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Li X, Xia F. Immunotherapy for hepatocellular carcinoma: molecular pathogenesis and clinical research progress. ONCOLOGY AND TRANSLATIONAL MEDICINE 2023. [DOI: 10.1097/ot9.0000000000000013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Abstract
The treatment of hepatocellular carcinoma (HCC) is advancing rapidly in the 21st century. Although there are various treatment methods, the most promising breakthrough seems to be in immunotherapy. Recent guidelines from the American Society of Clinical Oncology and the European Association for the Study of the Liver have recommended immunotherapies with strong antitumor effects for HCC treatment. Emerging systemic therapeutic strategies, such as immune checkpoint inhibitors combined with targeted therapy or local treatment, are among the most promising for improving overall and tumor-free survival times in patients with HCC. This review analyzes the molecular mechanisms of existing immune checkpoint inhibitors, vaccines, and chimeric antigen receptor–T cells; summarizes the latest progress in relevant clinical research; and outlines future trends and opportunities for HCC immunotherapy.
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Mohammed EE, Türkel N, Yigit UM, Dalan AB, Sahin F. Boron Derivatives Inhibit the Proliferation of Breast Cancer Cells and Affect Tumor-Specific T Cell Activity In Vitro by Distinct Mechanisms. Biol Trace Elem Res 2023; 201:5692-5707. [PMID: 36940038 DOI: 10.1007/s12011-023-03632-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Accepted: 03/11/2023] [Indexed: 03/21/2023]
Abstract
Breast cancer is the most frequently diagnosed cancer among women worldwide. Despite the initial clinical response obtained with the widely used conventional chemotherapy, an improved prognosis for breast cancer patients has been missing in the clinic because of the high toxicity to normal cells, induction of drug resistance, and the potential immunosuppressive effects of these agents. Therefore, we aimed to investigate the potential anti-carcinogenic effect of some boron derivatives (sodium pentaborate pentahydrate (SPP) and sodium perborate tetrahydrate (SPT)), which showed a promising effect on some types of cancers in the literature, on breast cancer cell lines, as well as immuno-oncological side effects on tumor-specific T cell activity. These findings suggest that both SPP and SPT suppressed proliferation and induced apoptosis in MCF7 and MDA-MB-231 cancer cell lines through downregulation of the monopolar spindle-one-binder (MOB1) protein. On the other hand, these molecules increased the expression of PD-L1 protein through their effect on the phosphorylation level of Yes-associated protein (Phospho-YAP (Ser127). In addition, they reduced the concentrations of pro-inflammatory cytokines such as IFN-γ and cytolytic effector cytokines such as sFasL, perforin, granzyme A, Granzyme B, and granulysin and increased the expression of PD-1 surface protein in activated T cells. In conclusion, SPP, SPT, and their combination could have growth inhibitory (antiproliferative) effects and could be a potential treatment for breast cancer. However, their stimulatory effects on the PD-1/PD-L1 signaling pathway and their effects on cytokines could ultimately account for the observed repression of the charging of specifically activated effector T cells against breast cancer cells.
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Affiliation(s)
- Eslam Essam Mohammed
- Department of Genetics and Bioengineering, Faculty of Engineering, Yeditepe University, Istanbul, 34755, Turkey
| | - Nezaket Türkel
- Department of Genetics and Bioengineering, Faculty of Engineering, Yeditepe University, Istanbul, 34755, Turkey
| | | | - Altay Burak Dalan
- Department of Medical Genetics, Faculty of Medicine, Yeditepe University, Istanbul, 34755, Turkey
| | - Fikrettin Sahin
- Department of Genetics and Bioengineering, Faculty of Engineering, Yeditepe University, Istanbul, 34755, Turkey.
