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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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2
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Fuster-Anglada C, Mauro E, Ferrer-Fàbrega J, Caballol B, Sanduzzi-Zamparelli M, Bruix J, Fuster J, Reig M, Díaz A, Forner A. Histological predictors of aggressive recurrence of hepatocellular carcinoma after liver resection. J Hepatol 2024; 81:995-1004. [PMID: 38925272 DOI: 10.1016/j.jhep.2024.06.018] [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: 10/09/2023] [Revised: 06/11/2024] [Accepted: 06/17/2024] [Indexed: 06/28/2024]
Abstract
BACKGROUND & AIMS Assessment of recurrence risk after liver resection (LR) is critical in hepatocellular carcinoma (HCC), particularly with the advent of effective adjuvant therapy. The aim of this study was to analyze the clinical and pathological factors associated with recurrence, aggressive recurrence, and survival after LR. METHOD We performed a retrospective study in which all single HCC (BCLC-0/A) patients treated with LR between February 2000 and November 2020 were included. The main clinical variables were recorded. Histological features were blindly evaluated by two independent pathologists. Aggressive recurrence was defined as those that exceeded the Milan criteria at 1st recurrence. RESULTS A total of 218 patients were included (30% BCLC 0 and 70% BCLC A), median (IQR) tumor size of 28 (19-42 mm). The prevalence of microvascular invasion and/or satellitosis (mVI/S) was 39%, with a kappa-index between both pathologists of 0.8. After a median follow-up of 49 (23-85) months, 61/218 (28%) patients died, 32/218 (15%) underwent liver transplantation, 127 (58%) developed HCC recurrence. The prevalence of aggressive recurrence was 35% (44/127 Milan-out, with 20 cases at advanced stage), and the 5-year survival rate was 81%. The presence of mVI/S was the only independent predictor of recurrence (hazard ratio [HR] 1.83, 95% CI 1.28-2.61, p <0.001), aggressive recurrence (HR 3.31, 95% CI 1.74-6.29, p <0.001) and mortality (HR 2.23, 95% CI 1.27-3.91, p = 0.005). The macrotrabecular-massive subtype was significantly associated with a higher prevalence of mVI/S, Edmonson Steiner grade III-IV, AFP values and vessels that encapsulate tumor clusters, but not with recurrence, aggressive recurrence, or overall survival. CONCLUSION The presence of mVI/S was the only independent risk factor for aggressive recurrence and mortality. This has important implications for early-stage patient management, especially in the setting of adjuvant immunotherapy or ab initio LT. IMPACT AND IMPLICATIONS Assessment of recurrence risk after liver resection is crucial in patients with hepatocellular carcinoma. Patients with a high risk of recurrence are candidates for liver transplantation as an ab initio indication or for the potential use of adjuvant therapy. Aggressive recurrences, defined as those exceeding the Milan criteria at first recurrence, have a significant impact on overall survival (OS). Fifty-eight percent of patients experienced hepatocellular carcinoma recurrence, with a prevalence of aggressive recurrence at the first occurrence standing at 35%. After a median follow-up of 49 (23-85) months, 61 (28%) patients died, and 32 (15%) underwent liver transplantation, resulting in a 5-year OS rate of 81%. Microvascular invasion and/or satellitosis was present in 39% of our cohort and was the only independent predictor of recurrence, aggressive recurrence, and OS on multivariate analysis. This is important as it could be used to guide therapeutic management.
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Affiliation(s)
- Carla Fuster-Anglada
- Pathology Department. CDB. Liver Oncology Unit. Hospital Clinic Barcelona. Barcelona. Spain; Barcelona Clinic Liver Cancer (BCLC) group. IDIBAPS. Barcelona. Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Ezequiel Mauro
- Barcelona Clinic Liver Cancer (BCLC) group. IDIBAPS. Barcelona. Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain; Liver Unit. Liver Oncology Unit. ICMDM. Hospital Clinic Barcelona. Barcelona, Spain
| | - Joana Ferrer-Fàbrega
- Barcelona Clinic Liver Cancer (BCLC) group. IDIBAPS. Barcelona. Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain; Hepatobiliopancreatic Surgery and Liver and Pancreatic Transplantation Unit, Department of Surgery. Liver Oncology Unit. ICMDM. Hospital Clinic Barcelona. Barcelona. Spain; Universitat de Barcelona, Barcelona, Spain
| | - Berta Caballol
- Liver Unit. Liver Oncology Unit. ICMDM. Hospital Clinic Barcelona. Barcelona, Spain
| | - Marco Sanduzzi-Zamparelli
- Barcelona Clinic Liver Cancer (BCLC) group. IDIBAPS. Barcelona. Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain; Liver Unit. Liver Oncology Unit. ICMDM. Hospital Clinic Barcelona. Barcelona, Spain
| | - Jordi Bruix
- Barcelona Clinic Liver Cancer (BCLC) group. IDIBAPS. Barcelona. Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain; Universitat de Barcelona, Barcelona, Spain; Liver Unit. Liver Oncology Unit. ICMDM. Hospital Clinic Barcelona. Barcelona, Spain
| | - Josep Fuster
- Barcelona Clinic Liver Cancer (BCLC) group. IDIBAPS. Barcelona. Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain; Hepatobiliopancreatic Surgery and Liver and Pancreatic Transplantation Unit, Department of Surgery. Liver Oncology Unit. ICMDM. Hospital Clinic Barcelona. Barcelona. Spain; Universitat de Barcelona, Barcelona, Spain
| | - María Reig
- Barcelona Clinic Liver Cancer (BCLC) group. IDIBAPS. Barcelona. Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain; Universitat de Barcelona, Barcelona, Spain; Liver Unit. Liver Oncology Unit. ICMDM. Hospital Clinic Barcelona. Barcelona, Spain
| | - Alba Díaz
- Pathology Department. CDB. Liver Oncology Unit. Hospital Clinic Barcelona. Barcelona. Spain; Barcelona Clinic Liver Cancer (BCLC) group. IDIBAPS. Barcelona. Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain; Universitat de Barcelona, Barcelona, Spain.
| | - Alejandro Forner
- Barcelona Clinic Liver Cancer (BCLC) group. IDIBAPS. Barcelona. Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain; Universitat de Barcelona, Barcelona, Spain; Liver Unit. Liver Oncology Unit. ICMDM. Hospital Clinic Barcelona. Barcelona, Spain.
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Kim K, Wang H, Lee J, Yeom C. Long-term tumor suppression in cholangiocarcinoma using cytokine-induced killer cell therapy and high-dose vitamin C: a case report. KOREAN JOURNAL OF CLINICAL ONCOLOGY 2024; 20:84-87. [PMID: 39778511 PMCID: PMC11717578 DOI: 10.14216/kjco.24012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 12/06/2024] [Accepted: 12/09/2024] [Indexed: 01/11/2025]
Abstract
This case study explores the effectiveness of autologous cytokine-induced killer (CIK) cell-based immunotherapy in a 49-year-old male patient with inoperable stage IIIb cholangiocarcinoma, characterized by high levels of the sodium-dependent vitamin C transporter-2 (SVCT2) in immune cells. Despite an initial lack of tumor reduction following chemotherapy, the patient showed a significant decrease in tumor markers and stabilization of the tumor after undergoing radiation and proton therapy. Subsequently, CIK cell therapy, combined with high-dose vitamin C, was administered 52 times over 6 years. The patient's tumor size reduced, and no cancer activity was detected for 7 years and 10 months post-diagnosis, indicating a successful long-term outcome without recurrence. This study suggests that CIK cell therapy, particularly in patients with elevated SVCT2 levels, may offer a promising adjuvant treatment for cholangiocarcinoma and potentially other cancers. Further research is needed to validate SVCT2 as a biomarker for the effectiveness of CIK cell therapy.
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Affiliation(s)
- Kangseok Kim
- Department of Surgery, Bangre Hospital, Incheon,
Korea
| | - Hyunhye Wang
- Department of Radiology, Bangre Hospital, Incheon,
Korea
| | - Jiewon Lee
- Department of Family Medicine, Yeom Chang Hwan Hospital, Seoul,
Korea
| | - Changhwan Yeom
- Department of Family Medicine, Yeom Chang Hwan Hospital, Seoul,
Korea
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Shin H, Lee JH. Adjuvant therapy in hepatocellular carcinoma: the IMbrave050 trial. Lancet 2024; 404:654-655. [PMID: 39153810 DOI: 10.1016/s0140-6736(24)00797-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 04/12/2024] [Indexed: 08/19/2024]
Affiliation(s)
- Hyunjae Shin
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul 03080, South Korea; Center for Liver and Pancreatobiliary Cancer, National Cancer Center, Goyang, South Korea
| | - Jeong-Hoon Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul 03080, South Korea.
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Lee HJ, Choi MS, Song BG, Kang WS, Gwak GY, Goh MJ, Paik YH, Lee JH, Sinn DH. Glycemic Burden and Clinical Outcomes of Early Stage Hepatocellular Carcinoma after Curative Treatment. Cancers (Basel) 2024; 16:2652. [PMID: 39123380 PMCID: PMC11311804 DOI: 10.3390/cancers16152652] [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: 07/06/2024] [Revised: 07/22/2024] [Accepted: 07/24/2024] [Indexed: 08/12/2024] Open
Abstract
Early-stage hepatocellular carcinoma (HCC) is still difficult to cure for its high recurrence rate. This study aimed to examine whether glycemic burden management could be one way to improve outcomes of early-stage HCC. A total of 137 very early or early-stage HCC patients who underwent resection or ablation at Samsung Medical Center and had glycemic burden assessment were analyzed. Glycemic burden was assessed using hemoglobin A1c (HbA1c) level. Outcomes were recurrence and overall survival. Risks of recurrence and overall survival were compared according to glycemic burden using a cut-off point of 6.5% or two cut-off points of 6.0% and 7.5%. Overall, 51 (37.2%) patients experienced HCC recurrence. The adjusted hazard ratio (aHR) for recurrence comparing patients with HbA1c > 6.5% to those with HbA1c ≤ 6.5% was 2.66 (95% CI: 1.26-5.78). The risk of recurrence increased in a dose-dependent manner by glycemic burden; aHR for 6.0 < HbA1c ≤ 7.5%: 2.00 (95% CI: 0.78-5.55); aHR for HbA1c > 7.5%: 6.05 (95% CI: 2.31-17.5). Mortality was observed in 16 (11.7%) patients. The risk of mortality was higher for HbA1c > 6.5% than for HbA1c ≤ 6.5% (aHR: 2.33; 95% CI: 1.10-5.08). There was also a dose-response relationship between overall survival and glycemic burden. Glycemic burden assessed using HbA1c level was significantly associated with outcomes of early-stage HCC patients. Good glycemic control could be a therapeutic goal to improve clinical outcomes in these populations.
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Affiliation(s)
| | | | - Byeong Geun Song
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea; (H.J.L.)
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Rossari F, Foti S, Camera S, Persano M, Casadei-Gardini A, Rimini M. Treatment options for advanced hepatocellular carcinoma: the potential of biologics. Expert Opin Biol Ther 2024; 24:455-470. [PMID: 38913107 DOI: 10.1080/14712598.2024.2363234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Accepted: 05/30/2024] [Indexed: 06/25/2024]
Abstract
INTRODUCTION Advanced hepatocellular carcinoma (HCC) represents a significant global health burden, whose treatment has been recently revolutionized by the advent of biologic treatments. Despite that, innovative therapeutic regimens and approaches, especially immune-based, remain to be explored aiming at extending the therapeutic benefits to a wider population of patients. AREAS COVERED This review comprehensively discusses the evolving landscape of biological treatment modalities for advanced HCC, including immune checkpoint inhibitors, antiangiogenic monoclonal antibodies, tumor-targeting monoclonal antibodies either naked or drug-conjugated, therapeutic vaccines, oncolytic viruses, adoptive cell therapies, and cytokine-based therapies. Key clinical trials and preclinical studies are examined, highlighting the actual or potential impact of these interventions in reshaping treatment paradigms for HCC. EXPERT OPINION Tailored and rational combination strategies, leveraging the synergistic effects of different modalities, represent a promising approach to maximize treatment efficacy in advanced HCC, which should aim at conversion endpoints to increase the fraction of patients eligible for curative approaches. The identification of predictive biomarkers holds the key to optimizing patient selection and improving therapeutic outcomes.
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Affiliation(s)
- Federico Rossari
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
- San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Silvia Foti
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Silvia Camera
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Mara Persano
- Medical Oncology, University and University Hospital of Cagliari, Cagliari, Italy
| | - Andrea Casadei-Gardini
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Margherita Rimini
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
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Boilève J, Guimas V, David A, Bailly C, Touchefeu Y. Combining Immune Checkpoint Inhibitors with Loco-Regional Treatments in Hepatocellular Carcinoma: Ready for Prime Time? Curr Oncol 2024; 31:3199-3211. [PMID: 38920726 PMCID: PMC11202666 DOI: 10.3390/curroncol31060242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 05/17/2024] [Accepted: 05/29/2024] [Indexed: 06/27/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a disease with a poor prognosis, often diagnosed at an advanced stage. Therapeutic options have developed considerably in recent years, particularly with trans-arterial treatments. Systemic treatments have also evolved significantly, with the rise of immune checkpoint inhibitors (ICI) as first-line treatment for advanced HCC. The combination of loco-regional treatments and ICI is opening up new prospects and is the subject of numerous clinical trials. Recently, two global phase 3 trials investigating ICI-based adjuvant combinations have demonstrated improvements in recurrence-free survival or progression-free survival in patients treated with resection, ablation, or trans-arterial chemoembolization. However, mature data and overall survival results are still awaited but will be difficult to interpret. We are at the start of a new era of combinations of loco-regional treatments and immunotherapy. The identification of the best therapeutic strategies and predictive biomarkers is a crucial issue for future standards in clinical practice.
