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Miri H, Rahimzadeh P, Hashemi M, Nabavi N, Aref AR, Daneshi S, Razzaghi A, Abedi M, Tahmasebi S, Farahani N, Taheriazam A. Harnessing immunotherapy for hepatocellular carcinoma: Principles and emerging promises. Pathol Res Pract 2025; 269:155928. [PMID: 40184729 DOI: 10.1016/j.prp.2025.155928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 03/12/2025] [Accepted: 03/26/2025] [Indexed: 04/07/2025]
Abstract
HCC is considered as one of the leadin causes of death worldwide, with the ability of resistance towards therapeutics. Immunotherapy, particularly ICIs, have provided siginficant insights towards harnessing the immune system. The present review introduces the concepts and possibilities of immunotherapy for HCC treatment, emphasizing its underlying mechanisms and capacity to enhance patient results, focusing on both pre-clinical and clinical insights. The functions of TME and immune evasion mechanisms typical of HCC would be evaluated along with how contemporary immunotherapeutic approaches are designed to address these challenges. Furthermore, the clinical application of immunotherapy in HCC is discussed, emphasizing recent trial findings demonstrating the effectiveness and safety of drugs. In addition, the problems caused by immune evasion and resistance would be discussed to increase potential of immunotherapy along with combination therapy.
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Affiliation(s)
- Hossein Miri
- Faculty of Medicine, Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran
| | - Payman Rahimzadeh
- Surgical Research Society (SRS), Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Noushin Nabavi
- Independent Researcher, Victoria, British Columbia V8V 1P7, Canada
| | - Amir Reza Aref
- Department of Vitro Vision, DeepkinetiX, Inc, Boston, MA, USA
| | - Salman Daneshi
- Department of Public Health, School of Health, Jiroft University Of Medical Sciences, Jiroft, Iran
| | - Alireza Razzaghi
- Social Determinants of Health Research Center, Research Institute for Prevention of Non-Communicable Diseases, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Maryam Abedi
- Department of Pathology, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran.
| | - Safa Tahmasebi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Najma Farahani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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Pérez-Picazo SE, Martínez-Morales P, Conde-Rodríguez I, Reyes-Leyva J, Vallejo-Ruiz V. High serum levels of soluble PD‑1 and PD‑L1 are associated with advanced clinical stages in patients with cervical cancer. Biomed Rep 2025; 22:70. [PMID: 40017501 PMCID: PMC11865715 DOI: 10.3892/br.2025.1948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Accepted: 02/10/2025] [Indexed: 03/01/2025] Open
Abstract
The binding of programmed cell death receptor-ligand 1 (PD-L1) to programmed cell death protein 1 (PD-1) inhibits T-cell activation, playing a negative role in the anticancer immune response. The soluble forms of these proteins, found in blood circulation, have recently received increasing attention and their function in the cancer immune response remains unclear. The present study evaluated the serum levels of soluble (s)PD-1 and sPD-L1 in patients with cervical cancer and healthy controls, and their associations with clinicopathological characteristics and clinical outcomes. The serum concentrations of both soluble proteins were determined via ELISA. The concentrations of sPD-1 and sPD-L1 were higher in patients with cervical cancer and advanced clinical stages. The evaluation of sPD-1 and clinical outcome revealed higher levels in deceased patients than in total remission patients. sPD-1 and sPD-L1 concentrations were moderately positively correlated; however, in patients with clinical stage IV disease, a very strong correlation was observed. sPD-1 and sPD-L1 could be used as potential diagnostic biomarkers for patients with cervical cancer. Considering the higher levels in advanced clinical stages, their role in cervical cancer progression or treatment response must be explored.
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Affiliation(s)
| | | | - Ileana Conde-Rodríguez
- Eastern Biomedical Research Center, Mexican Institute of Social Security, Atlixco, Puebla 72760, Mexico
| | - Julio Reyes-Leyva
- Faculty of Chemical Sciences, Autonomous University of Puebla, Puebla 72570, Mexico
| | - Verónica Vallejo-Ruiz
- Eastern Biomedical Research Center, Mexican Institute of Social Security, Atlixco, Puebla 72760, Mexico
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Dash P, Nayak S, Parida PK. The Efficacy of Curcumin in Reducing Immunosuppressive States of Peripheral Blood Mononuclear Cells Extracted From Oral Squamous Cell Carcinoma Patients: An In Vitro Study. Cureus 2025; 17:e77899. [PMID: 39991356 PMCID: PMC11847154 DOI: 10.7759/cureus.77899] [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] [Accepted: 01/23/2025] [Indexed: 02/25/2025] Open
Abstract
Background and objectives Prior studies have shown that patients with oral cancer overexpress programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) in cancer cells and immunocompetent lymphocytes. Current immunotherapeutic interventions include antibodies targeting PD-1/PD-L1. This observational, in vitro, cell culture-based study aimed to assess the concentrations of PD-1 and PD-L1 in the peripheral blood mononuclear cells (PBMCs) of patients with oral squamous cell carcinoma (OSCC) and compare their levels with those in healthy controls, both pre- and post-curcumin intervention. This study also compared the soluble fraction of PD-L1 in the serum of patients with that in controls. We aimed to determine a cutoff level for cell surface PD-1/PD-L1 to differentiate between patients and healthy controls, in order to identify potential targets for immunotherapy. Methodology Blood samples (5 mL) were collected from both controls (n=20) and patients (n=20). Of this, 2 mL was used to collect serum samples, and 3 mL was used for isolation and culture of PBMCs. Cells were analyzed pre- and post-intervention with curcumin for PD-1 and PD-L1 expression. Results This study provides relevant data regarding cellular and serum PD-1/PD-L1 levels in patients with OSCC, which were significantly higher than in controls. Intervention with curcumin decreased PD-L1/PD-1 levels, indicating the therapeutic efficacy of curcumin in suppressing immunotolerance in the tumor microenvironment. We also found that cell lysate PD-L1 and PD-1 had a sensitivity of 75% and specificity of 89%, with cutoff values of 0.602 and 5.53 ng/mL for PD-L1 and PD-1, respectively. The receiver operating characteristic (ROC) curve analysis determined that these markers were suitable for OSCC diagnosis and identifying the appropriate cohort for immunotherapy. Conclusions Our study showed that serum and PBMC lysate PD-1 and PD-L1 levels were higher in advanced cancer cases compared to patients with localized disease without metastasis. Curcumin reduced the levels of PD-1 and PD-L1 in PBMC lysates. Further studies and clinical trials are required to gain deeper insights into its utility as an effective chemo adjuvant.
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Affiliation(s)
- Prakruti Dash
- Biochemistry, All India Institute of Medical Sciences, Bhubaneswar, Bhubaneswar, IND
| | - Saurav Nayak
- Biochemistry, All India Institute of Medical Sciences, Bhubaneswar, Bhubaneswar, IND
| | - Pradipta K Parida
- Otorhinolaryngology, All India Institute of Medical Sciences, Bhubaneswar, Bhubaneswar, IND
- ENT-Head and Neck Surgery, All India Institute of Medical Sciences, Bhubaneswar, Bhubaneswar, IND
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Chen L, Chao Y, Li W, Wu Z, Wang Q. Soluble immune checkpoint molecules in cancer risk, outcomes prediction, and therapeutic applications. Biomark Res 2024; 12:95. [PMID: 39218939 PMCID: PMC11368031 DOI: 10.1186/s40364-024-00647-0] [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: 07/19/2024] [Accepted: 08/24/2024] [Indexed: 09/04/2024] Open
Abstract
Immunotherapy has emerged as a pivotal modality in cancer treatment, with immune checkpoint inhibitors effectively combating malignancies by impeding crucial pathways within the immune system and stimulating patients' immune responses. Soluble forms of immune checkpoints exhibit a remarkable diversity and can be readily tracked in circulation, holding immense potential as biomarkers for cancer treatment. An increasing number of studies focused on soluble immune checkpoints in cancer have emerged thanks to technological advancements. In this systematic review, we comprehensively summarized the recent studies on soluble immune checkpoints in human cancer risk prediction, outcome prediction, therapeutic applications, and potential molecular mechanisms, which demonstrated the promising future of soluble immune checkpoints in clinical applications. The clinical relevance of soluble immune checkpoints has been recognized in multiple cancers, yet the therapeutic applications and mechanisms remain obscure. Interpreting the impacts and mechanisms of soluble immune checkpoints could shed a light on the novel strategies of cancer screening, treatments, and outcome prediction.
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Affiliation(s)
- Lin Chen
- Department of Surgical Oncology, Affiliated Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang, 310009, Zhejiang, PR China
- School of Public Health, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Yuqing Chao
- Department of Surgical Oncology, Affiliated Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang, 310009, Zhejiang, PR China
- School of Public Health, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Wenjing Li
- Department of Surgical Oncology, Affiliated Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang, 310009, Zhejiang, PR China
- School of Public Health, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Zhixia Wu
- Department of Service and Purchase, Affiliated Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang, China
| | - Qinchuan Wang
- Department of Surgical Oncology, Affiliated Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang, 310009, Zhejiang, PR China.