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Sumransub N, Jirapongwattana N, Jamjuntra P, Thongchot S, Chieochansin T, Yenchitsomanus PT, Thuwajit P, Warnnissorn M, O-Charoenrat P, Thuwajit C. Breast cancer stem cell RNA-pulsed dendritic cells enhance tumor cell killing by effector T cells. Oncol Lett 2020; 19:2422-2430. [PMID: 32194742 PMCID: PMC7038997 DOI: 10.3892/ol.2020.11338] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Accepted: 12/12/2019] [Indexed: 12/18/2022] Open
Abstract
Cancer stem cells (CSCs) underpin the resistance of breast cancer (BC) cells to therapy. Dendritic cell (DC)-based treatment is efficacious and safe, but the efficiency of this technique for targeting CSCs in BC treatment requires further investigation. The present study aimed to investigate the ability of DCs pulsed with breast CSC antigens to activate effector lymphocytes for killing BC cells. CD44+/CD24− CSCs were isolated from BCA55-121, an in-house patient-derived BC cell line, and acquisition of stemness properties was confirmed by upregulated expression of OCT4A and a superior proliferative capacity in colony formation assays compared with whole population of BCA55-121 (BCA55-121-WP). DCs were differentiated from monocytes from peripheral blood of healthy donors and pulsed with CSC total RNA. Maturation of the CSC RNA-pulsed DCs was confirmed by increased expression of CD11c, CD40, CD83, CD86 and HLA-DR, as well as reduced CD14 expression compared with monocytes. Total lymphocytes co-cultured with CSC RNA-pulsed DCs were analyzed by flow cytometry for markers including CD3, CD4, CD8, CD16 and CD56. The results revealed that the co-cultures contained mostly cytotoxic CD8+ T lymphocytes followed by CD4+ T lymphocytes and smaller populations of natural killer (NK) and NKT cells. ELISA was used to measure IFN-γ production, and it was revealed that activated CD4+ and CD8+ lymphocytes produced more IFN-γ compared with naïve T cells, suggesting that CD8+ T cells were effector T cells. CSC RNA was a more efficient antigen source compared with RNA from mixed BC cells for activating tumor antigen-specific killing by T cells. These CSC-specific effector T cells significantly induced BC cell apoptosis at a 20:1 effector T cell:tumor cell ratio. Of note, the breast CSCs cultures demonstrated resistance to effector T cell killing, which was in part due to increased expression of programmed death ligand 1 in the CSC population. The present study highlights the potential use of CSC RNA for priming DCs in modulating an anticancer immune response against BC.
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Affiliation(s)
- Nuttavut Sumransub
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Niphat Jirapongwattana
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Pranisa Jamjuntra
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Suyanee Thongchot
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Thaweesak Chieochansin
- Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.,Department of Siriraj Center of Research Excellence for Cancer Immunotherapy (siCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Pa-Thai Yenchitsomanus
- Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.,Department of Siriraj Center of Research Excellence for Cancer Immunotherapy (siCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Peti Thuwajit
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Malee Warnnissorn
- Department of Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Pornchai O-Charoenrat
- Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Chanitra Thuwajit
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
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Cytolytic Activity of Effector T-lymphocytes Against Hepatocellular Carcinoma is Improved by Dendritic Cells Pulsed with Pooled Tumor Antigens. Sci Rep 2019; 9:17668. [PMID: 31776459 PMCID: PMC6881468 DOI: 10.1038/s41598-019-54087-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Accepted: 11/04/2019] [Indexed: 12/24/2022] Open
Abstract
Cellular immunotherapy is a promising new therapeutic approach for hepatocellular carcinoma (HCC), which has a high recurrence rate, irrespective of the treatment administered. In this study, we attempted to improve the cytolytic activity of effector T-lymphocytes against HCC. T-lymphocytes were activated by monocyte-derived dendritic cells (DCs) pulsed with cell lysate or RNA prepared from HCC cell lines. Monocytes were activated for differentiation into DCs by treatment with the IL4 and GM-CSF. DCs were pulsed with cell lysate or RNA prepared from a single cell line or combinations of two or three HCC cell lines, and then co-cultured with autologous T-lymphocytes with the intent of creating specific cytotoxicity. We discovered that DCs pulsed with total RNA effectuated greater T-lymphocyte function than DCs pulsed with total cell lysate, as evidenced by greater cytolytic activities against HCC target cells. The percentage of Huh7, HepG2, and SNU449 cell apoptosis at effector:target ratio of 10:1 was 42.6 ± 4.5% (p = 0.01), 33.6 ± 3.1% (p = 0.007), and 21.4 ± 1.4% (p < 0.001), respectively. DCs pulsed with pools of antigens prepared from three cell lines improved the cytolytic function of effector T-lymphocytes by approximately two-fold (p < 0.001), which suggests that this approach be further developed and applied for adoptive transfer treatment of HCC.