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Affiliation(s)
- Juliette Boilève
- Inserm CIC 1413, Hépato-Gastroentérologie, Institut des Maladies de l’Appareil Digestif (IMAD), CHU Nantes, Nantes Université, 44000 Nantes, France;
| | - Valentine Guimas
- Department of Radiation Oncology, Institut de Cancérologie de l’Ouest, Bd Professeur Jacques Monod, 44800 Saint-Herblain, France;
| | - Arthur David
- Department of Radiology, University Hospital, Nantes 1 Place Alexis Ricordeau, 44093 Nantes, France;
| | - Clément Bailly
- Nuclear Medicine Department, University Hospital, 44093 Nantes, France;
| | - Yann Touchefeu
- Inserm CIC 1413, Hépato-Gastroentérologie, Institut des Maladies de l’Appareil Digestif (IMAD), CHU Nantes, Nantes Université, 44000 Nantes, France;
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Heumann P, Albert A, Gülow K, Tümen D, Müller M, Kandulski A. Insights in Molecular Therapies for Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:1831. [PMID: 38791911 PMCID: PMC11120383 DOI: 10.3390/cancers16101831] [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: 04/03/2024] [Revised: 05/03/2024] [Accepted: 05/06/2024] [Indexed: 05/26/2024] Open
Abstract
We conducted a comprehensive review of the current literature of published data and clinical trials (MEDLINE), as well as published congress contributions and active recruiting clinical trials on targeted therapies in hepatocellular carcinoma. Combinations of different agents and medical therapy along with radiological interventions were analyzed for the setting of advanced HCC. Those settings were also analyzed in combination with adjuvant situations after resection or radiological treatments. We summarized the current knowledge for each therapeutic setting and combination that currently is or has been under clinical evaluation. We further discuss the results in the background of current treatment guidelines. In addition, we review the pathophysiological mechanisms and pathways for each of these investigated targets and drugs to further elucidate the molecular background and underlying mechanisms of action. Established and recommended targeted treatment options that already exist for patients are considered for systemic treatment: atezolizumab/bevacizumab, durvalumab/tremelimumab, sorafenib, lenvatinib, cabozantinib, regorafenib, and ramucirumab. Combination treatment for systemic treatment and local ablative treatment or transarterial chemoembolization and adjuvant and neoadjuvant treatment strategies are under clinical investigation.
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Affiliation(s)
- Philipp Heumann
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany (K.G.); (D.T.)
| | | | | | | | | | - Arne Kandulski
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany (K.G.); (D.T.)
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Yan J, Li KX, Yu L, Yuan HY, Zhao ZM, Lin J, Wang CS. PRMT1 Integrates Immune Microenvironment and Fatty Acid Metabolism Response in Progression of Hepatocellular Carcinoma. J Hepatocell Carcinoma 2024; 11:15-27. [PMID: 38213310 PMCID: PMC10778267 DOI: 10.2147/jhc.s443130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Accepted: 12/20/2023] [Indexed: 01/13/2024] Open
Abstract
Background Protein arginine methyltransferase (PRMT) family members have important roles in cancer processes. However, its functions in the regulation of cancer immunotherapy of hepatocellular carcinoma (HCC) are incompletely understood. This study aimed to investigate the roles of PRMT1 in HCC. Methods Single-cell RNA sequencing (scRNA-seq) and clinicopathological data were obtained and used to explore the diagnostic and prognostic value, cellular functions and roles in immune microenvironment regulation of PRMT1 in HCC. The functions of PRMT1 were explored using Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO), as well as gene set enrichment analysis (GSEA). TIMER and CIBERSORT were used to analyze the relationships between PRMT1 expression and immune cell infiltration. The STRING database was used to construct a protein-protein interaction (PPI) network. Results PRMT1 was aberrantly expressed in HCC, which high expression was associated with tumor progression, worse overall survival (OS) and disease-free survival (DFS) of patients with HCC. PRMT1 was also associated with immune cell infiltration. Moreover, it was specifically expressed in immune cells, including exhausted CD8 T cells, B cells, and mono/macro cells in patients with immunotherapy. The expression of immune checkpoints was significantly increased in the high-PRMT1 expression groups of HCC patients. Regarding biological mechanisms, cell viability, migration and invasion, and the expression of genes related to fatty acid metabolism were suppressed in PRMT1 knockdown HCC cells. Moreover, genes co-expressed with PRMT1 were involved in the fatty acid metabolic process and enriched in fatty and drug-induced liver disease. Conclusion Taken together, these results indicate that PRMT1 might exert its oncogenic effects via immune microenvironment regulation and fatty acid metabolism in HCC. Our finding will provide a foundation for further studies and indicate a potential clinical therapeutic target for liver cancer.
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Affiliation(s)
- Jia Yan
- School of Basic Medicine, Inner Mongolia Medical University, Hohhot, Inner Mongolia, People’s Republic of China
- College of Life Science, Inner Mongolia University, Hohhot, Inner Mongolia, People’s Republic of China
- Medical Experimental Center of Basic Medical School, Inner Mongolia Medical University, Hohhot, Inner Mongolia, People’s Republic of China
| | - Ke xin Li
- College of Life Science, Inner Mongolia University, Hohhot, Inner Mongolia, People’s Republic of China
| | - Lei Yu
- College of Life Science, Inner Mongolia University, Hohhot, Inner Mongolia, People’s Republic of China
| | - Heng ye Yuan
- College of Life Science, Inner Mongolia University, Hohhot, Inner Mongolia, People’s Republic of China
| | - Zhi min Zhao
- College of Life Science, Inner Mongolia University, Hohhot, Inner Mongolia, People’s Republic of China
| | - Jing Lin
- College of Life Science, Inner Mongolia University, Hohhot, Inner Mongolia, People’s Republic of China
- Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia, People’s Republic of China
| | - Chang Shan Wang
- College of Life Science, Inner Mongolia University, Hohhot, Inner Mongolia, People’s Republic of China
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10
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Vogel A, Grant RC, Meyer T, Sapisochin G, O'Kane GM, Saborowski A. Adjuvant and neoadjuvant therapies for hepatocellular carcinoma. Hepatology 2023:01515467-990000000-00690. [PMID: 38108634 DOI: 10.1097/hep.0000000000000726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Accepted: 11/29/2023] [Indexed: 12/19/2023]
Abstract
Immune-oncology-based regimens have shown efficacy in advanced HCC and have been implemented as standard of care as first-line therapy. Their efficacy, including high response rates, and safety justify their evaluation in earlier disease stages. Following negative results for adjuvant sorafenib in the global STORM trial in 2015, 4 global phase 3 trials, featuring different immune checkpoint inhibitor combinations, entered in parallel the race in the adjuvant setting. The IMbrave050 trial, comparing adjuvant atezolizumab in combination with bevacizumab to active surveillance following curative-intent resection or ablation, was the first to report, fast-tracking the results of the first interim analysis and demonstrating an improvement in recurrence-free survival. The trial has provoked a discussion on the horizon of expectations from adjuvant treatment and the clinical relevance of efficacy endpoints. Moreover, major pathological responses reported from early phase 2 data in the neoadjuvant setting provide a strong rationale for the evaluation of these concepts in phase 3 trials. In this review, we summarize current evidence and outline future directions for systemic therapies in early-stage HCC.
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Affiliation(s)
- Arndt Vogel
- Department of Gastroenterology and Hepatology, Toronto General Hospital, Toronto, ON, Canada
- Department of Medical Oncology, Princess Margaret Cancer Centre, Toronto, ON, Canada
- Department of Gastroenterology, Hepatology, Infectiology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Robert C Grant
- Department of Medical Oncology, Princess Margaret Cancer Centre, Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Tim Meyer
- Research Department of Oncology, UCL Cancer Institute, University College London, London, UK
- Royal Free Hospital, London, UK
| | - Gonzalo Sapisochin
- Department of Abdominal Transplant & HPB Surgical Oncology, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Grainne M O'Kane
- Trinity St. James's Cancer Institute, St. James's Hospital, Dublin, Ireland
| | - Anna Saborowski
- Department of Gastroenterology, Hepatology, Infectiology and Endocrinology, Hannover Medical School, Hannover, Germany
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11
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Wu D, Li Y. Application of adoptive cell therapy in hepatocellular carcinoma. Immunology 2023; 170:453-469. [PMID: 37435926 DOI: 10.1111/imm.13677] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 06/20/2023] [Indexed: 07/13/2023] Open
Abstract
Hepatocellular carcinoma (HCC) remains a global health challenge. Novel treatment modalities are urgently needed to extend the overall survival of patients. The liver plays an immunomodulatory function due to its unique physiological structural characteristics. Therefore, following surgical resection and radiotherapy, immunotherapy regimens have shown great potential in the treatment of hepatocellular carcinoma. Adoptive cell immunotherapy is rapidly developing in the treatment of hepatocellular carcinoma. In this review, we summarize the latest research on adoptive immunotherapy for hepatocellular carcinoma. The focus is on chimeric antigen receptor (CAR)-T cells and T cell receptor (TCR) engineered T cells. Then tumour-infiltrating lymphocytes (TILs), natural killer (NK) cells, cytokine-induced killer (CIK) cells, and macrophages are briefly discussed. The main overview of the application and challenges of adoptive immunotherapy in hepatocellular carcinoma. It aims to provide the reader with a comprehensive understanding of the current status of HCC adoptive immunotherapy and offers some strategies. We hope to provide new ideas for the clinical treatment of hepatocellular carcinoma.
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Affiliation(s)
- Dengqiang Wu
- Department of Clinical Laboratory, Ningbo No. 6 Hospital, Ningbo, China
| | - Yujie Li
- Clinical Laboratory of Ningbo Medical Centre Lihuili Hospital, Ningbo University, Zhejiang, Ningbo, China
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12
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Bicer F, Kure C, Ozluk AA, El-Rayes BF, Akce M. Advances in Immunotherapy for Hepatocellular Carcinoma (HCC). Curr Oncol 2023; 30:9789-9812. [PMID: 37999131 PMCID: PMC10670350 DOI: 10.3390/curroncol30110711] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 10/28/2023] [Accepted: 10/31/2023] [Indexed: 11/25/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related deaths in the world. More than half of patients with HCC present with advanced stage, and highly active systemic therapies are crucial for improving outcomes. Immune checkpoint inhibitor (ICI)-based therapies have emerged as novel therapy options for advanced HCC. Only one third of patients achieve an objective response with ICI-based therapies due to primary resistance or acquired resistance. The liver tumor microenvironment is naturally immunosuppressive, and specific mutations in cell signaling pathways allow the tumor to evade the immune response. Next, gene sequencing of the tumor tissue or circulating tumor DNA may delineate resistance mechanisms to ICI-based therapy and provide a rationale for novel combination therapies. In this review, we discuss the results of key clinical trials that have led to approval of ICI-based therapy options in advanced HCC and summarize the ongoing clinical trials. We review resistance mechanisms to ICIs and discuss how immunotherapies may be optimized based on the emerging research of tumor biomarkers and genomic alterations.
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Affiliation(s)
- Fuat Bicer
- Division of Hematology Oncology, Department of Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA;
| | - Catrina Kure
- Department of Medicine, Northside Hospital-Gwinnett, Lawrenceville, GA 30046, USA;
| | - Anil A. Ozluk
- Division of Hematology Oncology, Department of Medicine, O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL 35233, USA; (A.A.O.); (B.F.E.-R.)
| | - Bassel F. El-Rayes
- Division of Hematology Oncology, Department of Medicine, O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL 35233, USA; (A.A.O.); (B.F.E.-R.)
| | - Mehmet Akce
- Division of Hematology Oncology, Department of Medicine, O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL 35233, USA; (A.A.O.); (B.F.E.-R.)
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13
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Gao X, Zuo S. Immune landscape and immunotherapy of hepatocellular carcinoma: focus on innate and adaptive immune cells. Clin Exp Med 2023; 23:1881-1899. [PMID: 36773210 PMCID: PMC10543580 DOI: 10.1007/s10238-023-01015-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Accepted: 01/27/2023] [Indexed: 02/12/2023]
Abstract
Hepatocellular carcinoma (HCC) is responsible for roughly 90% of all cases of primary liver cancer, and the cases are on the rise. The treatment of advanced HCC is a serious challenge. Immune checkpoint inhibitor (ICI) therapy has marked a watershed moment in the history of HCC systemic treatment. Atezolizumab in combination with bevacizumab has been approved as a first-line treatment for advanced HCC since 2020; however, the combination therapy is only effective in a limited percentage of patients. Considering that the tumor immune microenvironment (TIME) has a great impact on immunotherapies for HCC, an in-depth understanding of the immune landscape in tumors and the current immunotherapeutic approaches is extremely necessary. We elaborate on the features, functions, and cross talk of the innate and adaptive immune cells in HCC and highlight the benefits and drawbacks of various immunotherapies for advanced HCC, as well as future projections. HCC consists of a heterogeneous group of cancers with distinct etiologies and immune microenvironments. Almost all the components of innate and adaptive immune cells in HCC have altered, showing a decreasing trend in the number of tumor suppressor cells and an increasing trend in the pro-cancer cells, and there is also cross talk between various cell types. Various immunotherapies for HCC have also shown promising efficacy and application prospect. There are multilayered interwoven webs among various immune cell types in HCC, and emerging evidence demonstrates the promising prospect of immunotherapeutic approaches for HCC.
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Affiliation(s)
- Xiaoqiang Gao
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guizhou Medical University, No. 28, Guiyi Street, Guiyang, 550000, Guizhou, China
- Guizhou Medical University, Guiyang, Guizhou, China
| | - Shi Zuo
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guizhou Medical University, No. 28, Guiyi Street, Guiyang, 550000, Guizhou, China.