- School of Public Health, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
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Zvirble M, Survila Z, Bosas P, Dobrovolskiene N, Mlynska A, Zaleskis G, Jursenaite J, Characiejus D, Pasukoniene V. Prognostic significance of soluble PD-L1 in prostate cancer. Front Immunol 2024; 15:1401097. [PMID: 39055716 PMCID: PMC11269106 DOI: 10.3389/fimmu.2024.1401097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 06/19/2024] [Indexed: 07/27/2024] Open
Abstract
Purpose The aim of this study was to assess the role of sPD-L1 and sPD-1 as potential biomarkers in prostate cancer (PCa). The association of the values of these soluble proteins were correlated to the clinical data: stage of disease, Gleason score, biochemical recurrence etc. For a comprehensive study, the relationship between sPD-L1 and sPD-1 and circulating immune cells was further investigated. Methods A total of 88 patients with pT2 and pT3 PCa diagnosis and 41 heathy men were enrolled. Soluble sPD-L1 and sPD-1 levels were measured in plasma by ELISA method. Immunophenotyping was performed by flow cytometry analysis. Results Our study's findings demonstrate that PCa patients had higher levels of circulating sPD-L1 and sPD-1 comparing to healthy controls (p < 0.001). We found a statistically significant (p < 0.05) relationship between improved progression free survival and lower initial sPD-L1 values. Furthermore, patients with a lower sPD-1/sPD-L1 ratio were associated with a higher probability of disease progression (p < 0.05). Additionally, a significant (p < 0.05) association was discovered between higher Gleason scores and elevated preoperative sPD-L1 levels and between sPD-1 and advanced stage of disease (p < 0.05). A strong correlation (p < 0.05), between immunosuppressive CD4+CD25+FoxP3+ regulatory T cells and baseline sPD-L1 was observed in patients with unfavorable postoperative course of the disease, supporting the idea that these elements influence each other in cancer progression. In addition to the postoperative drop in circulating PD-L1, the inverse relationship (p < 0.05), between the percentage of M-MDSC and sPD-L1 in patients with BCR suggests that M-MDSC is not a source of sPD-L1 in PCa patients. Conclusion Our findings suggest the potential of sPD-L1 as a promising prognostic marker in prostate cancer.
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Affiliation(s)
- Margarita Zvirble
- Laboratory of Immunology, National Cancer Institute, Vilnius, Lithuania
- Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Zilvinas Survila
- Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Paulius Bosas
- Department of Oncourology, National Cancer Institute, Vilnius, Lithuania
- Department of Immunology and Bioelectrochemistry, State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania
| | | | - Agata Mlynska
- Laboratory of Immunology, National Cancer Institute, Vilnius, Lithuania
- Department of Chemistry and Bioengineering, Vilnius Gediminas Technical University, Vilnius, Lithuania
| | - Gintaras Zaleskis
- Department of Immunology and Bioelectrochemistry, State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania
| | - Jurgita Jursenaite
- Department of Immunology and Bioelectrochemistry, State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania
| | - Dainius Characiejus
- Department of Immunology and Bioelectrochemistry, State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania
- Department of Pathology and Forensic Medicine, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Vita Pasukoniene
- Laboratory of Immunology, National Cancer Institute, Vilnius, Lithuania
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Wang C, Wei F, Sun X, Qiu W, Yu Y, Sun D, Zhi Y, Li J, Fan Z, Lv G, Wang G. Exploring potential predictive biomarkers through historical perspectives on the evolution of systemic therapies into the emergence of neoadjuvant therapy for the treatment of hepatocellular carcinoma. Front Oncol 2024; 14:1429919. [PMID: 38993637 PMCID: PMC11236692 DOI: 10.3389/fonc.2024.1429919] [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: 05/08/2024] [Accepted: 06/13/2024] [Indexed: 07/13/2024] Open
Abstract
Hepatocellular carcinoma (HCC), a type of liver cancer, ranks as the sixth most prevalent cancer globally and represents the third leading cause of cancer-related deaths. Approximately half of HCC patients miss the opportunity for curative treatment and are then limited to undergoing systemic therapies. Currently, systemic therapy has entered the era of immunotherapy, particularly with the advent of immune-checkpoint inhibitors (ICIs), which have significantly enhanced outcomes for patients with advanced HCC. Neoadjuvant treatment for HCC has become a possibility-findings from the IMbrave 050 trial indicated that ICIs offer the benefit of recurrence-free survival for high-risk HCC patients post-resection or local ablation. However, only a small fraction of individuals benefit from systemic therapy. Consequently, there is an urgent need to identify predictive biomarkers for treatment response and outcome assessment. This study reviewed the historical progression of systemic therapy for HCC, highlighting notable therapeutic advancements. This study examined the development of systemic therapies involving conventional drugs and clinical trials utilized in HCC treatment, as well as potential predictive biomarkers for advanced and/or locally advanced HCC. Various studies have revealed potential biomarkers in the context of HCC treatment. These include the association of dendritic cells (DCs) with a favorable response to neoadjuvant therapy, the presence of enriched T effector cells and tertiary lymphoid structures, the identification of CD138+ plasma cells, and distinct spatial arrangements of B cells in close proximity to T cells among responders with locally advanced HCC receiving neoadjuvant cabozantinib and nivolumab treatment. Furthermore, pathological response has been associated with intratumoral cellular triads consisting of progenitor CD8+ T cells and CXCL13+ CD4+ T helper cells surrounding mature DCs in patients receiving neoadjuvant cemiplimab for resectable HCC. Despite no widely recognized predictive biomarkers for HCC individualized treatment, we believe neoadjuvant trials hold the most promise in identifying and validating them. This is because they can collect multiple samples from resectable HCC patients across stages, especially with multi-omics, bridging preclinical and clinical gaps.
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Affiliation(s)
- Chuanlei Wang
- Department of Hepatobiliary and Pancreatic Surgery I, General Surgery Center, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of the General Surgery Health Department of Jilin Province, Changchun, China
| | - Feng Wei
- Department of Hepatobiliary and Pancreatic Surgery I, General Surgery Center, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of the General Surgery Health Department of Jilin Province, Changchun, China
| | - Xiaodong Sun
- Department of Hepatobiliary and Pancreatic Surgery I, General Surgery Center, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of the General Surgery Health Department of Jilin Province, Changchun, China
| | - Wei Qiu
- Department of Hepatobiliary and Pancreatic Surgery I, General Surgery Center, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of the General Surgery Health Department of Jilin Province, Changchun, China
| | - Ying Yu
- Department of Hepatobiliary and Pancreatic Surgery I, General Surgery Center, The First Hospital of Jilin University, Changchun, China
| | - Dawei Sun
- Department of Hepatobiliary and Pancreatic Surgery I, General Surgery Center, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of the General Surgery Health Department of Jilin Province, Changchun, China
| | - Yao Zhi
- Department of Hepatobiliary and Pancreatic Surgery I, General Surgery Center, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of the General Surgery Health Department of Jilin Province, Changchun, China
| | - Jing Li
- Department of Hepatobiliary and Pancreatic Surgery I, General Surgery Center, The First Hospital of Jilin University, Changchun, China
| | - Zhongqi Fan
- Department of Hepatobiliary and Pancreatic Surgery I, General Surgery Center, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of the General Surgery Health Department of Jilin Province, Changchun, China
| | - Guoyue Lv
- Department of Hepatobiliary and Pancreatic Surgery I, General Surgery Center, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of the General Surgery Health Department of Jilin Province, Changchun, China
| | - Guangyi Wang
- Department of Hepatobiliary and Pancreatic Surgery I, General Surgery Center, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of the General Surgery Health Department of Jilin Province, Changchun, China
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Yang M, Cui M, Sun Y, Liu S, Jiang W. Mechanisms, combination therapy, and biomarkers in cancer immunotherapy resistance. Cell Commun Signal 2024; 22:338. [PMID: 38898505 PMCID: PMC11186190 DOI: 10.1186/s12964-024-01711-w] [Citation(s) in RCA: 19] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 06/10/2024] [Indexed: 06/21/2024] Open
Abstract
Anti-programmed death 1/programmed death ligand 1 (anti-PD-1/PD-L1) antibodies exert significant antitumor effects by overcoming tumor cell immune evasion and reversing T-cell exhaustion. However, the emergence of drug resistance causes most patients to respond poorly to these immune checkpoint inhibitors (ICIs). Studies have shown that insufficient T-cell infiltration, lack of PD-1 expression, deficient interferon signaling, loss of tumor antigen presentation, and abnormal lipid metabolism are all considered to be closely associated with immunotherapy resistance. To address drug resistance in tumor immunotherapy, a lot of research has concentrated on developing combination therapy strategies. Currently, ICIs such as anti-PD-1 /PD-L1 antibody combined with chemotherapy and targeted therapy have been approved for clinical treatment. In this review, we analyze the mechanisms of resistance to anti-PD-1/PD-L1 therapy in terms of the tumor microenvironment, gut microbiota, epigenetic regulation, and co-inhibitory immune checkpoint receptors. We also discuss various promising combination therapeutic strategies to address resistance to anti-PD-1/PD-L1 drugs, including combining these therapies with traditional Chinese medicine, non-coding RNAs, targeted therapy, other ICIs, and personalized cancer vaccines. Moreover, we focus on biomarkers that predict resistance to anti-PD-1/PD-L1 therapy as well as combination therapy efficacy. Finally, we suggest ways to further expand the application of immunotherapy through personalized combination strategies using biomarker systems.
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Affiliation(s)
- Manshi Yang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, 130041, China
| | - Mengying Cui
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, 130041, China
| | - Yang Sun
- Department of Orthopaedic, The Second Hospital of Jilin University, Changchun, 130041, China
| | - Shui Liu
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, 130041, China
| | - Weibo Jiang
- Department of Orthopaedic, The Second Hospital of Jilin University, Changchun, 130041, China.
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Neairat T, Al-Gawati M, Tul Ain Q, Assaifan AK, Alshamsan A, Alarifi A, Alodhayb AN, Alzahrani KE, Albrithen H. Development of a microcantilever-based biosensor for detecting Programmed Death Ligand 1. Saudi Pharm J 2024; 32:102051. [PMID: 38812944 PMCID: PMC11134855 DOI: 10.1016/j.jsps.2024.102051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Accepted: 03/25/2024] [Indexed: 05/31/2024] Open
Abstract
The ongoing global concern of cancer worldwide necessitates the development of advanced diagnostic and therapeutic strategies. The majority of recent detection strategies involve the employment of biomarkers. A critical biomarker for cancer immunotherapy efficacy and patient prognosis is Programmed Death Ligand 1 (PD-L1), which is a key immune checkpoint protein. PD-L1 can be particularly linked to cancer progression and therapy response. Current detection methods, such as enzyme-linked immunosorbent assay (ELISA), face limitations like high cost, time consumption, and complexity. This study introduces a microcantilever-based biosensor designed for the detection of soluble PD-L1 (sPD-L1), which has a specific association with PD-L1. The biosensor utilizes anti-PD-L1 as the sensing layer, capitalizing on the specific binding affinity between anti-PD-L1 and sPD-L1. The presence of the sensing layer was confirmed through Atomic Force Microscopy (AFM) and contact angle measurements. Binding between sPD-L1 and anti-PD-L1 induces a shift in the microcantilever's resonance frequency, which is proportional to the PD-L1 concentration. Notably, the resonance frequency shift demonstrates a robust linear relationship with the increasing biomarker concentration, ranging from 0.05 ng/ml to 500 ng/ml. The detection limit of the biosensor was determined to be approximately 10 pg/ml. The biosensor demonstrates excellent performance in detecting PD-L1 with high specificity even in complex biological matrices. This innovative approach not only provides a promising tool for early cancer diagnosis but also holds potential for monitoring immunotherapy efficacy, paving the way for personalized and effective cancer treatments.
