 12:6273-6290. [PMID: 36168626 PMCID: PMC9475465 DOI: 10.7150/thno.76854] [Citation(s) in RCA: 73] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 08/17/2022] [Indexed: 11/17/2022] Open
Abstract
Chimeric antigen receptor (CAR)-T cell therapy represents a landmark advance in personalized cancer treatment. CAR-T strategy generally engineers T cells from a specific patient with a new antigen-specificity, which has achieved considerable success in hematological malignancies, but scarce benefits in solid tumors. Recent studies have demonstrated that tumor immune microenvironment (TIME) cast a profound impact on the immunotherapeutic response. The immunosuppressive landscape of TIME is a critical obstacle to the effector activity of CAR-T cells. Nevertheless, every cloud has a silver lining. The immunosuppressive components also shed new inspiration on reshaping a friendly TIME by targeting them with engineered CARs. Herein, we summarize recent advances in disincentives of TIME and discuss approaches and technologies to enhance CAR-T cell efficacy via addressing current hindrances. Simultaneously, we firmly believe that by parsing the immunosuppressive components of TIME, rationally manipulating the complex interactions of immunosuppressive components, and optimizing CAR-T cell therapy for each patient, the CAR-T cell immunotherapy responsiveness for solid malignancies will be substantially enhanced, and novel therapeutic targets will be revealed.
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Affiliation(s)
- Zaoqu Liu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.,Interventional Institute of Zhengzhou University, Zhengzhou, Henan 450052, China.,Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, Henan 450052, China
| | - Zhaokai Zhou
- Department of Pediatric Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Qin Dang
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Hui Xu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Jinxiang Lv
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Huanyun Li
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Xinwei Han
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.,Interventional Institute of Zhengzhou University, Zhengzhou, Henan 450052, China.,Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, Henan 450052, China
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44
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Costante F, Airola C, Santopaolo F, Gasbarrini A, Pompili M, Ponziani FR. Immunotherapy for nonalcoholic fatty liver disease-related hepatocellular carcinoma: Lights and shadows. World J Gastrointest Oncol 2022; 14:1622-1636. [PMID: 36187401 PMCID: PMC9516656 DOI: 10.4251/wjgo.v14.i9.1622] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 05/05/2022] [Accepted: 07/05/2022] [Indexed: 02/05/2023] Open
Abstract
About one-fourth of adults globally suffer from nonalcoholic fatty liver disease (NAFLD), which is becoming a leading cause of chronic liver disease worldwide. Its prevalence has rapidly increased in recent years, and is projected to increase even more. NAFLD is a leading cause of hepatocellular carcinoma (HCC), the sixth-most prevalent cancer worldwide and the fourth most common cause of cancer-related death. Although the molecular basis of HCC onset in NAFLD is not completely known, inflammation is a key player. The tumor microenvironment (TME) is heterogeneous in patients with HCC, and is characterized by complex interactions between immune system cells, tumor cells and other stromal and resident liver cells. The etiology of liver disease plays a role in controlling the TME and modulating the immune response. Markers of immune suppression in the TME are associated with a poor prognosis in several solid tumors. Immunotherapy with immune checkpoint inhibitors (ICIs) has become the main option for treating cancers, including HCC. However, meta-analyses have shown that patients with NAFLD-related HCC are less likely to benefit from therapy based on ICIs alone. Conversely, the addition of an angiogenesis inhibitor showed better results regarding the objective response rate and progression-free survival. Adjunctive diagnostic and therapeutic strategies, such as the application of novel biomarkers and the modulation of gut microbiota, should be considered in the future to guide personalized medicine and improve the response to ICIs in patients with NAFLD-related HCC.
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Affiliation(s)
- Federico Costante
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma 00168, Italy
| | - Carlo Airola
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma 00168, Italy
| | - Francesco Santopaolo
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma 00168, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma 00168, Italy
- Catholic University, Largo Francesco Vito 1, 00168 Roma, Italy
| | - Maurizio Pompili
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma 00168, Italy
- Catholic University, Largo Francesco Vito 1, 00168 Roma, Italy
| | - Francesca Romana Ponziani
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma 00168, Italy
- Catholic University, Largo Francesco Vito 1, 00168 Roma, Italy
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45
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Peng H, Zhu E, Zhang Y. Advances of cancer-associated fibroblasts in liver cancer. Biomark Res 2022; 10:59. [PMID: 35971182 PMCID: PMC9380339 DOI: 10.1186/s40364-022-00406-z] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 08/01/2022] [Indexed: 12/24/2022] Open
Abstract
Liver cancer is one of the most common malignant tumors worldwide, it is ranked sixth in incidence and fourth in mortality. According to the distinct origin of malignant tumor cells, liver cancer is mainly divided into hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). Since most cases are diagnosed at an advanced stage, the prognosis of liver cancer is poor. Tumor growth depends on the dynamic interaction of various cellular components in the tumor microenvironment (TME). As the most abundant components of tumor stroma, cancer-associated fibroblasts (CAFs) have been involved in the progression of liver cancer. The interplay between CAFs and tumor cells, immune cells, or vascular endothelial cells in the TME through direct cell-to-cell contact or indirect paracrine interaction, affects the initiation and development of tumors. Additionally, CAFs are not a homogeneous cell population in liver cancer. Recently, single-cell sequencing technology has been used to help better understand the diversity of CAFs in liver cancer. In this review, we mainly update the knowledge of CAFs both in HCC and CCA, including their cell origins, chemoresistance, tumor stemness induction, tumor immune microenvironment formation, and the role of tumor cells on CAFs. Understanding the context-dependent role of different CAFs subsets provides new strategies for precise liver cancer treatment.