- Guizhou Medical University, Guiyang, Guizhou, China.
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14
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Nevola R, Delle Femine A, Rosato V, Kondili LA, Alfano M, Mastrocinque D, Imbriani S, Perillo P, Beccia D, Villani A, Ruocco R, Criscuolo L, La Montagna M, Russo A, Marrone A, Sasso FC, Marfella R, Rinaldi L, Esposito N, Barberis G, Claar E. Neoadjuvant and Adjuvant Systemic Therapies in Loco-Regional Treatments for Hepatocellular Carcinoma: Are We at the Dawn of a New Era? Cancers (Basel) 2023; 15:2950. [PMID: 37296912 PMCID: PMC10251995 DOI: 10.3390/cancers15112950] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 05/20/2023] [Accepted: 05/26/2023] [Indexed: 06/12/2023] Open
Abstract
Despite maximizing techniques and patient selection, liver resection and ablation for HCC are still associated with high rates of recurrence. To date, HCC is the only cancer with no proven adjuvant or neoadjuvant therapy used in association to potentially curative treatment. Perioperative combination treatments are urgently needed to reduce recurrence rates and improve overall survival. Immunotherapy has demonstrated encouraging results in the setting of adjuvant and neoadjuvant treatments for non-hepatic malignancies. Conclusive data are not yet available in the context of liver neoplasms. However, growing evidence suggests that immunotherapy, and in particular immune checkpoint inhibitors, could represent the cornerstone of an epochal change in the treatment of HCC, improving recurrence rates and overall survival through combination treatments. Furthermore, the identification of predictive biomarkers of treatment response could drive the management of HCC into the era of a precision medicine. The purpose of this review is to analyze the state of the art in the setting of adjuvant and neoadjuvant therapies for HCC in association with loco-regional treatments in patients not eligible for liver transplantation and to hypothesize future scenarios.
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Affiliation(s)
- Riccardo Nevola
- Liver Unit, Ospedale Evangelico Betania, 80147 Naples, Italy; (V.R.); (P.P.); (N.E.); (E.C.)
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.D.F.); (M.A.); (S.I.); (D.B.); (A.V.); (R.R.); (L.C.); (M.L.M.); (A.M.); (F.C.S.); (R.M.); (L.R.)
| | - Augusto Delle Femine
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.D.F.); (M.A.); (S.I.); (D.B.); (A.V.); (R.R.); (L.C.); (M.L.M.); (A.M.); (F.C.S.); (R.M.); (L.R.)
| | - Valerio Rosato
- Liver Unit, Ospedale Evangelico Betania, 80147 Naples, Italy; (V.R.); (P.P.); (N.E.); (E.C.)
| | | | - Maria Alfano
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.D.F.); (M.A.); (S.I.); (D.B.); (A.V.); (R.R.); (L.C.); (M.L.M.); (A.M.); (F.C.S.); (R.M.); (L.R.)
| | - Davide Mastrocinque
- Liver Unit, Ospedale Evangelico Betania, 80147 Naples, Italy; (V.R.); (P.P.); (N.E.); (E.C.)
| | - Simona Imbriani
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.D.F.); (M.A.); (S.I.); (D.B.); (A.V.); (R.R.); (L.C.); (M.L.M.); (A.M.); (F.C.S.); (R.M.); (L.R.)
| | - Pasquale Perillo
- Liver Unit, Ospedale Evangelico Betania, 80147 Naples, Italy; (V.R.); (P.P.); (N.E.); (E.C.)
| | - Domenico Beccia
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.D.F.); (M.A.); (S.I.); (D.B.); (A.V.); (R.R.); (L.C.); (M.L.M.); (A.M.); (F.C.S.); (R.M.); (L.R.)
| | - Angela Villani
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.D.F.); (M.A.); (S.I.); (D.B.); (A.V.); (R.R.); (L.C.); (M.L.M.); (A.M.); (F.C.S.); (R.M.); (L.R.)
| | - Rachele Ruocco
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.D.F.); (M.A.); (S.I.); (D.B.); (A.V.); (R.R.); (L.C.); (M.L.M.); (A.M.); (F.C.S.); (R.M.); (L.R.)
| | - Livio Criscuolo
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.D.F.); (M.A.); (S.I.); (D.B.); (A.V.); (R.R.); (L.C.); (M.L.M.); (A.M.); (F.C.S.); (R.M.); (L.R.)
| | - Marco La Montagna
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.D.F.); (M.A.); (S.I.); (D.B.); (A.V.); (R.R.); (L.C.); (M.L.M.); (A.M.); (F.C.S.); (R.M.); (L.R.)
| | - Antonio Russo
- Department of Mental Health and Public Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy;
| | - Aldo Marrone
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.D.F.); (M.A.); (S.I.); (D.B.); (A.V.); (R.R.); (L.C.); (M.L.M.); (A.M.); (F.C.S.); (R.M.); (L.R.)
| | - Ferdinando Carlo Sasso
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.D.F.); (M.A.); (S.I.); (D.B.); (A.V.); (R.R.); (L.C.); (M.L.M.); (A.M.); (F.C.S.); (R.M.); (L.R.)
| | - Raffaele Marfella
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.D.F.); (M.A.); (S.I.); (D.B.); (A.V.); (R.R.); (L.C.); (M.L.M.); (A.M.); (F.C.S.); (R.M.); (L.R.)
| | - Luca Rinaldi
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.D.F.); (M.A.); (S.I.); (D.B.); (A.V.); (R.R.); (L.C.); (M.L.M.); (A.M.); (F.C.S.); (R.M.); (L.R.)
| | - Nicolino Esposito
- Liver Unit, Ospedale Evangelico Betania, 80147 Naples, Italy; (V.R.); (P.P.); (N.E.); (E.C.)
| | | | - Ernesto Claar
- Liver Unit, Ospedale Evangelico Betania, 80147 Naples, Italy; (V.R.); (P.P.); (N.E.); (E.C.)
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15
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Zhao M, Huang H, He F, Fu X. Current insights into the hepatic microenvironment and advances in immunotherapy for hepatocellular carcinoma. Front Immunol 2023; 14:1188277. [PMID: 37275909 PMCID: PMC10233045 DOI: 10.3389/fimmu.2023.1188277] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 05/04/2023] [Indexed: 06/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and shows high global incidence and mortality rates. The liver is an immune-tolerated organ with a specific immune microenvironment that causes traditional therapeutic approaches to HCC, such as chemotherapy, radiotherapy, and molecular targeted therapy, to have limited efficacy. The dramatic advances in immuno-oncology in the past few decades have modified the paradigm of cancer therapy, ushering in the era of immunotherapy. Currently, despite the rapid integration of cancer immunotherapy into clinical practice, some patients still show no response to treatment. Therefore, a rational approach is to target the tumor microenvironment when developing the next generation of immunotherapy. This review aims to provide insights into the hepatic immune microenvironment in HCC and summarize the mechanisms of action and clinical usage of immunotherapeutic options for HCC, including immune checkpoint blockade, adoptive therapy, cytokine therapy, vaccine therapy, and oncolytic virus-based therapy.
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Affiliation(s)
| | | | - Feng He
- *Correspondence: Feng He, ; Xiangsheng Fu,
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16
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Villarruel-Melquiades F, Mendoza-Garrido ME, García-Cuellar CM, Sánchez-Pérez Y, Pérez-Carreón JI, Camacho J. Current and novel approaches in the pharmacological treatment of hepatocellular carcinoma. World J Gastroenterol 2023; 29:2571-2599. [PMID: 37213397 PMCID: PMC10198058 DOI: 10.3748/wjg.v29.i17.2571] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 01/19/2023] [Accepted: 04/11/2023] [Indexed: 05/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal malignant tumours worldwide. The mortality-to-incidence ratio is up to 91.6% in many countries, representing the third leading cause of cancer-related deaths. Systemic drugs, including the multikinase inhibitors sorafenib and lenvatinib, are first-line drugs used in HCC treatment. Unfortunately, these therapies are ineffective in most cases due to late diagnosis and the development of tumour resistance. Thus, novel pharmacological alternatives are urgently needed. For instance, immune checkpoint inhibitors have provided new approaches targeting cells of the immune system. Furthermore, monoclonal antibodies against programmed cell death-1 have shown benefits in HCC patients. In addition, drug combinations, including first-line treatment and immunotherapy, as well as drug repurposing, are promising novel therapeutic alternatives. Here, we review the current and novel pharmacological approaches to fight HCC. Preclinical studies, as well as approved and ongoing clinical trials for liver cancer treatment, are discussed. The pharmacological opportunities analysed here should lead to significant improvement in HCC therapy.
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Affiliation(s)
- Fernanda Villarruel-Melquiades
- Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Mexico City 07360, Mexico
| | - María Eugenia Mendoza-Garrido
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Mexico City 07360, Mexico
| | - Claudia M García-Cuellar
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología (INCan), Mexico City 14080, Mexico
| | - Yesennia Sánchez-Pérez
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología (INCan), Mexico City 14080, Mexico
| | - Julio Isael Pérez-Carreón
- Instituto Nacional de Medicina Genómica, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City 14610, Mexico
| | - Javier Camacho
- Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Mexico City 07360, Mexico
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17
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Nong JS, Zhou X, Liu JQ, Luo JZ, Huang JM, Xie HX, Yang KJ, Wang J, Ye XP, Peng T. Nucleoporin 107 is a prognostic biomarker in hepatocellular carcinoma associated with immune infiltration. Cancer Med 2023; 12:10990-11009. [PMID: 36952458 DOI: 10.1002/cam4.5807] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 02/16/2023] [Accepted: 02/22/2023] [Indexed: 03/25/2023] Open
Abstract
OBJECTIVE To assess the diagnostic value and clinical significance of nucleoporin 107 (NUP107) in hepatocellular carcinoma (HCC), and explore the possible mechanisms. METHODS The transcriptomic and clinical data of HCC patients were retrieved from The Cancer Genome Atlas (TCGA) and GEO databases. Tissue specimens were collected from HCC patients in the Guangxi area. According to the expression levels and prognostic characteristics of NUP107, ROC curves and nomogram models were constructed using the R package. RESULTS NUP107 was highly expressed in 26 human cancers including HCC, and was associated with advanced HCC staging and worse prognosis. NUP107 showed satisfactory ability to predict the prognosis of HCC patients (AUC >0.8). Results of gene set enrichment analysis (GSEA) further showed that NUP107 was mainly associated with cell cycle-related pathways such as the cell cycle, DNA replication, G2M checkpoint, E2F target, and mitotic spindle. In addition, NUP107 was also associated with immune infiltration in HCC and showed significant positive correlation with immune checkpoints (PD-L1 and TIM-3).
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Affiliation(s)
- Ju-Sen Nong
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
- Key Laboratory of Early Prevention & Treatment for Regional High Frequency Tumor, Ministry of Education, Guangxi Medical University, Nanning, People's Republic of China
| | - Xin Zhou
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
- Key Laboratory of Early Prevention & Treatment for Regional High Frequency Tumor, Ministry of Education, Guangxi Medical University, Nanning, People's Republic of China
| | - Jun-Qi Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
- Key Laboratory of Early Prevention & Treatment for Regional High Frequency Tumor, Ministry of Education, Guangxi Medical University, Nanning, People's Republic of China
| | - Jian-Zhu Luo
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
- Key Laboratory of Early Prevention & Treatment for Regional High Frequency Tumor, Ministry of Education, Guangxi Medical University, Nanning, People's Republic of China
| | - Jia-Mi Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
- Key Laboratory of Early Prevention & Treatment for Regional High Frequency Tumor, Ministry of Education, Guangxi Medical University, Nanning, People's Republic of China
| | - Hai-Xiang Xie
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
- Key Laboratory of Early Prevention & Treatment for Regional High Frequency Tumor, Ministry of Education, Guangxi Medical University, Nanning, People's Republic of China
| | - Ke-Jian Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
- Key Laboratory of Early Prevention & Treatment for Regional High Frequency Tumor, Ministry of Education, Guangxi Medical University, Nanning, People's Republic of China
| | - Jing Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
- Key Laboratory of Early Prevention & Treatment for Regional High Frequency Tumor, Ministry of Education, Guangxi Medical University, Nanning, People's Republic of China
| | - Xin-Ping Ye
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
- Key Laboratory of Early Prevention & Treatment for Regional High Frequency Tumor, Ministry of Education, Guangxi Medical University, Nanning, People's Republic of China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
- Key Laboratory of Early Prevention & Treatment for Regional High Frequency Tumor, Ministry of Education, Guangxi Medical University, Nanning, People's Republic of China
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18
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2022 KLCA-NCC Korea practice guidelines for the management of hepatocellular carcinoma. JOURNAL OF LIVER CANCER 2023; 23:1-120. [PMID: 37384024 PMCID: PMC10202234 DOI: 10.17998/jlc.2022.11.07] [Citation(s) in RCA: 68] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Accepted: 11/07/2022] [Indexed: 06/30/2023]
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the fourth most common cancer among men in South Korea, where the prevalence of chronic hepatitis B infection is high in middle and old age. The current practice guidelines will provide useful and sensible advice for the clinical management of patients with HCC. A total of 49 experts in the fields of hepatology, oncology, surgery, radiology, and radiation oncology from the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2018 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions. These guidelines provide useful information and direction for all clinicians, trainees, and researchers in the diagnosis and treatment of HCC.