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Affiliation(s)
- Tajweed Neairat
- Department of Physics and Astronomy, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
| | - Mahmoud Al-Gawati
- Department of Physics and Astronomy, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
- Biological and Environmental Sensing Research Unit, King Abdullah Institute for Nanotechnology, King Saud University, Riyadh, Saudi Arabia
| | - Qura Tul Ain
- Department of Physics, The Women University Multan, Khawajabad, Multan, Pakistan
| | - Abdulaziz K. Assaifan
- Biological and Environmental Sensing Research Unit, King Abdullah Institute for Nanotechnology, King Saud University, Riyadh, Saudi Arabia
- Department of Biomedical Technology, College of Applied Medical Science, King Saud University, Riyadh, Saudi Arabia
| | - Aws Alshamsan
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Abdulaziz Alarifi
- Department of Basic Sciences, College of Science and Health Professions, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
| | - Abdullah N. Alodhayb
- Department of Physics and Astronomy, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
- Biological and Environmental Sensing Research Unit, King Abdullah Institute for Nanotechnology, King Saud University, Riyadh, Saudi Arabia
| | - Khalid E. Alzahrani
- Department of Physics and Astronomy, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
- Biological and Environmental Sensing Research Unit, King Abdullah Institute for Nanotechnology, King Saud University, Riyadh, Saudi Arabia
| | - Hamad Albrithen
- Department of Physics and Astronomy, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
- Biological and Environmental Sensing Research Unit, King Abdullah Institute for Nanotechnology, King Saud University, Riyadh, Saudi Arabia
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Pitts SC, Schlom J, Donahue RN. Soluble immune checkpoints: implications for cancer prognosis and response to immune checkpoint therapy and conventional therapies. J Exp Clin Cancer Res 2024; 43:155. [PMID: 38822401 PMCID: PMC11141022 DOI: 10.1186/s13046-024-03074-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 05/19/2024] [Indexed: 06/03/2024] Open
Abstract
Longitudinal sampling of tumor tissue from patients with solid cancers, aside from melanoma and a few other cases, is often unfeasible, and thus may not capture the plasticity of interactions between the tumor and immune system under selective pressure of a given therapy. Peripheral blood analyses provide salient information about the human peripheral immunome while offering technical and practical advantages over traditional tumor biopsies, and should be utilized where possible alongside interrogation of the tumor. Some common blood-based biomarkers used to study the immune response include immune cell subsets, circulating tumor DNA, and protein analytes such as cytokines. With the recent explosion of immune checkpoint inhibitors (ICI) as a modality of treatment in multiple cancer types, soluble immune checkpoints have become a relevant area of investigation for peripheral immune-based biomarkers. However, the exact functions of soluble immune checkpoints and their roles in cancer for the most part remain unclear. This review discusses current literature on the production, function, and expression of nine soluble immune checkpoints - sPD-L1, sPD-1, sCTLA4, sCD80, sTIM3, sLAG3, sB7-H3, sBTLA, and sHVEM - in patients with solid tumors, and explores their role as biomarkers of response to ICI as well as to conventional therapies (chemotherapy, radiotherapy, targeted therapy, and surgery) in cancer patients.
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Affiliation(s)
- Stephanie C Pitts
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Jeffrey Schlom
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
| | - Renee N Donahue
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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Kuang RZ, Wang J, Wang YC, Tang XP. Effects of Apatinib combined with Temozolomide on levels of sPD-1 and sPD-L1 in patients with drug-resistant recurrent glioblastoma. Clinics (Sao Paulo) 2024; 79:100376. [PMID: 38733690 PMCID: PMC11103373 DOI: 10.1016/j.clinsp.2024.100376] [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: 11/20/2023] [Revised: 03/15/2024] [Accepted: 04/19/2024] [Indexed: 05/13/2024] Open
Abstract
OBJECTIVE This study aimed to explore the effects of Apatinib combined with Temozolomide (TMZ) on the levels of Soluble PD-1 (sPD-1) and Soluble Programmed Death-1 Ligand (sPD-L1) in patients with drug-resistant recurrent Glioblastoma (GB). STUDY DESIGN A total of 69 patients with recurrent GB from September 2020 to March 2022 were recruited and assigned to the control group (n = 34) and observation group (n = 35) according to different treatment options after tumor recurrence. The control group was treated with TMZ, and the observation group was treated with Apatinib combined with TMZ. Levels of sPD-1 and spd-l1, clinical efficacy, survival time and adverse reactions were observed and compared between the two groups. RESULTS General data including gender, age, body mass index, and combined diseases indicated no statistical significance between groups (p > 0.05). Before the intervention, sPD-1 and sPD-L1 levels were not significantly different in the two groups (p > 0.05). After interventions, levels of PD-1 and sPD-L1 levels decreased significantly (p < 0.05). The objective remission rate and clinical benefit rate of the observation group were higher and overall survival and progression-free survival were longer than those of the control group (p < 0.05). No significant difference was observed in major adverse reactions among patients (p > 0.05). CONCLUSIONS Apatinib combined with TMZ is safe and effective in the treatment of recurrent GB. The combined application of the two can reduce the levels of sPD-1 and sPD-L1, which has important clinical application value.
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Affiliation(s)
- Ren Zhao Kuang
- Department of Neurosurgery, Affiliated Hospital of North Sichuan Medical College, Nanchong City, Sichuan Province, China
| | - Jun Wang
- Department of Orthopedics and Cosmetology, Affiliated Hospital of North Sichuan Medical College, Nanchong City, Sichuan Province, China
| | - Yuan Chuan Wang
- Department of Neurosurgery, Affiliated Hospital of North Sichuan Medical College, Nanchong City, Sichuan Province, China
| | - Xiao Ping Tang
- Department of Neurosurgery, Affiliated Hospital of North Sichuan Medical College, Nanchong City, Sichuan Province, China.
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Chovet F, Passot AS, Mangon Q, Rouzaire P, Dougé A. [The circulating PD-L1: An emerging predictive biomarker for immune checkpoint inhibitors response]. Bull Cancer 2024; 111:416-427. [PMID: 38438284 DOI: 10.1016/j.bulcan.2023.12.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 11/29/2023] [Accepted: 12/07/2023] [Indexed: 03/06/2024]
Abstract
Immune checkpoint inhibitors (ICI) have recently become the standard of care for many metastatic solid tumors, with considerable improvements in patient prognosis. However, a non-negligible proportion of patients does not respond to this type of treatment, making it essential to identify predictive factors of this response in order to better adapt the therapy. Among the biomarkers that have been most extensively studied in recent years, tumor PD-L1 levels come out on top, with controversial results for predicting response to ICI. The determination of circulating PD-L1 (or soluble PD-L1) in peripheral blood seems to be an interesting emerging biomarker. Indeed, several studies have investigated its prognostic value, and/or its potential predictive value of response to immunotherapy, and it would appear that there is a correlation between the level of soluble PD-L1 and the level of tumor aggressiveness and therefore prognosis. Furthermore, the results suggest that higher PD-L1 levels are associated with a poorer response to immunotherapy, although this remains to be confirmed in large-scale studies.
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Affiliation(s)
- Fanny Chovet
- Service d'oncologie médicale, CHU Gabriel-Montpied, 63000 Clermont-Ferrand, France
| | - Anne-Sophie Passot
- Service d'oncologie médicale, CHU Gabriel-Montpied, 63000 Clermont-Ferrand, France
| | - Quentin Mangon
- Service d'oncologie médicale, CHU Gabriel-Montpied, 63000 Clermont-Ferrand, France
| | - Paul Rouzaire
- Service d'histocompatibilité et d'immunogénétique, CHU Gabriel-Montpied, 63000 Clermont-Ferrand, France
| | - Aurore Dougé
- Service d'oncologie médicale, CHU Gabriel-Montpied, 63000 Clermont-Ferrand, France.
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12
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Zych M, Roszczyk A, Dąbrowski F, Kniotek M, Zagożdżon R. Soluble Forms of Immune Checkpoints and Their Ligands as Potential Biomarkers in the Diagnosis of Recurrent Pregnancy Loss-A Preliminary Study. Int J Mol Sci 2023; 25:499. [PMID: 38203670 PMCID: PMC10779235 DOI: 10.3390/ijms25010499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 11/30/2023] [Accepted: 12/21/2023] [Indexed: 01/12/2024] Open
Abstract
Immune checkpoints (ICPs) serve as regulatory switches on immune-competent cells. Soluble ICPs consist of fragments derived from ICP molecules typically located on cell membranes. Research has demonstrated that they perform similar functions to their membrane-bound counterparts but are directly present in the bloodstream. Effective control of the maternal immune system is vital for a successful pregnancy due to genetic differences between the mother and fetus. Abnormalities in the immune response are widely acknowledged as the primary cause of spontaneous abortions. In our research, we introduce a novel approach to understanding the immune-mediated mechanisms underlying recurrent miscarriages and explore new possibilities for diagnosing and preventing pregnancy loss. The female participants in the study were divided into three groups: RSA (recurrent spontaneous abortion), pregnant, and non-pregnant women. The analysis of soluble forms of immune checkpoints and their ligands in the serum of the study groups was conducted using the Luminex method Statistically significant differences in the concentrations of (ICPs) were observed between physiological pregnancies and the RSA group. Among patients with RSA, we noted reduced concentrations of sGalectin-9, sTIM-3, and sCD155, along with elevated concentrations of LAG-3, sCD80, and sCD86 ICPs, in comparison to physiological pregnancies. Our study indicates that sGalectin-9, TIM-3, sLAG-3, sCD80, sCD86, sVISTA, sNectin-2, and sCD155 could potentially serve as biological markers of a healthy, physiological pregnancy. These findings suggest that changes in the concentrations of soluble immune checkpoints may have the potential to act as markers for early pregnancy loss.