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Affiliation(s)
- Hao Peng
- Medical School, Southeast University, Nanjing, 210009, China
| | - Erwei Zhu
- The Second People's Hospital of Lianyungang (The Oncology Hospital of Lianyungang), Lianyungang, 222006, China
| | - Yewei Zhang
- Hepatopancreatobiliary Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210009, China.
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46
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Haque A, Sahu V, Lombardo JL, Xiao L, George B, Wolff RA, Morris JS, Rashid A, Kopchick JJ, Kaseb AO, Amin HM. Disruption of Growth Hormone Receptor Signaling Abrogates Hepatocellular Carcinoma Development. J Hepatocell Carcinoma 2022; 9:823-837. [PMID: 35996397 PMCID: PMC9391993 DOI: 10.2147/jhc.s368208] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 07/20/2022] [Indexed: 12/12/2022] Open
Abstract
Introduction Hepatocellular carcinoma (HCC) is the most common type of primary liver cancers. It is an aggressive neoplasm with dismal outcome because most of the patients present with an advanced-stage disease, which precludes curative surgical options. Therefore, these patients require systemic therapies that typically induce small improvements in overall survival. Hence, it is crucial to identify new and promising therapeutic targets for HCC to improve the current outcome. The liver is a key organ in the signaling cascade triggered by the growth hormone receptor (GHR). Previous studies have shown that GHR signaling stimulates the proliferation and regeneration of liver cells and tissues; however, a definitive role of GHR signaling in HCC pathogenesis has not been identified. Methods In this study, we used a direct and specific approach to analyze the role of GHR in HCC development. This approach encompasses mice with global (Ghr-/- ) or liver-specific (LiGhr-/- ) disruption of GHR expression, and the injection of diethylnitrosamine (DEN) to develop HCC in these mice. Results Our data show that DEN induced HCC in a substantial majority of the Ghr+/+ (93.5%) and Ghr +/- (87.1%) mice but not in the Ghr-/- (5.6%) mice (P < 0.0001). Although 57.7% of LiGhr-/- mice developed HCC after injection of DEN, these mice had significantly fewer tumors than LiGhr+/+ (P < 0.001), which implies that the expression of GHR in the liver cells might increase tumor burden. Notably, the pathologic, histologic, and biochemical characteristics of DEN-induced HCC in mice resembled to a great extent human HCC, despite the fact that etiologically this model does not mimic this cancer in humans. Our data also show that the effects of DEN on mice livers were primarily related to its carcinogenic effects and ability to induce HCC, with minimal effects related to toxic effects. Conclusion Collectively, our data support an important role of GHR in HCC development, and suggest that exploiting GHR signaling may represent a promising approach to treat HCC.