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Affiliation(s)
- Korean Liver Cancer Association (KLCA) and National Cancer Center (NCC) Korea
- Corresponding author: KLCA-NCC Korea Practice Guideline Revision Committee (KPGRC) (Committee Chair: Joong-Won Park) Center for Liver and Pancreatobiliary Cancer, Division of Gastroenterology, Department of Internal Medicine, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang 10408, Korea Tel. +82-31-920-1605, Fax: +82-31-920-1520, E-mail:
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19
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Minaei N, Ramezankhani R, Tamimi A, Piryaei A, Zarrabi A, Aref AR, Mostafavi E, Vosough M. Immunotherapeutic approaches in Hepatocellular carcinoma: Building blocks of hope in near future. Eur J Cell Biol 2023; 102:151284. [PMID: 36584598 DOI: 10.1016/j.ejcb.2022.151284] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 11/30/2022] [Accepted: 12/16/2022] [Indexed: 12/23/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary hepatic cancer and is among the major causes of mortality due to cancer. Due to the lack of efficient conventional therapeutic options for this cancer, particularly in advanced cases, novel treatments including immunotherapy have been considered. However, despite the encouraging clinical outcomes after implementing these innovative approaches, such as oncolytic viruses (OVs), adoptive cell therapies (ACT), immune checkpoint blockades (ICBs), and cancer vaccines, several factors have restricted their therapeutic effect. The main concern is the existence of an immunosuppressive tumor microenvironment (TME). Combination of different ICBs or ICBs plus tyrosine kinase inhibitors have shown promising results in overcoming these limiting factors to some extent. Combination of programmed cell death ligand-1 (PD-L1) antibody Atezolizumab and vascular endothelial growth factor (VEGF) antibody Bevacizumab has become the standard of care in the first-line therapy for untestable HCC, approved by regulatory agencies. This paper highlighted a wide overview of the direct and indirect immunotherapeutic strategies proposed for the treatment of HCC patients and the common challenges that have hindered their further clinical applications.
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Affiliation(s)
- Neda Minaei
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran; Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
| | - Roya Ramezankhani
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran; Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran; Department of Development and Regeneration, KU Leuven Stem Cell Institute, Leuven, Belgium
| | - Atena Tamimi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
| | - Abbas Piryaei
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul 34396, Turkey
| | - Amir Reza Aref
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Ebrahim Mostafavi
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran; Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran; Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institutet and Karolinska University Hospital-Huddinge, Sweden.
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20
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Guo B, Chen Q, Liu Z, Chen X, Zhu P. Adjuvant therapy following curative treatments for hepatocellular carcinoma: current dilemmas and prospects. Front Oncol 2023; 13:1098958. [PMID: 37139151 PMCID: PMC10149944 DOI: 10.3389/fonc.2023.1098958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 04/04/2023] [Indexed: 05/05/2023] Open
Abstract
Curative surgical treatments, mainly liver resection, are still one of the optimal options for patients with early-, mid-, and even progression-stage hepatocellular carcinoma (HCC). However, the recurrence rate within 5 years after surgery is as high as 70%, especially in patients with high risk factors for recurrence, most of whom experience early recurrence within 2 years. Effective adjuvant therapy may improve prognosis, previous studies found that adjuvant transarterial chemoembolization, antiviral, and traditional Chinese medicine et al. were helpful in preventing HCC recurrence. Nevertheless, due to controversial results or lack of high-level evidence, there is no standardized postoperative management protocol worldwide at present. Continued exploration of effective postoperative adjuvant treatments to improve surgical prognosis is necessary.
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Affiliation(s)
- Bin Guo
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Qian Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hepatobiliary Surgery Department, The First Affiliated Hospital of Shihezi University, Shihezi, Xinjiang, China
| | - Zhicheng Liu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiaoping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Peng Zhu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- *Correspondence: Peng Zhu,
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21
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Tumor immunology. Clin Immunol 2023. [DOI: 10.1016/b978-0-12-818006-8.00003-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
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22
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Chen L, Zhang R, Lin Z, Tan Q, Huang Z, Liang B. Radiation therapy in the era of immune treatment for hepatocellular carcinoma. Front Immunol 2023; 14:1100079. [PMID: 36742293 PMCID: PMC9895775 DOI: 10.3389/fimmu.2023.1100079] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 01/06/2023] [Indexed: 01/22/2023] Open
Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment in recent years and provide new opportunities to treat hepatocellular carcinoma (HCC). To date, several ICIs have been approved by the FDA for advanced HCC in first-line or second-line therapy. Downstaging conversion therapy for potentially resectable HCC to provide opportunities for surgical intervention is challenging. ICIs have become a hot spot in this field due to their high response rate. However, HCC has various etiologies and can evade the immune system through multiple mechanisms, which limit the efficacy of ICI monotherapy and demand novel combination strategies. Radiation therapy (RT) is also a candidate for conversion therapy in HCC and is currently gaining increasing attention as a good combination partner with ICIs due to its ability to modulate the tumor microenvironment. In this review, we illustrate the current indications for ICIs and RT in HCC, the rationale for their synergistic combination, and the current clinical trials in combination therapy. We also speculate on predictive biomarkers and novel future strategies to further enhance the efficacy of this combination. This review aims to provide references for future research on radiation and immunotherapy to arrive at a promising new era of HCC treatment.
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Affiliation(s)
- Lingjuan Chen
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ruiguang Zhang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhenyu Lin
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qiaoyun Tan
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhiyong Huang
- Hepatic Surgery Center, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Binyong Liang
- Hepatic Surgery Center, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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23
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2022 KLCA-NCC Korea Practice Guidelines for the Management of Hepatocellular Carcinoma. Korean J Radiol 2022; 23:1126-1240. [PMID: 36447411 PMCID: PMC9747269 DOI: 10.3348/kjr.2022.0822] [Citation(s) in RCA: 74] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 10/28/2022] [Indexed: 11/18/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the fourth most common cancer among men in South Korea, where the prevalence of chronic hepatitis B infection is high in middle and old age. The current practice guidelines will provide useful and sensible advice for the clinical management of patients with HCC. A total of 49 experts in the fields of hepatology, oncology, surgery, radiology, and radiation oncology from the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2018 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions. These guidelines provide useful information and direction for all clinicians, trainees, and researchers in the diagnosis and treatment of HCC.
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24
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2022 KLCA-NCC Korea practice guidelines for the management of hepatocellular carcinoma. Clin Mol Hepatol 2022; 28:583-705. [PMID: 36263666 PMCID: PMC9597235 DOI: 10.3350/cmh.2022.0294] [Citation(s) in RCA: 174] [Impact Index Per Article: 58.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 09/23/2022] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the fourth most common cancer among men in South Korea, where the prevalence of chronic hepatitis B infection is high in middle and old age. The current practice guidelines will provide useful and sensible advice for the clinical management of patients with HCC. A total of 49 experts in the fields of hepatology, oncology, surgery, radiology, and radiation oncology from the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2018 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions. These guidelines provide useful information and direction for all clinicians, trainees, and researchers in the diagnosis and treatment of HCC.
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25
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Choi JH, Nam GH, Hong JM, Cho IR, Paik WH, Ryu JK, Kim YT, Lee SH. Cytokine-Induced Killer Cell Immunotherapy Combined With Gemcitabine Reduces Systemic Metastasis in Pancreatic Cancer: An Analysis Using Preclinical Adjuvant Therapy-Mimicking Pancreatic Cancer Xenograft Model. Pancreas 2022; 51:1251-1257. [PMID: 37078953 DOI: 10.1097/mpa.0000000000002176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/21/2023]
Abstract
OBJECTIVES To evaluate the efficacy and safety of cytokine-induced killer (CIK) cell therapy in pancreatic cancer. METHODS An orthotopic murine model of pancreatic cancer and adjuvant therapy-mimicking xenograft murine model that underwent splenectomy was created. Eighty mice were randomized into four groups: the control, gemcitabine alone, CIK alone, and CIK with gemcitabine groups. The tumor growth was monitored using bioluminescence imaging once weekly. RESULTS In the orthotopic murine model, the treatment groups showed a significantly longer survival than the control group (median: not reached vs 125.0 days; 95% confidence interval, 119.87-130.13; P = 0.04); however, the overall survival did not differ significantly among the treatment groups (P = 0.779). The metastatic recurrence rate and overall survival were also not significantly different among the groups in the adjuvant therapy-mimicking xenograft murine model (P = 0.497). However, the CIK and gemcitabine combination suppressed the metastatic recurrence effectively, with recurrence-free survival being significantly longer in the CIK with gemcitabine group than in the control group (median, 54 days; 95% confidence interval, 25.00-102.00; P = 0.013). CONCLUSIONS The combination of CIK and gemcitabine suppressed systemic metastatic recurrence, with promising efficacy and good tolerability in an adjuvant setting of pancreatic cancer.
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Affiliation(s)
- Jin Ho Choi
- From the Department of Internal Medicine, Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Gun He Nam
- GC CELL Corp., Yongin-si, Republic of Korea
| | | | - In Rae Cho
- From the Department of Internal Medicine, Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Woo Hyun Paik
- From the Department of Internal Medicine, Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Ji Kon Ryu
- From the Department of Internal Medicine, Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Yong-Tae Kim
- From the Department of Internal Medicine, Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Sang Hyub Lee
- From the Department of Internal Medicine, Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
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Zeng ZM, Mo N, Zeng J, Ma FC, Jiang YF, Huang HS, Liao XW, Zhu GZ, Ma J, Peng T. Advances in postoperative adjuvant therapy for primary liver cancer. World J Gastrointest Oncol 2022; 14:1604-1621. [PMID: 36187393 PMCID: PMC9516643 DOI: 10.4251/wjgo.v14.i9.1604] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 05/13/2022] [Accepted: 07/26/2022] [Indexed: 02/05/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly heterogeneous, invasive, and conventional chemotherapy-insensitive tumor with unique biological characteristics. The main methods for the radical treatment of HCC are surgical resection or liver transplantation. However, recurrence rates are as high as 50% and 70% at 3 and 5 years after liver resection, respectively, and even in Milan-eligible recipients, the recurrence rate is approximately 20% at 5 years after liver transplantation. Therefore, reducing the postoperative recurrence rate is key to improving the overall outcome of liver cancer. This review discusses the risk factors for recurrence in patients with HCC radical surgical resection and adjuvant treatment options that may reduce the risk of recurrence and improve overall survival, including local adjuvant therapy (e.g., transcatheter arterial chemoembolization), adjuvant systemic therapy (e.g., molecular targeted agents and immunotherapy), and other adjuvant therapies (e.g., antiviral and herbal therapy). Finally, potential research directions that may change the paradigm of adjuvant therapy for HCC are analyzed.
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Affiliation(s)
- Zhi-Ming Zeng
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Ning Mo
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Jie Zeng
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Fu-Chao Ma
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Yan-Feng Jiang
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Hua-Sheng Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Xi-Wen Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Guang-Zhi Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Jie Ma
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
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Jost R, Al-Shatti N, Ghosn M, Bonnet B, Champiat S, Deschamps F, Gelli M, Boige V, Danlos FX, Susini S, Hollebecque A, Ammari S, Marabelle A, de Baere T, Tselikas L. Synergizing liver systemic treatments with interventional oncology: friend or foe? Br J Radiol 2022; 95:20220548. [PMID: 36075034 PMCID: PMC9815737 DOI: 10.1259/bjr.20220548] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 08/20/2022] [Accepted: 08/24/2022] [Indexed: 01/13/2023] Open
Abstract
Interventional radiology techniques provide excellent local tumor control for small tumors in various organs, but several limitations can hamper the oncological outcomes such as the tumor size or the number of lesions. Technical improvements, optimal patient selection and combination with systemic therapies, including immune checkpoint inhibitors, have been successfully developed to overcome these barriers.In this setting, chemotherapy and targeted therapies aim to diminish the tumor burden in addition to local treatments, while immunotherapies may have a synergistic effect in terms of mechanism of action on the tumor cell as well as the immune environment, with multiple treatment combinations being available. Finally, interventional Rrdiology treatments often increase tumor antigen exposure to the immune system, and thus stimulate a specific antitumor immune response that can act beyond the treated site. Notwithstanding their many benefits, combination treatment may also result in complications, the most feared may be auto-immune-related adverse events.In early studies, several combined therapies have shown promising levels of safety and efficacy, particularly in hepatocellular carcinoma.This review provides a comprehensive and up-to-date overview of results of combined therapies for primary and secondary liver malignancies. Recent advances and future perspectives will be discussed.
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Affiliation(s)
- Raphaël Jost
- Département d’Anésthésie, Chirurgie et Imagerie Interventionnelle, Gustave Roussy, Villejuif, France
| | | | - Mario Ghosn
- Département d’Anésthésie, Chirurgie et Imagerie Interventionnelle, Gustave Roussy, Villejuif, France
| | - Baptiste Bonnet
- Département d’Anésthésie, Chirurgie et Imagerie Interventionnelle, Gustave Roussy, Villejuif, France
| | | | - Frederic Deschamps
- Département d’Anésthésie, Chirurgie et Imagerie Interventionnelle, Gustave Roussy, Villejuif, France
| | - Maximiliano Gelli
- Département d’Anésthésie, Chirurgie et Imagerie Interventionnelle, Gustave Roussy, Villejuif, France
| | - Valérie Boige
- Department of medical oncology, Gustave Roussy, Villejuif, France
| | | | | | - Antoine Hollebecque
- Département d’Innovation Thérapeutique et d’Essais Précoces (DITEP), Gustave Roussy, Villejuif, France
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28
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NK and cells with NK-like activities in cancer immunotherapy-clinical perspectives. Med Oncol 2022; 39:131. [PMID: 35716327 DOI: 10.1007/s12032-022-01735-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 04/13/2022] [Indexed: 01/10/2023]
Abstract
Natural killer (NK) cells are lymphoid cells of innate immunity that take important roles in immune surveillance. NK cells are considered as a bridge between innate and adaptive immunity, and their infiltration into tumor area is related positively with prolonged patient survival. They are defined as CD16+ CD56+ CD3- cells in clinic. NK cells promote cytolytic effects on target cells and induce their apoptosis. Loss of NK cell cytotoxic activity and reduction in the number of activating receptors are the current issues for application of such cells in cellular immunotherapy, which resulted in the diminished long-term effects. The focus of this review is to discuss about the activity of NK cells and cells with NK-like activity including natural killer T (NKT), cytokine-induced killer (CIK) and lymphokine-activated killer (LAK) cells in immunotherapy of human solid cancers.