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Affiliation(s)
- Michał Zych
- Department of Clinical Immunology, Transplantation Institute, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Mazovian Voivodeship, Poland; (M.Z.); (A.R.); (R.Z.)
| | - Aleksander Roszczyk
- Department of Clinical Immunology, Transplantation Institute, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Mazovian Voivodeship, Poland; (M.Z.); (A.R.); (R.Z.)
| | - Filip Dąbrowski
- Department of Obstetrics, Perinatology and Neonatology, Center of Postgraduate Medical Education, Ceglowska 80, 01-809 Warsaw, Mazovian Voivodeship, Poland;
- Club35, Polish Society of Obstetricians and Gynecologists PTGiP, Cybernetyki7F/87, 02-677 Warsaw, Mazovian Voivodeship, Poland
- 1st Department of Obstetrics and Gynecology, Medical University of Warsaw, Starynkiewicza 1, 02-015 Warsaw, Mazovian Voivodeship, Poland
| | - Monika Kniotek
- Department of Clinical Immunology, Transplantation Institute, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Mazovian Voivodeship, Poland; (M.Z.); (A.R.); (R.Z.)
| | - Radosław Zagożdżon
- Department of Clinical Immunology, Transplantation Institute, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Mazovian Voivodeship, Poland; (M.Z.); (A.R.); (R.Z.)
- Department of Immunology, Transplantology, and Internal Diseases, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Mazovian Voivodeship, Poland
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Tanizaki J, Kuroda H, Yokoyama T, Takahama M, Shoda H, Nakamura A, Kitamura Y, Mamesaya N, Kadota Y, Sawa K, Okishio K, Okada M, Suminaka C, Noda K, Sakai K, Chiba Y, Nishio K, Chamoto K, Honjo T, Yamamoto N, Nakagawa K, Hayashi H. Lack of Association of Plasma Levels of Soluble Programmed Cell Death Protein 1, Programmed Death-Ligand 1, and CTLA-4 With Survival for Stage II to IIIA NSCLC After Complete Resection and Adjuvant Chemotherapy. JTO Clin Res Rep 2023; 4:100590. [PMID: 38029041 PMCID: PMC10679776 DOI: 10.1016/j.jtocrr.2023.100590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 10/05/2023] [Accepted: 10/10/2023] [Indexed: 12/01/2023] Open
Abstract
Introduction Perioperative treatment in NSCLC has gained marked attention with the introduction of immune checkpoint inhibitors. Such a paradigm shift has given us additional opportunities to evaluate potential biomarkers in patients with these curable disease stages. Methods This study (WJOG12319LTR) was designed as a biomarker study to evaluate whether soluble immune markers were prognostic or predictive on relapse-free survival in patients with stage II to IIIA NSCLC who underwent complete resection and adjuvant chemotherapy with cisplatin plus S-1, which is an oral fluoropyrimidine formulation that consists of tegafur, gimeracil, and oteracil, or S-1 alone in the previous WJOG4107 study. Archived plasma samples were assayed for soluble (s) forms of programmed cell death protein 1 (sPD-1), programmed death-ligand 1(sPD-L1), and CTLA-4 (sCTLA-4) with the highly sensitive HISCL system. Using time-dependent receiver operating characteristic curve analysis, the area under the curves were derived and optimal cutoff values were determined. Using the cutoff values, whether the marker was prognostic or predictive was assessed by survival analysis. Results A total of 150 patients were included in the study. The time-dependent receiver operating characteristics analysis revealed that the area under the curves for sPD-1, sPD-L1, and sCTLA-4 were 0.54, 0.51, and 0.58, respectively. The survival analysis did not reject that hazard ratios were 1 in terms of the soluble immune marker and the treatment-marker interaction for all three markers. Conclusions There was no proof that circulating concentrations of sPD-1, sPD-L1, and sCTLA-4 were prognostic or predictive factors of the outcome for adjuvant chemotherapy after complete resection in patients with NSCLC.
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Affiliation(s)
- Junko Tanizaki
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Hiroaki Kuroda
- Department of Thoracic Surgery, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Toshihide Yokoyama
- Department of Respiratory Medicine, Kurashiki Central Hospital, Kurashiki, Japan
| | - Makoto Takahama
- Department of General Thoracic Surgery, Osaka City General Hospital, Osaka, Japan
| | - Hiroyasu Shoda
- Department of Respiratory Medicine, Hiroshima City Hiroshima Citizens Hospital, Hiroshima, Japan
| | - Atsushi Nakamura
- Department of Pulmonary Medicine, Sendai Kousei Hospital, Sendai, Japan
| | | | - Nobuaki Mamesaya
- Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Yoshihisa Kadota
- Department of General Thoracic Surgery, Osaka Habikino Medical Center, Osaka, Japan
| | - Kenji Sawa
- Department of Clinical Oncology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Kyoichi Okishio
- Department of Thoracic Oncology, National Hospital Organization Kinki-Chuo Chest Medical Center, Sakai, Osaka, Japan
| | - Morihito Okada
- Department of Surgical Oncology, Hiroshima University, Hiroshima, Japan
| | | | - Kenta Noda
- Central Research Laboratories, Sysmex Corporation, Hyogo, Japan
| | - Kazuko Sakai
- Department of Genome Biology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Yasutaka Chiba
- Clinical Research Center, Kindai University Hospital, Osaka, Japan
| | - Kazuto Nishio
- Department of Genome Biology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Kenji Chamoto
- Department of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Immuno-Oncology PDT, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Tasuku Honjo
- Department of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | | | - Kazuhiko Nakagawa
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Hidetoshi Hayashi
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan
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Toledo A, Fragoso G, Carrillo-Mezo R, Romo ML, Sciutto E, Fleury A. Can sPD-1 and sPD-L1 Plasma Concentrations Predict Treatment Response among Patients with Extraparenchymal Neurocysticercosis? Pathogens 2023; 12:1116. [PMID: 37764924 PMCID: PMC10535301 DOI: 10.3390/pathogens12091116] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 08/14/2023] [Accepted: 08/30/2023] [Indexed: 09/29/2023] Open
Abstract
Extraparenchymal neurocysticercosis (EP-NC) is a chronic, potentially life-threatening disease that responds poorly to initial anthelmintic drug therapy. A depressed specific reactivity of peripheral lymphocytes and an increased level of specific Tregs accompanies EP-NC. The immune checkpoint pathway PD-1 and its ligand PD-L1 downregulates effector T cells, causing specific immune suppression in chronic diseases. This study explored whether their soluble forms, sPD-1/sPD-L1, are present in plasma among patients with EP-NC and if their levels could be associated with treatment response. A total of 21 patients with vesicular EP-NC and 22 healthy controls were included. Patients received standard treatment and were followed for six months to assess treatment response by assessing changes in cyst volume determined with 3D MRI. The presence of both sPD-1 and sPD-L1 was more frequently detected among patients with EP-NC than in healthy controls and had higher concentrations. Among patients, higher pre-treatment levels of both markers were associated with a poor treatment response, and the sensitivity and specificity of the sPD-1/sPD-L1 ratio for predicting any response to treatment were high. Our results are consistent with the presence of lymphocyte exhaustion and open new research perspectives to improve the prognosis of patients with this severe disease.
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Affiliation(s)
- Andrea Toledo
- Unidad de Neuro Inflamación, Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigación Biomédicas, Universidad Nacional Autónoma de México (UNAM)/Instituto Nacional de Neurología y Neurocirugía, Ciudad de México 14269, Mexico
- División de Investigación, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Ciudad de México 04510, Mexico
| | - Gladis Fragoso
- Departamento de Inmunología, Instituto de Investigación Biomédicas, Universidad Nacional Autónoma de México (UNAM), Ciudad de México 04510, Mexico
| | - Roger Carrillo-Mezo
- Departamento de Neurorradiología, Instituto Nacional de Neurología y Neurocirugía, Ciudad de México 14269, Mexico
| | - Matthew L Romo
- Department of Epidemiology & Biostatistics, CUNY Graduate School of Public Health and Health Policy, City University of New York, New York, NY 10027, USA
| | - Edda Sciutto
- Departamento de Inmunología, Instituto de Investigación Biomédicas, Universidad Nacional Autónoma de México (UNAM), Ciudad de México 04510, Mexico
| | - Agnès Fleury
- Unidad de Neuro Inflamación, Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigación Biomédicas, Universidad Nacional Autónoma de México (UNAM)/Instituto Nacional de Neurología y Neurocirugía, Ciudad de México 14269, Mexico
- Clínica de Neurocisticercosis, Instituto Nacional de Neurología y Neurocirugía, Ciudad de México 14269, Mexico
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15
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Ruan J, Zhao Z, Qian Y, Xu R, Liao G, Kong FM(S. The predictive role of soluble programmed death ligand 1 in digestive system cancers. Front Oncol 2023; 13:1170220. [PMID: 37519785 PMCID: PMC10374258 DOI: 10.3389/fonc.2023.1170220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 06/22/2023] [Indexed: 08/01/2023] Open
Abstract
Introduction The prognostic role of soluble programmed death ligand 1 (sPD-L1) in digestive system cancers (DSCs) remains inconclusive. This study aimed to explore the predictive value of sPD-L1 expression in DSCs. Methods Comprehensive searches were run on the electronic databases (PubMed, Web of Science, EMBASE, and the Cochrane Library) to identify studies that assessed the prognostic role of sPD-L1 in DSCs. Review Manager software (version 5.3) was used for all analyses. Pooled data for survival outcomes were measured as hazard ratios (HRs), 95% confidence intervals (CIs), and odds ratios and their 95% CIs. Results The search identified 18 studies involving 2,070 patients with DSCs. The meta-outcome revealed that a high level of sPD-L1 was related to poorer overall survival (HR, 3.06; 95% CI: 2.22-4.22, p<0.001) and disease-free survival (HR, 2.53; 95% CI: 1.67-3.83, p<0.001) in DSCs. Individually, the prognostic significance of high level of sPD-L1 expression was the highest in hepatic cell carcinoma (HR, 4.76; p<0.001) followed by gastric cancer (HR=3.55, p<0.001). Conclusion sPD-L1 may be a prognostic factor in DSCs for overall survival and disease-free survival. Inflammatory cytokines, treatment approaches, and other factors may affect the expression of sPD-L1. Therefore, the prognostic value of sPD-L1 for recurrence and metastasis should be further investigated. sPD-L1 may also predict response to treatment. Well-designed prospective studies with standard assessment methods should be conducted to determine the prognostic value of sPD-L1 in DSCs.