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Affiliation(s)
- Abedul Haque
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Vishal Sahu
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jamie Lynne Lombardo
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Lianchun Xiao
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Bhawana George
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Robert A Wolff
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jeffrey S Morris
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Asif Rashid
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - John J Kopchick
- Edison Biotechnology Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
| | - Ahmed O Kaseb
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hesham M Amin
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA
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47
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Ghorbaninezhad F, Masoumi J, Bakhshivand M, Baghbanzadeh A, Mokhtarzadeh A, Kazemi T, Aghebati-Maleki L, Shotorbani SS, Jafarlou M, Brunetti O, Santarpia M, Baradaran B, Silvestris N. CTLA-4 silencing in dendritic cells loaded with colorectal cancer cell lysate improves autologous T cell responses in vitro. Front Immunol 2022; 13:931316. [PMID: 35979362 PMCID: PMC9376327 DOI: 10.3389/fimmu.2022.931316] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 07/11/2022] [Indexed: 12/02/2022] Open
Abstract
Dendritic cell (DC)-based immunotherapy has increased interest among anti-cancer immunotherapies. Nevertheless, the immunosuppressive mechanisms in the tumor milieu, e.g., inhibitory immune checkpoint molecules, have been implicated in diminishing the efficacy of DC-mediated anti-tumoral immune responses. Therefore, the main challenge is to overcome inhibitory immune checkpoint molecules and provoke efficient T-cell responses to antigens specifically expressed by cancerous cells. Among the inhibitory immune checkpoints, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression on DCs diminishes their maturation and antigen presentation capability. Accordingly, we hypothesized that the expression of CTLA-4 on DCs inhibits the T cell-mediated anti-tumoral responses generated following the presentation of tumor antigens by DCs to T lymphocytes. In this study, we loaded colorectal cancer (CRC) cell lysate on DCs and inhibited the expression of CTLA-4 by small interfering RNA (siRNA) in them to investigate the DCs’ functional and phenotypical features, and T-cell mediated responses following DC/T cell co-culture. Our results demonstrated that blockade of CTLA-4 could promote stimulatory properties of DCs. In addition, CTLA-4 silenced CRC cell lysate-loaded DCs compared to the DCs without CTLA-4 silencing resulted in augmented T cell proliferation and cytokine production, i.e., IFN-γ and IL-4. Taken together, our findings suggest CTLA-4 silenced CRC cell lysate-loaded DCs as a promising therapeutic approach however further studies are needed before this strategy can be used in clinical practice.
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Affiliation(s)
- Farid Ghorbaninezhad
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javad Masoumi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Bakhshivand
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Baghbanzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ahad Mokhtarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Pharmaceutical Analysis Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Tohid Kazemi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Siamak Sandoghchian Shotorbani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahdi Jafarlou
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Oronzo Brunetti
- Medical Oncology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Tumori “Giovanni Paolo II” of Bari, Bari, Italy
| | - Mariacarmela Santarpia
- Medical Oncology Unit, Department of Human Pathology “G. Barresi”, University of Messina, Messina, Italy
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- *Correspondence: Behzad Baradaran, ; Nicola Silvestris,
| | - Nicola Silvestris
- Medical Oncology Unit, Department of Human Pathology “G. Barresi”, University of Messina, Messina, Italy
- *Correspondence: Behzad Baradaran, ; Nicola Silvestris,
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48
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Lu Y, Ma S, Ding W, Sun P, Zhou Q, Duan Y, Sartorius K. Resident Immune Cells of the Liver in the Tumor Microenvironment. Front Oncol 2022; 12:931995. [PMID: 35965506 PMCID: PMC9365660 DOI: 10.3389/fonc.2022.931995] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 06/13/2022] [Indexed: 12/30/2022] Open
Abstract
The liver is a central immunomodulator that ensures a homeostatic balance between protection and immunotolerance. A hallmark of hepatocellular carcinoma (HCC) is the deregulation of this tightly controlled immunological network. Immune response in the liver involves a complex interplay between resident innate, innate, and adaptive immune cells. The immune response in the liver is modulated by its continuous exposure to toxic molecules and microorganisms that requires a degree of immune tolerance to protect normal tissue from damage. In HCC pathogenesis, immune cells must balance a dual role that includes the elimination of malignant cells, as well as the repair of damaged liver tissue to maintain homeostasis. Immune response in the innate and adaptive immune systems extends to the cross-talk and interaction involving immune-regulating non-hematopoietic cells, myeloid immune cells, and lymphoid immune cells. In this review, we discuss the different immune responses of resident immune cells in the tumor microenvironment. Current FDA-approved targeted therapies, including immunotherapy options, have produced modest results to date for the treatment of advanced HCC. Although immunotherapy therapy to date has demonstrated its potential efficacy, immune cell pathways need to be better understood. In this review article, we summarize the roles of specific resident immune cell subsets and their cross-talk subversion in HCC pathogenesis, with a view to identifying potential new biomarkers and therapy options.