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29
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Liu Y, Zhang Z, Tian Y, Wang D, Liu S, Li L, Hao N, Qin G, Zhao X, Yang S, Huang J, Shen C, Lei Q, Wang L, Zhang Y. Long-term clinical efficacy of cytokine-induced killer cell-based immunotherapy in early-stage esophageal squamous cell carcinoma. Cytotherapy 2022; 24:526-533. [PMID: 35219583 DOI: 10.1016/j.jcyt.2021.12.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 12/25/2021] [Accepted: 12/27/2021] [Indexed: 11/03/2022]
Abstract
BACKGROUND AIMS In this retrospective clinical study, the authors investigated the impact of cytokine-induced killer (CIK) cell-based immunotherapies on the long-term survival of patients with esophageal squamous cell carcinoma (ESCC). METHODS A total of 87 patients with ESCC who received comprehensive treatment were enrolled in the study. Of these patients, 43 were in the control group and 44 were in the CIK treatment group. Flow cytometry analysis was performed to detect the phenotype and anti-tumor function of CIK cells. Clinical characteristics were compared between these two groups, and the survival estimates of ESCC patients were determined using Kaplan-Meier analysis. RESULTS CIK cells contained a high proportion of the main functional fraction (CD3+CD56+ group) and exhibited a strong killing ability for esophageal cancer cells in vitro. Importantly, overall survival (OS) and progression-free survival (PFS) were significantly higher in the CIK group than in the control group in early-stage ESCC. However, patients with advanced-stage ESCC did not benefit from CIK cell-based therapy in terms of OS and PFS compared with the control group. CONCLUSIONS These results demonstrate that CIK cells combined with conventional treatments potentially prolong long-term survival of patients and may serve as a combined therapeutic approach for the treatment of early-stage ESCC.
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Affiliation(s)
- Yanfen Liu
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou, China
| | - Zhen Zhang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou, China
| | - Yonggui Tian
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou, China
| | - Dan Wang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou, China
| | - Saisai Liu
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou, China
| | - Lin Li
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Na Hao
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Guohui Qin
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou, China
| | - Xuan Zhao
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou, China
| | - Shuangning Yang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jianmin Huang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou, China
| | - Chunyi Shen
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou, China
| | - Qingyang Lei
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou, China
| | - Liping Wang
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yi Zhang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou, China; School of Life Sciences, Zhengzhou University, Zhengzhou, China; State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, China.
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Fan Y, Xue H, Zheng H. Systemic Therapy for Hepatocellular Carcinoma: Current Updates and Outlook. J Hepatocell Carcinoma 2022; 9:233-263. [PMID: 35388357 PMCID: PMC8977221 DOI: 10.2147/jhc.s358082] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 03/15/2022] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) has emerged the culprit of cancer-related mortality worldwide with its dismal prognosis climbing. In recent years, ground-breaking progress has been made in systemic therapy for HCC. Targeted therapy based on specific signaling molecules, including sorafenib, lenvatinib, regorafenib, cabozantinib, and ramucirumab, has been widely used for advanced HCC (aHCC). Immunotherapies such as pembrolizumab and nivolumab greatly improve the survival of aHCC patients. More recently, synergistic combination therapy has boosted first-line (atezolizumab in combination with bevacizumab) and second-line (ipilimumab in combination with nivolumab) therapeutic modalities for aHCC. This review aims to summarize recent updates of systemic therapy relying on the biological mechanisms of HCC, particularly highlighting the approved agents for aHCC. Adjuvant and neoadjuvant therapy, as well as a combination with locoregional therapies (LRTs), are also discussed. Additionally, we describe the promising effect of traditional Chinese medicine (TCM) as systemic therapy on HCC. In this setting, the challenges and future directions of systemic therapy for HCC are also explored.
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Affiliation(s)
- Yinjie Fan
- College of Integrated Chinese and Western Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, 110847, People’s Republic of China
- Department of Oncology and Experimental Center, the Affiliated Hospital of Chengde Medical University, Chengde, Hebei, 067000, People’s Republic of China
| | - Hang Xue
- Department of Oncology and Experimental Center, the Affiliated Hospital of Chengde Medical University, Chengde, Hebei, 067000, People’s Republic of China
| | - Huachuan Zheng
- Department of Oncology and Experimental Center, the Affiliated Hospital of Chengde Medical University, Chengde, Hebei, 067000, People’s Republic of China
- Correspondence: Huachuan Zheng, Department of Oncology and Experimental Center, the Affiliated Hospital of Chengde Medical University, Chengde, Hebei, 067000, People’s Republic of China, Tel +86-0314-2279458, Fax +86-0314-2279458, Email
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Cai J, Zhao J, Liu D, Xie H, Qi H, Ma J, Sun Z, Zhao H. Efficacy and Safety of Central Memory T Cells Combined With Adjuvant Therapy to Prevent Recurrence of Hepatocellular Carcinoma With Microvascular Invasion: A Pilot Study. Front Oncol 2021; 11:781029. [PMID: 34926296 PMCID: PMC8679661 DOI: 10.3389/fonc.2021.781029] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 11/08/2021] [Indexed: 01/27/2023] Open
Abstract
Background Postoperative adjuvant transcatheter arterial chemoembolization (TACE) following curative hepatectomy has been reported to improve the clinical outcomes of hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI), but more endeavors are required to achieve greater clinical benefit. Central memory T-cell (Tcm) self-transfusion has shown superior antitumor activity in several preclinical studies; however, clinical studies are rare. The aim of this study was to evaluate the clinical benefit and safety of combination treatment with Tcm self-transfusion and TACE as adjuvant treatment in HCC patients with MVI after curative hepatectomy. Methods From October 2016 to September 2018, primary HCC patients with histologically confirmed MVI who underwent curative hepatectomy at the Cancer Hospital of the Chinese Academy of Medical Sciences were recruited for this study. The patients were divided into a Tcm group (combined Tcm self-transfusion with TACE treatment) or a control group (TACE treatment alone) according to their willingness. The recurrence-free survival (RFS), quality-of-life (QOL) score, and adverse events of each patient were recorded within 2 years. Results A total of 52 patients were enrolled, and 48 were eligible for the final data analysis. The median follow-up time was 20.5 months (95% CI: 17.05–22.55 months). The median RFS time was 9.5 months in the control group; the cutoff date was not reached in the Tcm group (when the follow-up duration was 12 months, p = 0.049, HR = 0.40; 95% CI: 0.16–0.99). Compared with the control group, 1- and 2-year RFS rates were higher in the Tcm group (72.0% vs. 46.4% and 58.18% vs. 39.14%, respectively). Multivariate analysis did not indicate that Tcm treatment was an independent prognostic factor associated with HCC recurrence (p = 0.107, HR = 2.312; 95% CI: 0.835–6.400), which might be due to the small sample size of this study. Nevertheless, Tcm treatment effectively improved a reduced QOL due to HCC and liver function injury. Finally, the safety profile of Tcm treatment in this study was good, without any serious adverse events. Conclusions This pilot study showed that Tcm self-transfusion combined with TACE treatment might be a beneficial adjuvant therapy with good safety for primary HCC patients with MVI after curative hepatectomy. Trial registration number NCT03575806
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Affiliation(s)
- Jianqiang Cai
- Department of Hepatobiliary Surgery, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jianjun Zhao
- Department of Hepatobiliary Surgery, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Defang Liu
- Department of New Drug Registration, Hebei Immune Cell Application Engineering Research Center/Baoding Newish Technology Co., LTD/Newish Technology (Beijing) Co., LTD, Beijing, China
| | - Huangfan Xie
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, China
| | - Hailong Qi
- Department of New Drug Registration, Hebei Immune Cell Application Engineering Research Center/Baoding Newish Technology Co., LTD/Newish Technology (Beijing) Co., LTD, Beijing, China.,School of Pharmaceutical Sciences, Tsinghua University, Beijing, China
| | - Junfan Ma
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, China
| | - Zhongjie Sun
- State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin, China
| | - Hong Zhao
- Department of Hepatobiliary Surgery, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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32
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Sparchez Z, Radu P, Bartos A, Nenu I, Craciun R, Mocan T, Horhat A, Spârchez M, Dufour JF. Combined treatments in hepatocellular carcinoma: Time to put them in the guidelines? World J Gastrointest Oncol 2021; 13:1896-1918. [PMID: 35070032 PMCID: PMC8713312 DOI: 10.4251/wjgo.v13.i12.1896] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 05/03/2021] [Accepted: 11/05/2021] [Indexed: 02/06/2023] Open
Abstract
The time for battling cancer has never been more suitable than nowadays and fortunately against hepatocellular carcinoma (HCC) we do have a far-reaching arsenal. Moreover, because liver cancer comprises a plethora of stages-from very early to advanced disease and with many treatment options-from surgery to immunotherapy trials-it leaves the clinician a wide range of options. The scope of our review is to throw light on combination treatments that seem to be beyond guidelines and to highlight these using evidence-based analysis of the most frequently used combination therapies, discussing their advantages and flaws in comparison to the current standard of care. One particular combination therapy seems to be in the forefront: Transarterial chemoembolization plus ablation for medium-size non-resectable HCC (3-5 cm), which is currently at the frontier between Barcelona Clinic Liver Cancer classification A and B. Not only does it improve the outcome in contrast to each individual therapy, but it also seems to have similar results to surgery. Also, the abundance of immune checkpoint inhibitors that have appeared lately in clinical trials are bringing promising results against HCC. Although the path of combination therapies in HCC is still filled with uncertainty and caveats, in the following years the hepatology and oncology fields could witness an HCC guideline revolution.
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Affiliation(s)
- Zeno Sparchez
- 3rd Medical Department, “Ïuliu Hatieganu” University of Medicine and Pharmacy, Institute for Gastroenterology and Hepatology, Cluj-Napoca 400162, Romania
| | - Pompilia Radu
- Department of Visceral Surgery and Medicine, Hepatology, Inselspital, Bern University Hospital, University of Bern, Bern 3010, Switzerland
| | - Adrian Bartos
- Department of Surgery, “Ïuliu Hatieganu” University of Medicine and Pharmacy, Institute for Gastroenterology and Hepatology, Cluj-Napoca 400162, Romania
| | - Iuliana Nenu
- 3rd Medical Department, “Ïuliu Hatieganu” University of Medicine and Pharmacy, Institute for Gastroenterology and Hepatology, Cluj-Napoca 400162, Romania
| | - Rares Craciun
- 3rd Medical Department, “Ïuliu Hatieganu” University of Medicine and Pharmacy, Institute for Gastroenterology and Hepatology, Cluj-Napoca 400162, Romania
| | - Tudor Mocan
- 3rd Medical Department, “Ïuliu Hatieganu” University of Medicine and Pharmacy, Institute for Gastroenterology and Hepatology, Cluj-Napoca 400162, Romania
| | - Adelina Horhat
- 3rd Medical Department, “Ïuliu Hatieganu” University of Medicine and Pharmacy, Institute for Gastroenterology and Hepatology, Cluj-Napoca 400162, Romania
| | - Mihaela Spârchez
- Department of Mother and Child, 2nd Paediatric Clinic, “Ïuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca 400177, Romania
| | - Jean-François Dufour
- Department for BioMedical Research, Hepatology, University of Bern, Bern 3008, Switzerland
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Cho JY, Kwon SH, Lee EK, Lee JH, Kim HL. Cost-Effectiveness of Adjuvant Immunotherapy With Cytokine-Induced Killer Cell for Hepatocellular Carcinoma Based on a Randomized Controlled Trial and Real-World Data. Front Oncol 2021; 11:728740. [PMID: 34926248 PMCID: PMC8682810 DOI: 10.3389/fonc.2021.728740] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 11/16/2021] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Studies using data from randomized controlled trials (RCTs) and real-world data (RWD) have suggested that adjuvant cytokine-induced killer (CIK) cell immunotherapy after curative treatment for hepatocellular carcinoma (HCC) prolongs recurrence-free survival (RFS) and overall survival (OS). However, the cost-effectiveness of CIK cell immunotherapy as an adjuvant therapy for HCC compared to no adjuvant therapy is uncertain. METHODS We constructed a partitioned survival model to compare the expected costs, life-year (LY), and quality-adjusted life-year (QALY) of a hypothetical population of 10,000 patients between CIK cell immunotherapy and no adjuvant therapy groups. Patients with HCC aged 55 years who underwent a potentially curative treatment were simulated with the model over a 20-year time horizon, from a healthcare system perspective. To model the effectiveness, we used OS and RFS data from RCTs and RWD. We estimated the incremental cost-effectiveness ratios (ICERs) and performed extensive sensitivity analyses. RESULTS Based on the RCT data, the CIK cell immunotherapy incrementally incurred a cost of $61,813, 2.07 LYs, and 1.87 QALYs per patient compared to no adjuvant therapy, and the estimated ICER was $33,077/QALY. Being less than the willingness-to-pay threshold of $50,000/QALY, CIK cell immunotherapy was cost-effective. Using the RWD, the ICER was estimated as $25,107/QALY, which is lower than that obtained using RCT. The time horizon and cost of productivity loss were the most influential factors on the ICER. CONCLUSION We showed that receiving adjuvant CIK cell immunotherapy was more cost-effective than no adjuvant therapy in patients with HCC who underwent a potentially curative treatment, attributed to prolonged survival, reduced recurrence of HCC, and better prognosis of recurrence. Receiving CIK cell immunotherapy may be more cost-effective in real-world clinical practice.