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Affiliation(s)
- Jian Ruan
- The Second Clinical Medical College, Jinan University, Guangdong, China
| | - Zhihong Zhao
- Department of Nephrology, Shenzhen People’s Hospital, The Second Clinical Medical College, Jinan University, Guangdong, China
| | - Yuting Qian
- The Second Clinical Medical College, Jinan University, Guangdong, China
| | - Ruilian Xu
- The Second Clinical Medical College, Jinan University, Guangdong, China
| | - Guixiang Liao
- The Second Clinical Medical College, Jinan University, Guangdong, China
| | - Feng-Ming (Spring) Kong
- Department of Clinical Oncology, Hong Kong University Shenzhen Hospital and Queen Mary Hospital, Hong Kong University Li Ka Shing Medical School, Hong Kong, Hong Kong SAR, China
- Department of Clinical Oncology, Queen Mary Hospital, Hong Kong University Li Ka Shing Faculty of Medicine, Hong Kong, Hong Kong SR, China
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Lu L, Risch E, Halaban R, Zhen P, Bacchiocchi A, Risch HA. Dynamic changes of circulating soluble PD-1/PD-L1 and its association with patient survival in immune checkpoint blockade-treated melanoma. Int Immunopharmacol 2023; 118:110092. [PMID: 37004344 DOI: 10.1016/j.intimp.2023.110092] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/10/2023] [Accepted: 03/22/2023] [Indexed: 04/03/2023]
Abstract
Immune checkpoint PD-1 and its ligand PD-L1 lead to T cell exhaustion, and a high level of circulating soluble PD-L1 at baseline indicates a poor prognosis in melanoma and other solid tumor types. Here we show that the dynamic changes of circulating soluble PD-1 and PD-L1 across the course of immune checkpoint blockades (ICBs) and their changes associate with patient survival in melanoma in a retrospective study. A high change of soluble PD-L1 level at a time-point but not PD-1 significantly increased the mortality, whereas a high change of soluble PD-1/PD-L1 ratio significantly reduced the mortality. After the initial immunotherapy, both soluble PD-1 and PD-L1 increased. However, the change pattern of soluble PD-L1 level was particularly dependent on patients' survival status. These findings indicate that the magnitudes of circulating soluble PD-L1 and PD-1/PD-L1 ratio changes over the time may reflect the patients' response to ICBs or the progression of the disease and predict the survival in melanoma patients treated with ICBs.
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Park SJ, Park JY, Shin K, Hong TH, Lee M, Kim Y, Kim IH. Clinical significance of serum-derived exosomal PD-L1 expression in patients with advanced pancreatic cancer. BMC Cancer 2023; 23:389. [PMID: 37127565 PMCID: PMC10150468 DOI: 10.1186/s12885-023-10811-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 04/05/2023] [Indexed: 05/03/2023] Open
Abstract
BACKGROUND Interactions between the programmed cell death receptor 1 (PD-1) and its ligand (PD-L1) lead to immune evasion in various tumors and are associated with poor prognosis in patients with pancreatic cancer; however, the roles of PD-L1-containing exosomes in pancreatic cancer is poorly understood. Here, we investigated the correlation between circulating exosomal PD-L1 (exoPD-L1) and PD-L1 expression in tumor tissue, and survival outcomes in patients with advanced PDAC. METHODS Exosomes were derived from pre-treatment serum samples isolated using ExoQuick kit from 77 patients with advanced pancreatic cancer. Exosomal PD-L1 (exoPD-L1) was detected by enzyme-linked immunosorbent assay, and matched tumor tissues PD-L1 expression were evaluated by PD-L1 immunohistochemistry (22C3) assay, described with combined positive score. Cutoff value of exoPD-L1 for survival was assessed with receiver operating characteristic curve analysis. Kaplan-Meier analysis was performed to obtain median overall survival (OS), and hazard ratio was estimated using a stratified Cox regression model. RESULTS The median exoPD-L1 serum concentration was 0.16 pg/mg, with undetected levels in seven patients. ExoPD-L1 levels were significantly higher in patients with systemic disease than in those with locally advanced disease (p = 0.023). There was a significantly higher proportion of elevated exoPD-L1 levels in patients with positive PD-L1 expression compared to patients with negative PD-L1 expression (p = 0.001). Patients were classified into groups with low and high exoPD-L1 levels using ROC curve-derived cutoffs (0.165 pg/mg; area under the curve, 0.617; p = 0.078). At a median follow-up of 8.39 months, the median OS was 13.2 (95% CI, 8.17-18.3) and 6.36 months (95% CI, 3.27-9.45) in the low and high exoPD-L1 groups, respectively (HR = 0.61; 95% CI, 0.35-1.04; p = 0.059). ExoPD-L1 levels did not affect the proportion of CD8+CD69+ effector cytotoxic T cells in either of the groups (p = 0.166). CONCLUSIONS The serum-derived exoPD-L1 levels were higher in metastatic pancreatic cancer than locally advanced disease. Collectively, higher serum exoPD-L1 levels in patients with advanced pancreatic cancer suggested worse survival outcomes and may have clinical implications.
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Affiliation(s)
- Se Jun Park
- Division of Medical Oncology, Department of Internal Medicine, The Catholic University of Korea, Seoul St. Mary's Hospital, 222 Banpo-daero, Secho-gu, Seoul, Korea
| | - Ju Yeon Park
- Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Kabsoo Shin
- Division of Medical Oncology, Department of Internal Medicine, The Catholic University of Korea, Seoul St. Mary's Hospital, 222 Banpo-daero, Secho-gu, Seoul, Korea
| | - Tae Ho Hong
- Department of General Surgery, The Catholic University of Korea, Seoul St. Mary's Hospital, Seoul, Korea
| | - MyungAh Lee
- Division of Medical Oncology, Department of Internal Medicine, The Catholic University of Korea, Seoul St. Mary's Hospital, 222 Banpo-daero, Secho-gu, Seoul, Korea
| | - Younghoon Kim
- Department of Pathology, The Catholic University of Korea, Seoul St. Mary's Hospital, College of Medicine, Seoul, Korea
| | - In-Ho Kim
- Division of Medical Oncology, Department of Internal Medicine, The Catholic University of Korea, Seoul St. Mary's Hospital, 222 Banpo-daero, Secho-gu, Seoul, Korea.
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Ji JH, Ha SY, Lee D, Sankar K, Koltsova EK, Abou-Alfa GK, Yang JD. Predictive Biomarkers for Immune-Checkpoint Inhibitor Treatment Response in Patients with Hepatocellular Carcinoma. Int J Mol Sci 2023; 24:7640. [PMID: 37108802 PMCID: PMC10144688 DOI: 10.3390/ijms24087640] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 04/15/2023] [Accepted: 04/18/2023] [Indexed: 04/29/2023] Open
Abstract
Hepatocellular carcinoma (HCC) has one of the highest mortality rates among solid cancers. Late diagnosis and a lack of efficacious treatment options contribute to the dismal prognosis of HCC. Immune checkpoint inhibitor (ICI)-based immunotherapy has presented a new milestone in the treatment of cancer. Immunotherapy has yielded remarkable treatment responses in a range of cancer types including HCC. Based on the therapeutic effect of ICI alone (programmed cell death (PD)-1/programmed death-ligand1 (PD-L)1 antibody), investigators have developed combined ICI therapies including ICI + ICI, ICI + tyrosine kinase inhibitor (TKI), and ICI + locoregional treatment or novel immunotherapy. Although these regimens have demonstrated increasing treatment efficacy with the addition of novel drugs, the development of biomarkers to predict toxicity and treatment response in patients receiving ICI is in urgent need. PD-L1 expression in tumor cells received the most attention in early studies among various predictive biomarkers. However, PD-L1 expression alone has limited utility as a predictive biomarker in HCC. Accordingly, subsequent studies have evaluated the utility of tumor mutational burden (TMB), gene signatures, and multiplex immunohistochemistry (IHC) as predictive biomarkers. In this review, we aim to discuss the current state of immunotherapy for HCC, the results of the predictive biomarker studies, and future direction.