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Affiliation(s)
- Yunjie Lu
- The Third Affiliated Hospital of Soochow University, Chanozhou, China
| | - Shiying Ma
- The Third Affiliated Hospital of Soochow University, Chanozhou, China
| | - Wei Ding
- Department of General Surgery, Wujin Hospital Affiliated to Jiangsu University, Changzhou, China
| | - Pengcheng Sun
- The Third Affiliated Hospital of Soochow University, Chanozhou, China
| | - Qi Zhou
- The Third Affiliated Hospital of Soochow University, Chanozhou, China
| | - Yunfei Duan
- The Third Affiliated Hospital of Soochow University, Chanozhou, China
| | - Kurt Sartorius
- Hepatitis Diversity Research Unit, School of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa
- Africa Hepatopancreatobiliary Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, FL, United States
- University of Kwazulu-Natal Gastrointestinal Cancer Research Unit (UKZN/GICRC), Durban, South Africa
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49
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Chan SL, Wong N, Lam WKJ, Kuang M. Personalized treatment for hepatocellular carcinoma: Current status and future perspectives. J Gastroenterol Hepatol 2022; 37:1197-1206. [PMID: 35570200 DOI: 10.1111/jgh.15889] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 05/08/2022] [Indexed: 12/24/2022]
Abstract
Systemic treatment for hepatocellular carcinoma (HCC) has been advancing rapidly over the last decade. More novel agents, including both targeted agents and immune checkpoint inhibitors, are available for physicians to use sequentially or concurrently for patients with advanced HCC. Despite more options, only a proportion of patients benefit from each regimen. Therefore, clinicians are facing challenges on how to choose the right regimen for the right patient with HCC, which raises the importance of personalized treatment approach. To advance personalized treatment for HCC, one approach relies on the acquisition of biomarker data from clinical trials to evaluate clinical parameters or genotypes in association with outcomes of selected drugs. This approach has led to finding of high baseline alpha-fetoprotein levels in association with benefits of ramucirumab. Cumulative findings from multiple clinical trials and translational studies also suggest that selected etiology and/or genotype of HCC could predict resistance to immune checkpoint inhibitors. The second approach is to decipher the tumor heterogeneity of HCC with an aim to identify clinically relevant patterns to guide clinical decisions. Tumor heterogeneity could exist within a single tumor (intra-tumoral heterogeneity), among different tumors in the same patient (inter-tumoral heterogeneity) or between primary and recurrent tumors (temporal tumor heterogeneity). The analyses of tumor heterogeneity have also been powered by coverage of tumor immune environment and incorporation of circulating tumor nucleic acid technology. Emerging publications have been reported above tumor heterogeneity exist in HCC, which is potentially clinically impactful.
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Affiliation(s)
- Stephen L Chan
- Department of Clinical Oncology, Sir Y.K. Pao Centre for Cancer, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.,State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong, China
| | - Nathalie Wong
- State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong, China.,Department of Surgery at Sir Y.K. Pao Center for Cancer, The Chinese University of Hong Kong, Hong Kong, China
| | - W K Jacky Lam
- Li Ka Shing Institute of Health Sciences, Department of Chemical Pathology, The Chinese University of Hong Kong, Hong Kong, China.,Department of Chemical Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Ming Kuang
- Center of Hepatopancreatobiliary Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.,Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
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50
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Chen Y, Hu H, Yuan X, Fan X, Zhang C. Advances in Immune Checkpoint Inhibitors for Advanced Hepatocellular Carcinoma. Front Immunol 2022; 13:896752. [PMID: 35757756 PMCID: PMC9226303 DOI: 10.3389/fimmu.2022.896752] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 05/16/2022] [Indexed: 02/05/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is usually diagnosed in an advanced stage and has become the second deadliest type of cancer worldwide. The systemic treatment of advanced HCC has been a challenge, and for decades was limited to treatment with tyrosine kinase inhibitors (TKIs) until the application of immune checkpoint inhibitors (ICIs) became available. Due to drug resistance and unsatisfactory therapeutic effects of monotherapy with TKIs or ICIs, multi-ICIs, or the combination of ICIs with antiangiogenic drugs has become a novel strategy to treat advanced HCC. Antiangiogenic drugs mostly include TKIs (sorafenib, lenvatinib, regorafenib, cabozantinib and so on) and anti-vascular endothelial growth factor (VEGF), such as bevacizumab. Common ICIs include anti-programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1), including nivolumab, pembrolizumab, durvalumab, and atezolizumab, and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4), including tremelimumab and ipilimumab. Combination therapies involving antiangiogenic drugs and ICIs or two ICIs may have a synergistic action and have shown greater efficacy in advanced HCC. In this review, we present an overview of the current knowledge and recent clinical developments in ICI-based combination therapies for advanced HCC and we provide an outlook on future prospects.
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Affiliation(s)
- Yue Chen
- Department of Pathology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Haoyue Hu
- Department of Medical Oncology, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, Medicine School of University of Electronic Science and Technology, Chengdu, China
| | - Xianglei Yuan
- Department of Gastroenterology, West China Hospital of Sichuan University, Chengdu, China
| | - Xue Fan
- Department of Medical Oncology, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, Medicine School of University of Electronic Science and Technology, Chengdu, China
| | - Chengda Zhang
- Department of Gastroenterology, The Third Hospital of Mianyang (Sichuan Mental Health Center), Mianyang, China
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