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Affiliation(s)
- Jeong-Yeon Cho
- School of Pharmacy, Sungkyunkwan University, Suwon, South Korea
| | - Sun-Hong Kwon
- School of Pharmacy, Sungkyunkwan University, Suwon, South Korea
| | - Eui-Kyung Lee
- School of Pharmacy, Sungkyunkwan University, Suwon, South Korea
| | - Jeong-Hoon Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Hye-Lin Kim
- College of Pharmacy, Sahmyook University, Seoul, South Korea
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Shang BB, Chen J, Wang ZG, Liu H. Significant correlation between HSPA4 and prognosis and immune regulation in hepatocellular carcinoma. PeerJ 2021; 9:e12315. [PMID: 34754620 PMCID: PMC8555498 DOI: 10.7717/peerj.12315] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 09/24/2021] [Indexed: 12/24/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is an inflammation-associated tumor involved in immune tolerance and evasion in the immune microenvironment. Heat shock proteins (HSPs) are involved in the occurrence, progression, and immune regulation of tumors. Therefore, HSPs have been considered potential therapeutic targets. Here, we aimed to elucidate the value of HSP family A (Hsp70) member 4 (HSPA4) in the diagnosis and predicting prognosis of HCC, and its relationship with immune cell infiltration, immune cell biomarkers, and immune checkpoints. Gene mutation, DNA methylation, and the pathway involved in HCC were also analyzed. Methods The gene expression omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases were used to compare HSPA4 expression, and the results were confirmed by immunohistochemical staining of clinical samples. R package was used to analyze the correlation between HSPA4 and cancer stage, and to establish receiver operating characteristic (ROC) curve of diagnosis, time-dependent survival ROC curve, and a nomogram model. cBioPortal and MethSurv were used to identify genetic alterations and DNA methylation, and their effect on prognosis. The Tumor Immune Estimation Resource (TIMER) was used to analyze immune cell infiltration, immune cell biomarkers, and immune checkpoints. The STRING database was used to analyze protein-protein interaction network information. Gene Ontology (GO) analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to investigate the functions of HSPA4 and its functional partner genes. Results Overexpression of HSPA4 was identified in 25 cancers. Overexpression of HSPA4 considerably correlated with cancer stage and alpha-fetoprotein (AFP) level in HCC. Patients with higher HSPA4 expression showed poorer prognosis. HSPA4 expression can accurately identify tumor from normal tissue (AUC = 0.957). The area under 1-, 3-, and 5-year survival ROCs were above 0.6. The HSPA4 genetic alteration rate was 1.3%. Among the 14 DNA methylation CpG sites, seven were related to the prognosis of HCC. HSPA4 was positively related to immune cell infiltration and immune checkpoints (PD-1 and CTLA-4) in HCC. The KEGG pathway enrichment analysis revealed HSPA4 enrichment in antigen processing and presentation together with HSPA8 and HSP90AA1. We verified the value of HSPA4 in the diagnosis and predicting prognosis of HCC. HSPA4 may not only participate in the occurrence and progression but also the immune regulation of HCC. Therefore, HSPA4 can be a potential diagnostic and prognostic biomarker and a therapeutic target for HCC.
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Affiliation(s)
| | - Jun Chen
- Laboratory Animal Center, Dalian Medical University, Dalian, China
| | - Zhi-Guo Wang
- Second Hospital of Dalian Medical University, Dalian, China
| | - Hui Liu
- Second Hospital of Dalian Medical University, Dalian, China
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Wu X, Sharma A, Oldenburg J, Weiher H, Essler M, Skowasch D, Schmidt-Wolf IGH. NKG2D Engagement Alone Is Sufficient to Activate Cytokine-Induced Killer Cells While 2B4 Only Provides Limited Coactivation. Front Immunol 2021; 12:731767. [PMID: 34691037 PMCID: PMC8529192 DOI: 10.3389/fimmu.2021.731767] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 09/08/2021] [Indexed: 12/29/2022] Open
Abstract
Cytokine-induced killer (CIK) cells are an ex vivo expanded heterogeneous cell population with an enriched NK-T phenotype (CD3+CD56+). Due to the convenient and relatively inexpensive expansion capability, together with low incidence of graft versus host disease (GVHD) in allogeneic cancer patients, CIK cells are a promising candidate for immunotherapy. It is well known that natural killer group 2D (NKG2D) plays an important role in CIK cell-mediated antitumor activity; however, it remains unclear whether its engagement alone is sufficient or if it requires additional co-stimulatory signals to activate the CIK cells. Likewise, the role of 2B4 has not yet been identified in CIK cells. Herein, we investigated the individual and cumulative contribution of NKG2D and 2B4 in the activation of CIK cells. Our analysis suggests that (a) NKG2D (not 2B4) is implicated in CIK cell (especially CD3+CD56+ subset)-mediated cytotoxicity, IFN-γ secretion, E/T conjugate formation, and degranulation; (b) NKG2D alone is adequate enough to induce degranulation, IFN-γ secretion, and LFA-1 activation in CIK cells, while 2B4 only provides limited synergy with NKG2D (e.g., in LFA-1 activation); and (c) NKG2D was unable to costimulate CD3. Collectively, we conclude that NKG2D engagement alone suffices to activate CIK cells, thereby strengthening the idea that targeting the NKG2D axis is a promising approach to improve CIK cell therapy for cancer patients. Furthermore, CIK cells exhibit similarities to classical invariant natural killer (iNKT) cells with deficiencies in 2B4 stimulation and in the costimulation of CD3 with NKG2D. In addition, based on the current data, the divergence in receptor function between CIK cells and NK (or T) cells can be assumed, pointing to the possibility that molecular modifications (e.g., using chimeric antigen receptor technology) on CIK cells may need to be customized and optimized to maximize their functional potential.
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Affiliation(s)
- Xiaolong Wu
- Department of Integrated Oncology, Center of Integrated Oncology (CIO) Bonn, University Hospital Bonn, Bonn, Germany
| | - Amit Sharma
- Department of Integrated Oncology, Center of Integrated Oncology (CIO) Bonn, University Hospital Bonn, Bonn, Germany.,Department of Neurosurgery, University Hospital Bonn, Bonn, Germany
| | - Johannes Oldenburg
- Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Bonn, Germany
| | - Hans Weiher
- Department of Applied Natural Sciences, Bonn-Rhein-Sieg University of Applied Sciences, Rheinbach, Germany
| | - Markus Essler
- Department of Nuclear Medicine, University Hospital Bonn, Bonn, Germany
| | - Dirk Skowasch
- Department of Internal Medicine II, University Hospital Bonn, Bonn, Germany
| | - Ingo G H Schmidt-Wolf
- Department of Integrated Oncology, Center of Integrated Oncology (CIO) Bonn, University Hospital Bonn, Bonn, Germany
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Adoptive T-cell immunotherapy in digestive tract malignancies: Current challenges and future perspectives. Cancer Treat Rev 2021; 100:102288. [PMID: 34525422 DOI: 10.1016/j.ctrv.2021.102288] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 08/31/2021] [Accepted: 09/02/2021] [Indexed: 12/15/2022]
Abstract
Multiple systemic treatments are currently available for advanced cancers of the digestive tract, but none of them is curative. Adoptive T-cell immunotherapy refers to the extraction, modification and re-infusion of autologous or allogenic T lymphocytes for therapeutic purposes. A number of clinical trials have investigated either non-engineered T cells (i.e., lymphokine-activated killer cells, cytokine induced killer cells, or tumor-infiltrating lymphocytes) or engineered T cells (T cell receptor-redirected T cells or chimeric antigen receptor T cells) in patients with digestive tract malignancies over the past two decades, with variable degrees of success. While the majority of completed trials have been primarily aimed at assessing the safety of T-cell transfer strategies, a new generation of studies is being designed to formally evaluate the antitumor potential of adoptive T-cell immunotherapy in both the metastatic and adjuvant settings. In this review, we provide an overview of completed and ongoing clinical trials of passive T-cell immunotherapy in patients with cancers of the digestive tract, focusing on present obstacles and future strategies for achieving potential success.
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Miao L, Zhang Z, Ren Z, Li Y. Application of Immunotherapy in Hepatocellular Carcinoma. Front Oncol 2021; 11:699060. [PMID: 34513678 PMCID: PMC8426571 DOI: 10.3389/fonc.2021.699060] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 08/09/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma is one of the most common malignancies globally. It not only has a hidden onset but also progresses rapidly. Most HCC patients are already in the advanced stage of cancer when they are diagnosed, and have even lost the opportunity for surgical treatment. As an inflammation-related tumor, the immunosuppressive microenvironment of HCC can promote immune tolerance through a variety of mechanisms. Immunotherapy can activate tumor-specific immune responses, which brings a new hope for the treatment of HCC. At the present time, main immunotherapy strategies of HCC include immune checkpoint inhibitors, tumor vaccines, adoptive cell therapy, and so on. This article reviews the application and research progress of immune checkpoint inhibitors, tumor vaccines, and adoptive cell therapy in the treatment of HCC.
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Affiliation(s)
- Lele Miao
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, China.,Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou, China
| | - Zhengchao Zhang
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, China.,Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou, China
| | - Zhijian Ren
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, China.,Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou, China
| | - Yumin Li
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, China.,Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou, China
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Natural Killer Cells and Type 1 Innate Lymphoid Cells in Hepatocellular Carcinoma: Current Knowledge and Future Perspectives. Int J Mol Sci 2021; 22:ijms22169044. [PMID: 34445750 PMCID: PMC8396475 DOI: 10.3390/ijms22169044] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 08/10/2021] [Accepted: 08/18/2021] [Indexed: 02/07/2023] Open
Abstract
Natural killer (NK) cells and type 1 innate lymphoid cells (ILC1) are specific innate lymphoid cell subsets that are key for the detection and elimination of pathogens and cancer cells. In liver, while they share a number of characteristics, they differ in many features. These include their developmental pathways, tissue distribution, phenotype and functions. NK cells and ILC1 contribute to organ homeostasis through the production of key cytokines and chemokines and the elimination of potential harmful bacteria and viruses. In addition, they are equipped with a wide range of receptors, allowing them to detect “stressed cells’ such as cancer cells. Our understanding of the role of innate lymphoid cells in hepatocellular carcinoma (HCC) is growing owing to the development of mouse models, the progress in immunotherapeutic treatment and the recent use of scRNA sequencing analyses. In this review, we summarize the current understanding of NK cells and ILC1 in hepatocellular carcinoma and discuss future strategies to take advantage of these innate immune cells in anti-tumor immunity. Immunotherapies hold great promise in HCC, and a better understanding of the role and function of NK cells and ILC1 in liver cancer could pave the way for new NK cell and/or ILC1-targeted treatment.
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Ni H, Xue J, Wang F, Sun X, Niu M. Nanomedicine Approach to Immunotherapy of Hepatocellular Carcinoma. J Biomed Nanotechnol 2021; 17:771-792. [PMID: 34082866 DOI: 10.1166/jbn.2021.3055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
In recent years, the growing studies focused on the immunotherapy of hepatocellular carcinoma and proved the preclinical and clinical promises of host antitumor immune response. However, there were still various obstacles in meeting satisfactory clinic need, such as low response rate, primary resistance and secondary resistance to immunotherapy. Tackling these barriers required a deeper understanding of immune underpinnings and a broader understanding of advanced technology. This review described immune microenvironment of liver and HCC which naturally decided the complexity of immunotherapy, and summarized recent immunotherapy focusing on different points. The ever-growing clues indicated that the instant killing of tumor cell and the subsequent relive of immunosuppressive microenvironment were both indis- pensables. The nanotechnology applied in immunotherapy and the combination with intervention technology was also discussed.
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Affiliation(s)
- Hongbo Ni
- Department of Interventional Radiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110000, China
| | - Jian Xue
- Department of Interventional Radiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110000, China
| | - Fan Wang
- Department of Interventional Radiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110000, China
| | - Xiaohan Sun
- Department of Interventional Radiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110000, China
| | - Meng Niu
- Department of Interventional Radiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110000, China
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Kim JM, Cho SY, Rhu J, Jung M, Her JH, Lim O, Choi GS, Shin EC, Hwang YK, Joh JW. Adjuvant therapy using ex vivo-expanded allogenic natural killer cells in hepatectomy patients with hepatitis B virus related solitary hepatocellular carcinoma: MG4101 study. Ann Hepatobiliary Pancreat Surg 2021; 25:206-214. [PMID: 34053923 PMCID: PMC8180393 DOI: 10.14701/ahbps.2021.25.2.206] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 10/10/2020] [Accepted: 10/11/2020] [Indexed: 12/12/2022] Open
Abstract
Backgrounds/Aims Fewer reports have been published regarding hepatectomy patients with solitary hepatocellular carcinoma (HCC) who received immunotherapeutic agents as adjuvant therapy. We evaluated the safety and efficacy of ex vivo-expanded allogenic natural killer (NK) cells in those patients with modified International Union Against Cancer (UICC) stage T3. Methods From August 2014 to October 2015, five patients who underwent hepatic resection received ex vivo-expanded allogenic NK cells. Patients received five rounds of NK cells (2-3×107 cells/kg) at postoperative 4, 6, 8, 12, and 16 weeks. This study is registered with ClinicalTrials.gov, number NCT02008929. Results The median age of the five patients (three men and two women) was 44.8 years (range, 36-54 years). All had hepatitis B virus-related HCC, and the median tumor size was 2.2 cm (range, 2.1-8.2 cm). None of the patients had any adverse events. HCC recurrence developed in two patients at one year after hepatic resection, but four patients were alive at 3 years. The two recurrence-free patients showed a higher ratio of CD8+ T lymphocyte populations before and after administration of ex vivo-expanded allogenic NK cells compared with the three patients who experienced recurrence. Conclusions Immunotherapy using ex vivo-expanded allogenic NK cells in hepatectomy patients can be used safely. Further studies should be investigated for efficacy.