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Affiliation(s)
- Jun Ho Ji
- Division of Hematology and Oncology, Department of Internal Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon 51353, Republic of Korea
- Karsh Division of Gastroenterology and Hepatology, Comprehensive Transplant Center, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Sang Yun Ha
- Karsh Division of Gastroenterology and Hepatology, Comprehensive Transplant Center, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 03181, Republic of Korea
| | - Danbi Lee
- Karsh Division of Gastroenterology and Hepatology, Comprehensive Transplant Center, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
| | - Kamya Sankar
- Division of Medical Oncology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Ekaterina K. Koltsova
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Ghassan K. Abou-Alfa
- Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Weil Cornell Medicine, Cornell University, New York, NY 14853, USA
| | - Ju Dong Yang
- Karsh Division of Gastroenterology and Hepatology, Comprehensive Transplant Center, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
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Ailia MJ, Heo J, Yoo SY. Navigating through the PD-1/PDL-1 Landscape: A Systematic Review and Meta-Analysis of Clinical Outcomes in Hepatocellular Carcinoma and Their Influence on Immunotherapy and Tumor Microenvironment. Int J Mol Sci 2023; 24:ijms24076495. [PMID: 37047482 PMCID: PMC10095164 DOI: 10.3390/ijms24076495] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 03/24/2023] [Accepted: 03/27/2023] [Indexed: 04/03/2023] Open
Abstract
This systematic review aimed to assess the prognostic significance of programmed cell death-ligand 1 (PDL-1) and programmed cell death protein 1 (PD-1) in hepatocellular carcinoma (HCC). Medline, EMBASE, and Cochrane Library database searches were conducted, revealing nine relevant cohort studies (seven PDL-1 and three PD-1). Our meta-analysis showed that PD-1/PDL-1 was a marker of poor survival, regardless of the assessment method (PD-1 overall survival (OS): hazard ratio (HR) 2.40; 95% confidence interval (CI), 1.30–4.42; disease-free survival (DFS): HR 2.12; 95% CI, 1.45–3.10; PDL-1: OS: HR 3.61; 95% CI, 2.75–4.75; and DFS: HR 2.74; 95% CI, 2.09–3.59). Additionally, high level of PD-1/PDL-1 expression was associated with aging, multiple tumors, high alpha-fetoprotein levels, and advanced Barcelona Clinic Liver Cancer stage. This high level significantly predicted a poor prognosis for HCC, suggesting that anti-PD-1 therapy is plausible for patients with HCC. Furthermore, HIF-1 induces PD-1 expression, and PD1lowSOCS3high is associated with a better prognosis. Taken together, combination therapy may be the key to effective immunotherapy. Thus, exploring other markers, such as HIF-1 and SOCS3, along with PD-1/PDL-1 immunotherapy, may lead to improved outcomes.
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Affiliation(s)
- Muhammad Joan Ailia
- BIO-IT Foundry Technology Institute, Pusan National University, Busan 46241, Republic of Korea
| | - Jeong Heo
- Department of Internal Medicine, College of Medicine, Pusan National University and Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Republic of Korea
| | - So Young Yoo
- BIO-IT Foundry Technology Institute, Pusan National University, Busan 46241, Republic of Korea
- Correspondence: or ; Tel.: +82-51-510-3402
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20
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Yi L, Wang X, Fu S, Yan Z, Ma T, Li S, Wei P, Zhang H, Wang J. Association between response to anti-PD-1 treatment and blood soluble PD-L1 and IL-8 changes in patients with NSCLC. Discov Oncol 2023; 14:35. [PMID: 36991160 PMCID: PMC10060455 DOI: 10.1007/s12672-023-00641-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Accepted: 03/22/2023] [Indexed: 03/31/2023] Open
Abstract
In this study, we explored the dynamic changes in blood sPD-L1 and its clinical value during anti-PD-1 immunotherapy in non-small cell lung cancer (NSCLC) patients. First, we established a sandwich ELISA for functional sPD-L1 that can bind to PD-1 and has biological functions. By monitoring functional sPD-L1 in 39 NSCLC patients treated with anti-PD-1 antibodies, we found a positive correlation between baseline sPD-L1 and tissue PD-L1 (P = 0.0376, r = 0.3581), with patients with lymph node metastasis having higher sPD-L1 levels (P = 0.0037) than those without lymph node metastasis. Although baseline functional sPD-L1 and PFS did not correlate significantly in this study, changes in sPD-L1 in patients with different clinical responses showed different trends. Blood sPD-L1 increased in 93% of patients after two cycles of anti-PD-1 treatment (P = 0.0054); sPD-L1 in nonresponsive patients continued to increase (P = 0.0181), but sPD-L1 started to decline in responsive patients. Blood IL-8 levels were associated with tumor load, and when combined with IL-8, the evaluation accuracy of sPD-L1 improved to 86.4%. This study preliminarily shows that the combination of sPD-L1 and IL-8 is a convenient and effective method for monitoring and evaluating the effectiveness of anti-PD-1 immunotherapy in NSCLC patients.
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Affiliation(s)
- Ling Yi
- Department of Central Laboratory, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, China
| | - Xiaojue Wang
- Department of Central Laboratory, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, China
| | - Siyun Fu
- Department of Medical Oncology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, China
| | - Zhuohong Yan
- Department of Central Laboratory, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, China
| | - Tianyu Ma
- No. 2 Department of Thoracic Surgery, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, China
| | - Siqi Li
- No. 2 Department of Thoracic Surgery, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, China
| | - Panjian Wei
- Department of Central Laboratory, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, China
| | - Hongtao Zhang
- Department of Central Laboratory, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, China.
| | - Jinghui Wang
- Department of Medical Oncology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, China.
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21
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Yu SJ. Immunotherapy for hepatocellular carcinoma: Recent advances and future targets. Pharmacol Ther 2023; 244:108387. [PMID: 36948423 DOI: 10.1016/j.pharmthera.2023.108387] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 02/12/2023] [Accepted: 03/15/2023] [Indexed: 03/24/2023]
Abstract
Immunotherapy is a promising approach to treating various types of cancers, including hepatocellular carcinoma (HCC). While single immunotherapy drugs show limited effectiveness on a small subset of patients, the combination of the anti PD-L1 atezolizumab and anti-vascular endothelial growth factor bevacizumab has shown significant improvement in survival compared to sorafenib as a first-line treatment. However, the current treatment options still have a low success rate of about 30%. Thus, more effective treatments for HCC are urgently required. Several novel immunotherapeutic methods, including the use of novel immune checkpoint inhibitors, innovative immune cell therapies like chimeric antigen receptor T cells (CAR-T), TCR gene-modified T cells and stem cells, as well as combination strategies are being tested in clinical trials for the treatment of HCC. However, some crucial issues still exist such as the presence of heterogeneous antigens in solid tumors, the immune-suppressive environment within tumors, the risk of on-target/off-tumor, infiltrating CAR-T cells, immunosuppressive checkpoint molecules, and cytokines. Overall, immunotherapy is on the brink of major advancements in the fight against HCC.
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Affiliation(s)
- Su Jong Yu
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
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22
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Han J, Correa da Rosa J, Agarwal A, Owji S, Yassky D, Luu Y, Shah A, Estrada Y, Ungar J, Sarin KY, Krueger JG, Gulati N. Modulation of Inflammatory Proteins in Serum May Reflect Cutaneous Immune Responses in Cancer Immunotherapy. JID INNOVATIONS 2023; 3:100179. [PMID: 36876222 PMCID: PMC9982329 DOI: 10.1016/j.xjidi.2022.100179] [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: 06/14/2022] [Revised: 11/28/2022] [Accepted: 12/05/2022] [Indexed: 01/30/2023] Open
Abstract
Diphencyprone (DPCP), a topical contact sensitizer, has shown efficacy in treating cutaneous melanoma metastases, including at times beyond the directly treated sites, but biomarkers indicative of treatment response have not been characterized. Thus, we performed a proteomic analysis of the skin and serum of five patients with cutaneous melanoma metastases treated with DPCP on days 0, 63, and 112 of the treatment course. In the serum, we found a significant upregulation (P < 0.05) in 13 of 96 assessed immuno-oncology proteins after DPCP treatment. Upregulated proteins included those of the T helper 1 axis (CXCL9, CXCL10), immune checkpoint proteins (PD-1), and various proteins with roles in promoting tumor immunity such as CD80 and TNFRSF4/9. Given the positive clinical response to topical treatment noted in the five patients studied, these proteins may represent prognostic biomarkers in the serum for evaluating the efficacy of DPCP treatment of cutaneous melanoma metastases. Because DPCP does not lead to nonspecific immune-related adverse events seen with immune checkpoint inhibitors, our study provides evidence for potential tumor-specific systemic immune activation and systemic antitumor effectors elicited by topical DPCP.
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Affiliation(s)
- Joseph Han
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Joel Correa da Rosa
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Aneesh Agarwal
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Shayan Owji
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Daniel Yassky
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Yen Luu
- School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, USA
| | - Aatman Shah
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Yeriel Estrada
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Jonathan Ungar
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Kavita Y. Sarin
- Department of Dermatology, Stanford University School of Medicine, Stanford, California, USA
| | - James G. Krueger
- Laboratory for Investigative Dermatology, The Rockefeller University, New York, New York, USA
| | - Nicholas Gulati
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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23
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Molga-Magusiak M, Rzepakowska A, Żurek M, Kotuła I, Demkow U, Niemczyk K. Prognostic and predictive role of soluble programmed death ligand-1 in head and neck cancer. Braz J Otorhinolaryngol 2023; 89:417-424. [PMID: 36868994 PMCID: PMC10164823 DOI: 10.1016/j.bjorl.2023.02.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 12/30/2022] [Accepted: 02/10/2023] [Indexed: 02/23/2023] Open
Abstract
OBJECTIVES The aim of the study was to investigate clinical significance of soluble PD-L1 (sPD-L1) serum level in head and neck cancer and to evaluate its role as a possible prognostic and predictive biomarker. METHODS A prospective analysis of sPD-L1 levels in 60 patients diagnosed and treated due to malignant and non-malignant lesions in the region of head and neck was performed in peripheral blood by an ELISA test. RESULTS The range of sPD-L1 in the study group was 0.16-1.63ng/mL, mean 0.64±0.32. There were no differences in the mean sPD-L1 regarding patients' age, sex, and the localization of the lesion. Statistically significant difference was revealed in the average sPD-L1 level (p= 0.006) depending on the histopathological advancement of the lesions, 0.704 ± 0.349 and 0.512 ± 0.177 respectively in the malignant and benign group. The separate analysis of laryngeal lesions confirmed statistical difference in sPD-L1 (p= 0.002) for the malignant lesions (0.741 ± 0.353) compared with the benign (0.489 ± 0.175). The sPD-L1 level of 0.765 ng/mL or higher, revealed 35% sensitivity and 95.5% specificity for the diagnosis of head and neck malignant lesions (AUC=0.664, 95% CI 0.529‒0.8, p-value=0.039). The 1-year DFS was 83.3% in the group of patients with low sPD-L1 levels (< 0.765ng/mL) and 53.8% in patients with high sPD-L1 (≥0.765ng/mL). The 2-year OS were 68% and 69.2% respectively in both groups. The log-rank test confirmed statistically significant prognostic value of sPD-L1 level for 1-year DFS (p-value=0.035). CONCLUSIONS sPD-L1 is a promising prognostic and early recurrence predictive biomarker for head and neck cancers, most significantly for laryngeal lesions. LEVEL OF EVIDENCE: 3
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Affiliation(s)
- Maria Molga-Magusiak
- Medical University of Warsaw, Department of Otorhinolaryngology Head and Neck Surgery, Warsaw, Poland
| | - Anna Rzepakowska
- Medical University of Warsaw, Department of Otorhinolaryngology Head and Neck Surgery, Warsaw, Poland.