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Mukaida N, Nakamoto Y. Emergence of immunotherapy as a novel way to treat hepatocellular carcinoma. World J Gastroenterol 2018; 24:1839-1858. [PMID: 29740200 PMCID: PMC5937202 DOI: 10.3748/wjg.v24.i17.1839] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 04/15/2018] [Accepted: 04/23/2018] [Indexed: 02/06/2023] Open
Abstract
Tumor immunity proceeds through multiple processes, which consist of antigen presentation by antigen presenting cells (APCs) to educate effector cells and destruction by the effector cytotoxic cells. However, tumor immunity is frequently repressed at tumor sites. Malignantly transformed cells rarely survive the attack by the immune system, but cells that do survive change their phenotypes to reduce their immunogenicity. The resultant cells evade the attack by the immune system and form clinically discernible tumors. Tumor microenvironments simultaneously contain a wide variety of immune suppressive molecules and cells to dampen tumor immunity. Moreover, the liver microenvironment exhibits immune tolerance to reduce aberrant immune responses to massively-exposed antigens via the portal vein, and immune dysfunction is frequently associated with liver cirrhosis, which is widespread in hepatocellular carcinoma (HCC) patients. Immune therapy aims to reduce tumor burden, but it is also expected to prevent non-cancerous liver lesions from progressing to HCC, because HCC develops or recurs from non-cancerous liver lesions with chronic inflammatory states and/or cirrhosis and these lesions cannot be cured and/or eradicated by local and/or systemic therapies. Nevertheless, cancer immune therapy should augment specific tumor immunity by using two distinct measures: enhancing the effector cell functions such as antigen presentation capacity of APCs and tumor cell killing capacity of cytotoxic cells, and reactivating the immune system in immune-suppressive tumor microenvironments. Here, we will summarize the current status and discuss the future perspective on immune therapy for HCC.
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MESH Headings
- Antigen Presentation/genetics
- Antigens, Neoplasm/immunology
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/therapy
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/immunology
- Humans
- Immune Tolerance/genetics
- Immunotherapy/methods
- Immunotherapy/trends
- Liver/immunology
- Liver/pathology
- Liver Neoplasms/genetics
- Liver Neoplasms/immunology
- Liver Neoplasms/pathology
- Liver Neoplasms/therapy
- Lymphocyte Activation/genetics
- Neoplasm Recurrence, Local/genetics
- Neoplasm Recurrence, Local/immunology
- Neoplasm Recurrence, Local/pathology
- Neoplasm Recurrence, Local/therapy
- Tumor Microenvironment/immunology
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Affiliation(s)
- Naofumi Mukaida
- Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Ishikawa, Kanazawa 920-1192, Japan
| | - Yasunari Nakamoto
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Eiheiji-cho, Fukui 910-1193, Japan
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Cellular and molecular targets for the immunotherapy of hepatocellular carcinoma. Mol Cell Biochem 2017; 437:13-36. [PMID: 28593566 DOI: 10.1007/s11010-017-3092-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 06/01/2017] [Indexed: 02/06/2023]
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Nakamoto Y. Promising new strategies for hepatocellular carcinoma. Hepatol Res 2017; 47:251-265. [PMID: 27558453 DOI: 10.1111/hepr.12795] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Revised: 08/16/2016] [Accepted: 08/19/2016] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer death worldwide. It usually arises based on a background of chronic liver diseases, defined as the hypercarcinogenic state. The current treatment options for HCC ranging from locoregional treatments to chemotherapies, including sorafenib, effectively regulate the limited sizes and numbers of the nodules. However, these treatments remain unsatisfactory because they have insufficient antitumor effects on the large and numerous nodules associated with HCC and because of a high recurrence rate in the surrounding inflamed liver. To develop novel and promising therapies with higher antitumor effects, recent progress in identifying molecular targets and developing immunological procedures for HCC are reviewed. The molecular targets discussed include the intracellular signaling pathways of protein kinase B/mammalian target of rapamycin and RAS/RAF/mitogen-activated protein kinase, Wnt/β-catenin and glutamine synthetase, insulin-like growth factor, signal transducer and activator of transcription 3, nuclear factor-κB and telomerase reverse transcriptase, and c-MET. Immunological studies have focused mainly on target identification, T cells, natural killer cells, dendritic cells, natural killer T cells, and vaccine development.
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Affiliation(s)
- Yasunari Nakamoto
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
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Markov OV, Mironova NL, Shmendel EV, Serikov RN, Morozova NG, Maslov MA, Vlassov VV, Zenkova MA. Multicomponent mannose-containing liposomes efficiently deliver RNA in murine immature dendritic cells and provide productive anti-tumour response in murine melanoma model. J Control Release 2015; 213:45-56. [DOI: 10.1016/j.jconrel.2015.06.028] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Revised: 06/15/2015] [Accepted: 06/21/2015] [Indexed: 12/21/2022]
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