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Affiliation(s)
- Jong Man Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sung Yoo Cho
- Cell Therapy Research Center, GC LabCell, Yongin, Korea
| | - Jinsoo Rhu
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Miyoung Jung
- Cell Therapy Research Center, GC LabCell, Yongin, Korea
| | - Jung Hyun Her
- Cell Therapy Research Center, GC LabCell, Yongin, Korea
| | - Okjae Lim
- Cell Therapy Research Center, GC LabCell, Yongin, Korea
| | - Gyu-Seong Choi
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Eui-Cheol Shin
- Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea
| | | | - Jae-Won Joh
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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41
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Natural Killer Cells and T Cells in Hepatocellular Carcinoma and Viral Hepatitis: Current Status and Perspectives for Future Immunotherapeutic Approaches. Cells 2021; 10:cells10061332. [PMID: 34071188 PMCID: PMC8227136 DOI: 10.3390/cells10061332] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 05/13/2021] [Accepted: 05/22/2021] [Indexed: 02/06/2023] Open
Abstract
Natural killer (NK) cells account for 25–50% of the total number of hepatic lymphocytes, which implicates that NK cells play an important role in liver immunity. The frequencies of both circulating and tumor infiltrating NK cells are positively correlated with survival benefit in hepatocellular cancer (HCC) and have prognostic implications, which suggests that functional impairment in NK cells and HCC progression are strongly associated. In HCC, T cell exhaustion is accompanied by the interaction between immune checkpoint ligands and their receptors on tumor cells and antigen presenting cells (APC). Immune checkpoint inhibitors (ICIs) have been shown to interfere with this interaction and have altered the therapeutic landscape of multiple cancer types including HCC. Immunotherapy with check-point inhibitors, aimed at rescuing T-cells from exhaustion, has been applied as first-line therapy for HCC. NK cells are the first line effectors in viral hepatitis and play an important role by directly eliminating virus infected cells or by activating antigen specific T cells through IFN-γ production. Furthermore, chimeric antigen receptor (CAR)-engineered NK cells and T cells offer unique opportunities to create CAR-NK with multiple specificities learning from the experience gained with CAR-T cells with potentially less adverse effects. This review focus on the abnormalities of NK cells, T cells, and their functional impairment in patients with chronic viral hepatitis, which contributes to progression to hepatic malignancy. Furthermore, we discuss and summarize recent advances in the NK cell and T cell based immunotherapeutic approaches in HCC.
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Guo J, Wang S, Han Y, Jia Z, Wang R. Effects of transarterial chemoembolization on the immunological function of patients with hepatocellular carcinoma. Oncol Lett 2021; 22:554. [PMID: 34084221 PMCID: PMC8161415 DOI: 10.3892/ol.2021.12815] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 03/25/2021] [Indexed: 12/18/2022] Open
Abstract
The present study aimed to investigate the effects of transarterial chemoembolization (TACE) on the immune function of patients with hepatocellular carcinoma (HCC). A total of 114 patients with HCC were selected and their peripheral blood was collected before and 1 month after TACE treatment. Flow cytometry and reverse transcription-quantitative PCR were performed to analyze the changes in immune function in patients before and after treatment. Kaplan-Meier curves were plotted for survival analysis. The programmed cell death ligand 1 (PD-L1) and programmed cell death protein 1 (PD1) expression before TACE treatment were significantly higher in patients with poor TACE response compared with those patients with well response. Higher PD-L1 mRNA expression in the peripheral blood mononuclear cells after TACE predicted a superior prognosis. After TACE treatment, the proportion of CD4+/CD8+ cells were decreased while the expression levels of programmed cell death protein 1 (PD1) were significantly increased. To conclude, TACE could reduce the proportion of CD4+/CD8+ cells and improve the mRNA expression levels of PD1 in patients with HCC. The expression levels of PD1 and PD-L1 were closely related to the therapeutic effect of TACE and the prognosis of patients with HCC. TACE combined with immunotherapy may have potential clinical value for patients with HCC.
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Affiliation(s)
- Jingjing Guo
- Interventional Department of Liver Diseases, Qingdao Sixth People's Hospital, Qingdao, Shandong 266000, P.R. China
| | - Saixia Wang
- Integrated Outpatient Department, Qingdao Sixth People's Hospital, Qingdao, Shandong 266000, P.R. China
| | - Yujing Han
- Integrated Traditional Chinese Medicine and Western Medicine Department, Qingdao Sixth People's Hospital, Qingdao, Shandong 266000, P.R. China
| | - Zhongyuan Jia
- Department of General Practice, Jinan Maternity and Child Care Hospital Affiliated to Shandong First Medical University, Jinan Maternity and Child Care Hospital, Jinan, Shandong 250000, P.R. China
| | - Runchao Wang
- Integrated Traditional Chinese Medicine and Western Medicine Department, Qingdao Sixth People's Hospital, Qingdao, Shandong 266000, P.R. China
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Damiris K, Abbad H, Pyrsopoulos N. Cellular based treatment modalities for unresectable hepatocellular carcinoma. World J Clin Oncol 2021; 12:290-308. [PMID: 34131562 PMCID: PMC8173328 DOI: 10.5306/wjco.v12.i5.290] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 04/19/2021] [Accepted: 04/28/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and is unfortunately associated with an overall poor prognosis and high mortality. Early and intermediate stages of HCC allow for treatment with surgical resection, ablation and even liver transplantation, however disease progression warrants conventional systemic therapy. For years treatment options were limited to molecular-targeting medications, of which sorafenib remains the standard of care. The recent development and success of immune checkpoint inhibitors has proven to be a breakthrough in the treatment of HCC, but there is an urgent need for the development of further novel therapeutic treatments that prolong overall survival and minimize recurrence. Current investigation is focused on adoptive cell therapy including chimeric antigen receptor-T cells (CAR-T cells), T cell receptor (TCR) engineered T cells, dendritic cells, natural killer cells, and tumor infiltrating lymphocyte cells, which have shown remarkable success in the treatment of hematological and solid tumor malignancies. In this review we briefly introduce readers to the currently approved systemic treatment options and present clinical and experimental evidence of HCC immunotherapeutic treatments that will hopefully one day allow for revolutionary change in the treatment modalities used for unresectable HCC. We also provide an up-to-date compilation of ongoing clinical trials investigating CAR-T cells, TCR engineered T cells, cancer vaccines and oncolytic viruses, while discussing strategies that can help overcome commonly faced challenges when utilizing cellular based treatments.
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Affiliation(s)
- Konstantinos Damiris
- Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, United States
| | - Hamza Abbad
- Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, United States
| | - Nikolaos Pyrsopoulos
- Department of Medicine, Division of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, Newark, NJ 07103, United States
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Reig M, Forner A, Ávila MA, Ayuso C, Mínguez B, Varela M, Bilbao I, Bilbao JI, Burrel M, Bustamante J, Ferrer J, Gómez MÁ, Llovet JM, De la Mata M, Matilla A, Pardo F, Pastrana MA, Rodríguez-Perálvarez M, Tabernero J, Urbano J, Vera R, Sangro B, Bruix J. Diagnosis and treatment of hepatocellular carcinoma. Update of the consensus document of the AEEH, AEC, SEOM, SERAM, SERVEI, and SETH. Med Clin (Barc) 2021; 156:463.e1-463.e30. [PMID: 33461840 DOI: 10.1016/j.medcli.2020.09.022] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 09/12/2020] [Accepted: 09/15/2020] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver neoplasm and one of the most common causes of death in patients with cirrhosis of the liver. In parallel, with recognition of the clinical relevance of this cancer, major new developments have recently appeared in its diagnosis, prognostic assessment and in particular, in its treatment. Therefore, the Spanish Association for the Study of the Liver (AEEH) has driven the need to update the clinical practice guidelines, once again inviting all the societies involved in the diagnosis and treatment of this disease to participate in the drafting and approval of the document: Spanish Society for Liver Transplantation (SETH), Spanish Society of Diagnostic Radiology (SERAM), Spanish Society of Vascular and Interventional Radiology (SERVEI), Spanish Association of Surgeons (AEC) and Spanish Society of Medical Oncology (SEOM). The clinical practice guidelines published in 2016 and accepted as National Health System Clinical Practice Guidelines were taken as the reference documents, incorporating the most important recent advances. The scientific evidence and the strength of the recommendation is based on the GRADE system.
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Affiliation(s)
- María Reig
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Hepatología, Hospital Clínic, IDIBAPS, Universidad de Barcelona, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Barcelona, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España
| | - Alejandro Forner
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Hepatología, Hospital Clínic, IDIBAPS, Universidad de Barcelona, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Barcelona, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España
| | - Matías A Ávila
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Programa de Hepatología, Centro de Investigación Médica Aplicada, Universidad de Navarra-IDISNA, Pamplona, España
| | - Carmen Ayuso
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Servicio de Radiodiagnóstico, Hospital Clínic Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, España
| | - Beatriz Mínguez
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Servicio de Hepatología, Hospital Universitario Vall d́Hebron, Grupo de Investigación en Enfermedades Hepáticas (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universidad Autónoma de Barcelona. Barcelona, España
| | - María Varela
- Sección de Hepatología, Servicio de Aparato Digestivo, Hospital Universitario Central de Asturias. Oviedo, España
| | - Itxarone Bilbao
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Servicio de Cirugía Hepatobiliopancreática y Trasplantes Digestivos, Hospital Universitario Vall d'Hebron, Universidad Autónoma de Barcelona. Barcelona, España
| | - José Ignacio Bilbao
- Unidad de Radiología Vascular e Intervencionista, Departamento de Radiodiagnóstico, Clínica Universidad de Navarra, Pamplona, España
| | - Marta Burrel
- Servicio de Radiodiagnóstico, Hospital Clínic Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, España
| | - Javier Bustamante
- Servicio de Gastroenterología y Hepatología, Sección de Hepatología y Trasplante, Hospital Universitario de Cruces, Baracaldo, España
| | - Joana Ferrer
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Cirugía Hepatobiliopancreática, Hospital Clínic, IDIBAPS, Universidad de Barcelona, Barcelona, España
| | - Miguel Ángel Gómez
- Unidad de Cirugía Hepatobiliopancreática y Trasplantes, Hospital Universitario Virgen del Rocío, Sevilla, España
| | - Josep María Llovet
- Grupo de Investigación Traslacional en Oncología Hepática, Servicio de Hepatología, Hospital Clínic, IDIBAPS, Universidad de Barcelona, Barcelona, España
| | - Manuel De la Mata
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Unidad Clínica de Aparato Digestivo, Hospital Universitario Reina Sofía, Córdoba, España
| | - Ana Matilla
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Sección de Hepatología, Servicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón, Madrid, España
| | - Fernando Pardo
- Servicio de Cirugía Hepatobiliopancreática y Trasplante, Clínica Universidad de Navarra, Pamplona, España
| | - Miguel A Pastrana
- Servicio de Radiodiagnóstico, Hospital Universitario Puerta de Hierro, Universidad Autónoma de Madrid, Madrid, España
| | - Manuel Rodríguez-Perálvarez
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Unidad Clínica de Aparato Digestivo, Hospital Universitario Reina Sofía, Córdoba, España
| | - Josep Tabernero
- Servicio de Oncología Médica, Hospital Universitario Vall d'Hebron, Universidad Autónoma de Barcelona, Barcelona, España
| | - José Urbano
- Unidad de Radiología Vascular e Intervencionista, Servicio de Radiodiagnóstico, Hospital Universitario Ramón y Cajal, Universidad de Alcalá, Madrid, España
| | - Ruth Vera
- Servicio de Oncología Médica, Complejo hospitalario de Navarra, Navarrabiomed-IDISNA, Pamplona, España
| | - Bruno Sangro
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Unidad de Hepatología y Área de Oncología HBP, Clínica Universidad de Navarra-IDISNA, Pamplona, España.
| | - Jordi Bruix
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Hepatología, Hospital Clínic, IDIBAPS, Universidad de Barcelona, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Barcelona, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España.
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Guan MC, Wang MD, Liu SY, Ouyang W, Liang L, Pawlik TM, Xu QR, Huang DS, Shen F, Zhu H, Yang T. Early diagnosis and therapeutic strategies for hepatocellular carcinoma: From bench to bedside. World J Gastrointest Oncol 2021; 13:197-215. [PMID: 33889272 PMCID: PMC8040062 DOI: 10.4251/wjgo.v13.i4.197] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/14/2021] [Accepted: 03/11/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths worldwide. The prognosis of patients with HCC remains poor largely due to the late diagnosis and lack of effective treatments. Despite being widely used, alpha-fetoprotein serology and ultrasonography have limited diagnostic performance for early-stage HCC. The emergence of omics strategies has contributed to significant advances in the development of non-invasive biomarkers for the early diagnosis of HCC including proteins, metabolites, circulating tumor deoxyribonucleic acid, and circulating non-coding ribonucleic acid. Early diagnosis is beneficial to patients as it increases the proportion who can be treated with curative treatment, thus prolonging survival outcomes. Currently, multiple clinical trials involving locoregional, systemic therapies, and combinations of these modalities are changing therapeutic strategies for different stage HCC. Success in several preclinical trials that involve immunotherapeutic innovations has created the potential to complement and enforce other treatment strategies in the future. This review summarizes the most recent advances in non-invasive early molecular detection, current therapy strategies, and potential immunotherapeutic innovations of HCC.