| | - Michał Żurek
- Medical University of Warsaw, Department of Otorhinolaryngology Head and Neck Surgery, Warsaw, Poland
| | - Iwona Kotuła
- Medical University of Warsaw, Department of Laboratory Diagnostics and Clinical Immunology of Developmental Age, Warsaw, Poland
| | - Urszula Demkow
- Medical University of Warsaw, Department of Laboratory Diagnostics and Clinical Immunology of Developmental Age, Warsaw, Poland
| | - Kazimierz Niemczyk
- Medical University of Warsaw, Department of Otorhinolaryngology Head and Neck Surgery, Warsaw, Poland
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24
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AmeliMojarad M, AmeliMojarad M, Cui X. Prospective role of PD-1/PD-L1 immune checkpoint inhibitors in GI cancer. Pathol Res Pract 2023; 244:154338. [PMID: 36905697 DOI: 10.1016/j.prp.2023.154338] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 01/16/2023] [Accepted: 01/21/2023] [Indexed: 01/24/2023]
Abstract
One of the mechanisms by which tumor cells can evade the immune system is over activation of the programmed cell death protein-1 (PD-1) / programmed death-ligand 1 (PD-L1) pathway. The binding of PD-1 to its ligand PD-L1 can trigger an inhibitory signal for reducing T-cell proliferation, inhibiting the anticancer effect of T cells, and limiting the anti-tumor immunity of effectors T cell responses to protect tissues from immune-mediated tissue damage in the tumor microenvironment (TME). PD-1/PD-L1 immune checkpoint inhibitors have created a new pattern in cancer immunotherapy and can increase T cell- surveillance; therefore, the development of better clinical application of PD-1/PD-L1 inhibitors can significantly enhance antitumor immunity and prolong survival in GI cancer patients.
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Affiliation(s)
- Mandana AmeliMojarad
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, PR China
| | - Melika AmeliMojarad
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, PR China
| | - Xiaonan Cui
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, PR China.
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25
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Chen L, Liu S, Adah D, Sun Q, Liang Z, Ho M, Sun B. Soluble programmed death ligand-1-induced immunosuppressive effects on chimeric antigen receptor-natural killer cells targeting Glypican-3 in hepatocellular carcinoma. Immunology 2023; 169:204-218. [PMID: 36640111 DOI: 10.1111/imm.13624] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Accepted: 01/11/2023] [Indexed: 01/15/2023] Open
Abstract
Although the pre-clinical study of chimeric antigen receptor (CAR)-natural killer (NK) cell was effective against various tumours, immunosuppression mediated by tumour microenvironment hampers their application and several efforts have been explored to improve their effect in combating solid tumours. Glypican 3 (GPC3) is a promising target for hepatocellular carcinoma (HCC), and CAR-T cells targeting GPC3 have been tested in clinical trials. Based on an affinity-enhanced antibody (hYP7) targeting GPC3, we constructed GPC3-CAR-NK cells to explore their potential function in the treatment of HCC. We found that patients with HCC secreted high levels of soluble programmed death-ligand 1 (sPD-L1), which inhibits the function of CAR-NK cells targeting GPC3. In addition, we combined high-affinity sPD-L1 variant (L3C7c-Fc) with GPC3-CAR-NK cells to solve the problem of GPC3-CAR-NK inhibition. Our studies demonstrated that L3C7c-Fc could enhance the therapeutic effect of CAR-NK cells by reversing the suppression of sPD-L1, which provides the experimental evidence for the subsequent development of HCC immunotherapy strategies.
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Affiliation(s)
- Lin Chen
- Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People's Republic of China
| | - Siyuan Liu
- Department of Hepatobiliary surgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, People's Republic of China
| | - Dickson Adah
- State Key Laboratory of Respiratory Disease, Center of Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science, Guangzhou, People's Republic of China
| | - Qingyang Sun
- Department of Pathology, Affiliated Drum Tower Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Zhaoduan Liang
- State Key Laboratory of Respiratory Disease, Center of Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science, Guangzhou, People's Republic of China
| | - Mitchell Ho
- Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Beicheng Sun
- Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People's Republic of China.,Department of Hepatobiliary surgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, People's Republic of China
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26
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He Y, Zhang X, Zhu M, He W, Hua H, Ye F, Zhou X, Chen N, Li Y, Zhong W, Wu G, Cai H, Jiang W. Soluble PD-L1: a potential dynamic predictive biomarker for immunotherapy in patients with proficient mismatch repair colorectal cancer. J Transl Med 2023; 21:25. [PMID: 36639643 PMCID: PMC9837921 DOI: 10.1186/s12967-023-03879-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Accepted: 01/07/2023] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND Circulating soluble programmed death ligand 1 (sPD-L1) can negatively regulate T-cell function and serve as a prognostic or predictive marker in a variety of cancers. However, rare studies have evaluated the potential roles of sPD-L1, and no study has estimated its predictive value for the efficacy of immune treatment in colorectal cancer (CRC). METHODS Plasma samples from 192 CRC patients were used to estimate correlations between clinicopathological features and sPD-L1, secreted PD-L1 (secPD-L1) and exosomal PD-L1 (exoPD-L1). Baseline and posttreatment sPD-L1 levels were also investigated in 55 patients with metastatic CRC (mCRC) treated with chemotherapy ± targeted therapy and 40 patients with proficient mismatch repair (pMMR) mCRC treated with combination immunotherapy. Both sPD-L1 and secPD-L1 were quantified by enzyme-linked immunosorbent assay, while exoPD-L1 was analyzed using flow cytometry. RESULTS secPD-L1 was the major component and positively correlated with sPD-L1 in CRC, while exoPD-L1 was almost undetectable. Higher levels of sPD-L1 were detected in patients with distant metastasis, especially those with distant lymph node metastasis and tissue combined positive score (CPS) instead of tumor proportion score (TPS). Chemotherapy or targeted therapy did not significantly impact sPD-L1 concentration. Progressive disease on combination immunotherapy was associated with an increase in sPD-L1 level, whereas no significant change was observed in patients with durable clinical benefit. CONCLUSION sPD-L1 mainly consisted of secPD-L1, and its level was higher in patients with distant metastasis, especially distant lymph node metastasis and positive CPS. sPD-L1 is a potential dynamic marker to identify rapid progression on combination immunotherapy and avoid ineffective treatment for pMMR CRC.
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Affiliation(s)
- Yinjun He
- grid.13402.340000 0004 1759 700XDepartment of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China ,grid.13402.340000 0004 1759 700XCollege of Medicine, Zhejiang University, Hangzhou, China
| | - Xiang Zhang
- grid.417234.70000 0004 1808 3203General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou, China ,grid.412643.60000 0004 1757 2902The First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Ming Zhu
- grid.13402.340000 0004 1759 700XCollege of Medicine, Zhejiang University, Hangzhou, China
| | - Wenguang He
- grid.13402.340000 0004 1759 700XDepartment of Radiology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hanju Hua
- grid.13402.340000 0004 1759 700XDepartment of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Feng Ye
- grid.13402.340000 0004 1759 700XDepartment of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xile Zhou
- grid.13402.340000 0004 1759 700XDepartment of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Nan Chen
- Department of Colorectal Surgery, Yuyao Hospital of Traditional Chinese Medicine, Ningbo, China
| | - Yandong Li
- grid.13402.340000 0004 1759 700XDepartment of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Weixiang Zhong
- grid.13402.340000 0004 1759 700XDepartment of Pathology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Guosheng Wu
- grid.13402.340000 0004 1759 700XDepartment of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hui Cai
- grid.417234.70000 0004 1808 3203General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou, China ,grid.412643.60000 0004 1757 2902The First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Weiqin Jiang
- grid.13402.340000 0004 1759 700XDepartment of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Zhang Y, Wu J, Zhao C, Zhang S, Zhu J. Recent Advancement of PD-L1 Detection Technologies and Clinical Applications in the Era of Precision Cancer Therapy. J Cancer 2023; 14:850-873. [PMID: 37056391 PMCID: PMC10088895 DOI: 10.7150/jca.81899] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 03/14/2023] [Indexed: 04/15/2023] Open
Abstract
Programmed death-1 is a protein found on the surface of immune cells that can interact with its ligand, programmed death-ligand 1 (PD-L1), which is expressed on the plasma membrane, the surface of secreted cellular exosomes, in cell nuclei, or as a circulating soluble protein. This interaction can lead to immune escape in cancer patients. In clinical settings, PD-L1 plays an important role in tumor disease diagnosis, determining therapeutic effectiveness, and predicting patient prognosis. PD-L1 inhibitors are also essential components of tumor immunotherapy. Thus, the detection of PD-L1 levels is crucial, especially in the era of precision cancer therapy. In recent years, innovations have been made in traditional immunoassay methods and the development of new immunoassays for PD-L1 detection. This review aims to summarize recent research progress in tumor PD-L1 detection technology and highlight the clinical applications of PD-L1.