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Affiliation(s)
- Ming-Cheng Guan
- Department of Medical Oncology, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
| | - Ming-Da Wang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital (Navy Medical University), Second Military Medical University, Shanghai 200438, China
| | - Si-Yu Liu
- Department of Laboratory, Lishui Municipal Central Hospital, Lishui 323000, Zhejiang Province, China
| | - Wei Ouyang
- Department of Medical Oncology, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
| | - Lei Liang
- Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People’s Hospital (People’s Hospital of Hangzhou Medical College), Hangzhou 310000, Zhejiang Province, China
- Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
| | - Timothy M Pawlik
- Department of Surgery, Ohio State University, Wexner Medical Center, Columbus, OH 43210, United States
| | - Qiu-Ran Xu
- Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People’s Hospital (People’s Hospital of Hangzhou Medical College), Hangzhou 310000, Zhejiang Province, China
- Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
| | - Dong-Sheng Huang
- Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People’s Hospital (People’s Hospital of Hangzhou Medical College), Hangzhou 310000, Zhejiang Province, China
- Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
| | - Feng Shen
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital (Navy Medical University), Second Military Medical University, Shanghai 200438, China
| | - Hong Zhu
- Department of Medical Oncology, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
| | - Tian Yang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital (Navy Medical University), Second Military Medical University, Shanghai 200438, China
- Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People’s Hospital (People’s Hospital of Hangzhou Medical College), Hangzhou 310000, Zhejiang Province, China
- Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
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46
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Zhang W, Zhang B, Chen XP. Adjuvant treatment strategy after curative resection for hepatocellular carcinoma. Front Med 2021; 15:155-169. [PMID: 33754281 DOI: 10.1007/s11684-021-0848-3] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 02/20/2021] [Indexed: 01/27/2023]
Abstract
Hepatic resection represents the first-line treatment for patients with resectable hepatocellular carcinoma (HCC). However, the 5-year recurrence rates of HCC after surgery have been reported to range from 50% to 70%. In this review, we evaluated the available evidence for the efficiency of adjuvant treatments to prevent HCC recurrence after curative liver resection. Antiviral therapy has potential advantages in terms of reducing the recurrence rate and improving the overall survival (OS) and/or disease-free survival of patients with hepatitis-related HCC. Postoperative adjuvant transarterial chemoembolization can significantly reduce the intrahepatic recurrence rate and improve OS, especially for patients with a high risk of recurrence. The efficacy of molecular targeted drugs as an adjuvant therapy deserves further study. Adjuvant adoptive immunotherapy can significantly improve the clinical prognosis in the early stage. Randomized controlled trial (RCT) studies evaluating adjuvant immune checkpoint inhibitors are ongoing, and the results are highly expected. Adjuvant hepatic artery infusion chemotherapy might be beneficial in patients with vascular invasion. Huaier granule, a traditional Chinese medicine, has been proved to be effective in prolonging the recurrence-free survival and reducing extrahepatic recurrence. The efficiency of other adjuvant treatments needs to be further confirmed by large RCT studies.
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Affiliation(s)
- Wei Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Xiao-Ping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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47
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Hong S, Yu C, Wang P, Shi Y, Cao W, Cheng B, Chapla DG, Ma Y, Li J, Rodrigues E, Narimatsu Y, Yates JR, Chen X, Clausen H, Moremen KW, Macauley MS, Paulson JC, Wu P. Glycoengineering of NK Cells with Glycan Ligands of CD22 and Selectins for B‐Cell Lymphoma Therapy. Angew Chem Int Ed Engl 2021. [DOI: 10.1002/ange.202005934] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Senlian Hong
- Department of Molecular Medicine The Scripps Research Institute La Jolla CA 92037 USA
| | - Chenhua Yu
- Department of Molecular Medicine The Scripps Research Institute La Jolla CA 92037 USA
- Tianjin Medical University Cancer Institute & Hospital Key laboratory of Breast Cancer Prevention and Therapy School of Medicine Nankai University Tianjin 300071 China
| | - Peng Wang
- Department of Molecular Medicine The Scripps Research Institute La Jolla CA 92037 USA
| | - Yujie Shi
- Department of Molecular Medicine The Scripps Research Institute La Jolla CA 92037 USA
| | - Weiqian Cao
- Department of Molecular Medicine The Scripps Research Institute La Jolla CA 92037 USA
- Department of Chemistry and Institutes of Biomedical Sciences The Fifth People's Hospital Fudan University Shanghai 200433 China
| | - Bo Cheng
- College of Chemistry and Molecular Engineering Beijing University Beijing 100871 China
| | | | - Yuanhui Ma
- Department of Molecular Medicine The Scripps Research Institute La Jolla CA 92037 USA
| | - Jie Li
- Department of Molecular Medicine The Scripps Research Institute La Jolla CA 92037 USA
| | - Emily Rodrigues
- Department of Chemistry University of Alberta 11227 Saskatchewan Dr NW Edmonton, AB T6G 2G2 Alberta Canada
| | - Yoshiki Narimatsu
- Copenhagen Center for Glycomics Department of Cellular and Molecular Medicine University of Copenhagen Copenhagen Denmark
| | - John R. Yates
- Department of Molecular Medicine The Scripps Research Institute La Jolla CA 92037 USA
| | - Xing Chen
- College of Chemistry and Molecular Engineering Beijing University Beijing 100871 China
| | - Henrik Clausen
- Copenhagen Center for Glycomics Department of Cellular and Molecular Medicine University of Copenhagen Copenhagen Denmark
| | - Kelly W. Moremen
- Complex Carbohydrate Research Center University of Georgia Athens GA 30602 USA
| | - Matthew Scott Macauley
- Department of Chemistry University of Alberta 11227 Saskatchewan Dr NW Edmonton, AB T6G 2G2 Alberta Canada
| | - James C. Paulson
- Department of Molecular Medicine The Scripps Research Institute La Jolla CA 92037 USA
| | - Peng Wu
- Department of Molecular Medicine The Scripps Research Institute La Jolla CA 92037 USA
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Hong S, Yu C, Wang P, Shi Y, Cao W, Cheng B, Chapla DG, Ma Y, Li J, Rodrigues E, Narimatsu Y, Yates JR, Chen X, Clausen H, Moremen KW, Macauley MS, Paulson JC, Wu P. Glycoengineering of NK Cells with Glycan Ligands of CD22 and Selectins for B-Cell Lymphoma Therapy. Angew Chem Int Ed Engl 2021; 60:3603-3610. [PMID: 33314603 PMCID: PMC7980786 DOI: 10.1002/anie.202005934] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 07/14/2020] [Indexed: 12/29/2022]
Abstract
CD22, a member of Siglec family of sialic acid binding proteins, has restricted expression on B cells. Antibody-based agents targeting CD22 or CD20 on B lymphoma and leukemia cells exhibit clinical efficacy for treating these malignancies, but also attack normal B cells leading to immune deficiency. Here, we report a chemoenzymatic glycocalyx editing strategy to introduce high-affinity and specific CD22 ligands onto NK-92MI and cytokine-induced natural killer cells to achieve tumor-specific CD22 targeting. These CD22-ligand modified cells exhibited significantly enhanced tumor cell binding and killing in vitro without harming healthy B cells. For effective lymphoma cell killing in vivo, we further functionalized CD22 ligand-modified NK-92MI cells with the E-selectin ligand sialyl Lewis X to promote trafficking to bone marrow. The dual-functionalized cells resulted in the efficient suppression of B lymphoma in a xenograft model. Our results suggest that natural killer cells modified with glycan ligands to CD22 and selectins promote both targeted killing of B lymphoma cells and improved trafficking to sites where the cancer cells reside, respectively.
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Affiliation(s)
- Senlian Hong
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA
| | - Chenhua Yu
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA
- Tianjin Medical University Cancer Institute & Hospital, Key laboratory of Breast Cancer Prevention and Therapy, School of Medicine, Nankai University, Tianjin, 300071, China
| | - Peng Wang
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA
| | - Yujie Shi
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA
| | - Weiqian Cao
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA
- Department of Chemistry and Institutes of Biomedical Sciences, The Fifth People's Hospital, Fudan University, Shanghai, 200433, China
| | - Bo Cheng
- College of Chemistry and Molecular Engineering, Beijing University, Beijing, 100871, China
| | - Digantkumar G Chapla
- Complex Carbohydrate Research Center, University of Georgia, Athens, GA, 30602, USA
| | - Yuanhui Ma
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA
| | - Jie Li
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA
| | - Emily Rodrigues
- Department of Chemistry, University of Alberta, 11227 Saskatchewan Dr NW, Edmonton, AB, T6G 2G2, Alberta, Canada
| | - Yoshiki Narimatsu
- Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
| | - John R Yates
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA
| | - Xing Chen
- College of Chemistry and Molecular Engineering, Beijing University, Beijing, 100871, China
| | - Henrik Clausen
- Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Kelly W Moremen
- Complex Carbohydrate Research Center, University of Georgia, Athens, GA, 30602, USA
| | - Matthew Scott Macauley
- Department of Chemistry, University of Alberta, 11227 Saskatchewan Dr NW, Edmonton, AB, T6G 2G2, Alberta, Canada
| | - James C Paulson
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA
| | - Peng Wu
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA
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Peng Y, Liu C, Li M, Li W, Zhang M, Jiang X, Chang Y, Liu L, Wang F, Zhao Q. Identification of a prognostic and therapeutic immune signature associated with hepatocellular carcinoma. Cancer Cell Int 2021; 21:98. [PMID: 33568167 PMCID: PMC7877064 DOI: 10.1186/s12935-021-01792-4] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 01/27/2021] [Indexed: 02/07/2023] Open
Abstract
Background Hepatocellular carcinoma (HCC) is one of the most prevalent and inflammation-associated cancers. The tumor microenvironment (TME) plays an essential role in HCC development and metastasis, leading to poor prognosis. The overall TME immune cells infiltration characterizations mediated by immune-related genes (IRGs) remain unclear. In this study, we aimed to investigate whether immune-related genes could be indicators for the prognosis of HCC patients and TME cell infiltration characterization as well as responses to immunotherapy. Methods We obtained differentially expressed immune-related genes (DE IRGs) between normal liver tissues and liver cancer tissues from The Cancer Genome Atlas (TCGA) database. To identify the prognostic genes and establish an immune risk signature, we performed univariable Cox regression survival analysis and the Least Absolute Shrinkage and Selector Operation (LASSO) regression based on the DE IRGs by robust rank aggregation method. Cox regression analysis was used to identify independent prognostic factors in HCC. We estimated the immune cell infiltration in TME via CIBERSORT and immunotherapy response through TIDE algorithm. Results We constructed an immune signature and validated its predictive capability. The immune signature included 7 differentially expressed IRGs: BIRC5, CACYBP, NR0B1, RAET1E, S100A8, SPINK5, and SPP1. The univariate and multivariate cox analysis showed that the 7-IRGs signature was a robust independent prognostic factor in the overall survival of HCC patients. The 7-IRG signature was associated with some clinical features, including gender, vascular invasion, histological grade, clinical stage, T stage. We also found that the 7-IRG signature could reflect the infiltration characterization of different immunocytes in the tumor microenvironment (TME) and had a good correlation with immune checkpoint molecules, revealing that the poor prognosis might be partly due to immunosuppressive TME. The Tumour Immune Dysfunction and Exclusion (TIDE) analysis data showed that the 7-IRG signature had great potential for indicating the immunotherapy response in HCC patients. The mutation analysis demonstrated a significant difference in the tumor mutation burden (TMB) between the high- and low-risk groups, partially explaining this signature's predictive value. Conclusion In a word, we constructed and validated a novel, immune-related prognostic signature for HCC patients. This signature could effectively indicate HCC patients' survival and immunotherapy response. And it might act as potential immunotherapeutic targets for HCC patients.
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Affiliation(s)
- Yanan Peng
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Chang Liu
- Department of Obstetrics, Renmin Hospital of Wuhan University, Wuhan, China
| | - Mengting Li
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Wenjie Li
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Mengna Zhang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Xiang Jiang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Ying Chang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Lan Liu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Fan Wang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China. .,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China.
| | - Qiu Zhao
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China. .,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China.
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50
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Ruf B, Heinrich B, Greten TF. Immunobiology and immunotherapy of HCC: spotlight on innate and innate-like immune cells. Cell Mol Immunol 2021; 18:112-127. [PMID: 33235387 PMCID: PMC7852696 DOI: 10.1038/s41423-020-00572-w] [Citation(s) in RCA: 206] [Impact Index Per Article: 51.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 09/29/2020] [Indexed: 12/24/2022] Open
Abstract
Immune-based therapies such as immune checkpoint inhibitors have revolutionized the systemic treatment of various cancer types. The therapeutic application of monoclonal antibodies targeting inhibitory pathways such as programmed cell death-1(PD-1)/programmed cell death ligand 1 (PD-L1) and CTLA-4 to cells of the adaptive immune system has recently been shown to generate meaningful improvement in the clinical outcome of hepatocellular carcinoma (HCC). Nevertheless, current immunotherapeutic approaches induce durable responses in only a subset of HCC patients. Since immunologic mechanisms such as chronic inflammation due to chronic viral hepatitis or alcoholic and nonalcoholic fatty liver disease play a crucial role in the initiation, development, and progression of HCC, it is important to understand the underlying mechanisms shaping the unique tumor microenvironment of liver cancer. The liver is an immunologic organ with large populations of innate and innate-like immune cells and is exposed to bacterial, viral, and fungal antigens through the gut-liver axis. Here, we summarize and highlight the role of these cells in liver cancer and propose strategies to therapeutically target them. We also discuss current immunotherapeutic strategies in HCC and outline recent advances in our understanding of how the therapeutic potential of these agents might be enhanced.
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Affiliation(s)
- Benjamin Ruf
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Centre for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Bernd Heinrich
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Centre for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Tim F Greten
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Centre for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
- NCI CCR Liver Cancer Program, National Institutes of Health, Bethesda, MD, 20892, USA.
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