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Affiliation(s)
- Yuanfeng Zhang
- Binzhou Medical University, Yantai, Shandong, 264003, China
| | - Juanjuan Wu
- Binzhou People's Hospital Affiliated to Shandong First Medical University, Binzhou, Shandong, 256600, China
| | - Chaobin Zhao
- Binzhou Medical University, Yantai, Shandong, 264003, China
| | - Shuyuan Zhang
- Binzhou Medical University, Yantai, Shandong, 264003, China
| | - Jianbo Zhu
- Binzhou People's Hospital Affiliated to Shandong First Medical University, Binzhou, Shandong, 256600, China
- ✉ Corresponding author: Pro. Jianbo Zhu, Binzhou People's Hospital Affiliated to Shandong First Medical University, 515 Yellow River Seven Road, Binzhou, Shandong, 256600, China; ,
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Pre-treatment soluble PD-L1 as a predictor of overall survival for immune checkpoint inhibitor therapy: a systematic review and meta-analysis. Cancer Immunol Immunother 2022; 72:1061-1073. [PMID: 36385210 PMCID: PMC10110702 DOI: 10.1007/s00262-022-03328-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 11/04/2022] [Indexed: 11/17/2022]
Abstract
Abstract
Introduction
Immune checkpoint inhibitors (ICI) such as anti-PD-L1 and anti-PD-1 agents have been proven to be effective in various cancers. However, the rate of non-responders is still high in all cancer entities. Therefore, the identification of biomarkers that could help to optimize therapeutic decision-making is of great clinical importance. Soluble PD-L1 (sPD-L1) and PD-1 (sPD-1) are emerging blood-based biomarkers and were previously shown to be prognostic in various clinical studies.
Objective
We aimed to evaluate the prognostic relevance of sPD-L1 and sPD-1 in patients with different tumor entities who underwent ICI therapy.
Methods
We searched for articles in PubMed via Medline, Embase, Scopus, and Cochrane databases. The primary outcome was overall survival (OS) and progression-free survival (PFS); furthermore, we analyzed on-treatment serum level changes of sPD-L1 and sPD-1 during ICI therapy.
Results
We synthesized the data of 1,054 patients with different cancer types from 15 articles. Pooled univariate analysis showed that elevated levels of sPD-L1 were significantly associated with inferior OS (HR = 1.67; CI:1.26–2.23, I2 = 79%, p < 0.001). The strongest association was found in non-small cell lung cancer, whereas weaker or no association was observed in melanoma as well as in renal cell and esophageal cancers. Pooled multivariate analysis also showed that elevated levels of sPD-L1 correlated with worse OS (HR = 1.62; CI: 1.00–2.62, I2 = 84%, p = 0.05) and PFS (HR = 1.71; CI:1.00–2.94, I2 = 82%, p = 0.051). Furthermore, we observed that one or three months of anti-PD-L1 treatment caused a strong (27.67-fold) elevation of sPD-L1 levels in malignant mesothelioma and urothelial cancer.
Conclusions
We found significantly inferior OS in ICI-treated cancer patients with elevated pre-treatment sPD-L1 levels, but this association seems to be tumor type dependent. In addition, sPD-L1 increases during anti-PD-L1 therapy seems to be therapy specific.
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Botticelli A, Pomati G, Cirillo A, Scagnoli S, Pisegna S, Chiavassa A, Rossi E, Schinzari G, Tortora G, Di Pietro FR, Cerbelli B, Di Filippo A, Amirhassankhani S, Scala A, Zizzari IG, Cortesi E, Tomao S, Nuti M, Mezi S, Marchetti P. The role of immune profile in predicting outcomes in cancer patients treated with immunotherapy. Front Immunol 2022; 13:974087. [PMID: 36405727 PMCID: PMC9671166 DOI: 10.3389/fimmu.2022.974087] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 09/22/2022] [Indexed: 11/06/2022] Open
Abstract
Background Despite the efficacy of immunotherapy, only a small percentage of patients achieves a long-term benefit in terms of overall survival. The aim of this study was to define an immune profile predicting the response to immune checkpoint inhibitors (ICIs). Methods Patients with advanced solid tumors, who underwent ICI treatment were enrolled in this prospective study. Blood samples were collected at the baseline. Thirteen soluble immune checkpoints, 3 soluble adhesion molecules, 5 chemokines and 11 cytokines were analyzed. The results were associated with oncological outcomes. Results Regardless of tumor type, patients with values of sTIM3, IFNα, IFNγ, IL1β, IL1α, IL12p70, MIP1β, IL13, sCD28, sGITR, sPDL1, IL10 and TNFα below the median had longer overall survival (p<0.05). By using cluster analysis and grouping the patients according to the trend of the molecules, two clusters were found. Cluster A had a significantly higher mean progression free survival (Cluster A=11.9 months vs Cluster B=3.5 months, p<0.01), a higher percentage of disease stability (Cluster A=34.5% vs. Cluster B=0%, p<0.05) and a lower percentage of disease progression (Cluster A=55.2% vs. Cluster B = 94.4%, p=0.04). Conclusion The combined evaluation of soluble molecules, rather than a single circulating factor, may be more suitable to represent the fitness of the immune system status in each patient and could allow to identify two different prognostic and predictive outcome profiles.
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Affiliation(s)
- Andrea Botticelli
- Department of Radiological, Oncological and Pathological Science, Sapienza University of Rome, Rome, Italy
| | - Giulia Pomati
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Alessio Cirillo
- Department of Radiological, Oncological and Pathological Science, Sapienza University of Rome, Rome, Italy
- *Correspondence: Alessio Cirillo,
| | - Simone Scagnoli
- Department of Medical and Surgical Sciences and Translational Medicine, University of Rome “Sapienza”, Rome, Italy
| | - Simona Pisegna
- Department of Radiological, Oncological and Pathological Science, Sapienza University of Rome, Rome, Italy
| | - Antonella Chiavassa
- Department of Radiological, Oncological and Pathological Science, Sapienza University of Rome, Rome, Italy
| | - Ernesto Rossi
- Medical Oncology, Fondazione Policlinico Universitario Agostino Gemelli Istituti di Ricovero e Cura a Carattere Scientifico (IRCSS), Rome, Italy
| | - Giovanni Schinzari
- Medical Oncology, Fondazione Policlinico Universitario Agostino Gemelli Istituti di Ricovero e Cura a Carattere Scientifico (IRCSS), Rome, Italy
- Medical Oncology, Universitá Cattolica del Sacro Cuore, Rome, Italy
| | - Giampaolo Tortora
- Medical Oncology, Fondazione Policlinico Universitario Agostino Gemelli Istituti di Ricovero e Cura a Carattere Scientifico (IRCSS), Rome, Italy
- Medical Oncology, Universitá Cattolica del Sacro Cuore, Rome, Italy
| | | | - Bruna Cerbelli
- Department of Medico-Surgical Sciences and Biotechnology, Polo Pontino, Sapienza University, Rome, Italy
| | - Alessandra Di Filippo
- Laboratory of Tumor Immunology and Cell Therapy, Department of Experimental Medicine, Policlinico Umberto I, University of Rome “Sapienza”, Rome, Italy
| | - Sasan Amirhassankhani
- Department of Urology, S. Orsola-Malpighi Hospital University of Bologna, Via Palagi, Bologna, Italy
| | - Alessandro Scala
- Medical Oncology, Fondazione Policlinico Universitario Agostino Gemelli Istituti di Ricovero e Cura a Carattere Scientifico (IRCSS), Rome, Italy
| | - Ilaria Grazia Zizzari
- Laboratory of Tumor Immunology and Cell Therapy, Department of Experimental Medicine, Policlinico Umberto I, University of Rome “Sapienza”, Rome, Italy
| | - Enrico Cortesi
- Department of Radiological, Oncological and Pathological Science, Sapienza University of Rome, Rome, Italy
| | - Silverio Tomao
- Department of Radiological, Oncological and Pathological Science, Sapienza University of Rome, Rome, Italy
| | - Marianna Nuti
- Laboratory of Tumor Immunology and Cell Therapy, Department of Experimental Medicine, Policlinico Umberto I, University of Rome “Sapienza”, Rome, Italy
| | - Silvia Mezi
- Department of Radiological, Oncological and Pathological Science, Sapienza University of Rome, Rome, Italy
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Sung PS, Lee IK, Roh PR, Kang MW, Ahn J, Yoon SK. Blood-based biomarkers for immune-based therapy in advanced HCC: Promising but a long way to go. Front Oncol 2022; 12:1028728. [PMID: 36387149 PMCID: PMC9659956 DOI: 10.3389/fonc.2022.1028728] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 10/17/2022] [Indexed: 09/08/2024] Open
Abstract
The introduction of immune checkpoint inhibitors (ICIs) represents a key shift in the management strategy for patients with hepatocellular carcinoma (HCC). However, there is a paucity of predictive biomarkers that facilitate the identification of patients that would respond to ICI therapy. Although several researchers have attempted to resolve the issue, the data is insufficient to alter daily clinical practice. The use of minimally invasive procedures to obtain patient-derived specimen, such as using blood-based samples, is increasingly preferred. Circulating tumor DNA (ctDNA) can be isolated from the blood of cancer patients, and liquid biopsies can provide sufficient material to enable ongoing monitoring of HCC. This is particularly significant for patients for whom surgery is not indicated, including those with advanced HCC. In this review, we summarize the current state of understanding of blood-based biomarkers for ICI-based therapy in advanced HCC, which is promising despite there is still a long way to go.
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Affiliation(s)
- Pil Soo Sung
- Department of Biomedicine and Health Sciences, The Catholic University Liver Research Center, College of Medicine, POSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul, South Korea
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, South Korea
| | - Isaac Kise Lee
- Department of Computer Science and Engineering, Incheon National University, Incheon, South Korea
| | - Pu Reun Roh
- Department of Biomedicine and Health Sciences, The Catholic University Liver Research Center, College of Medicine, POSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul, South Korea
| | - Min Woo Kang
- Department of Biomedicine and Health Sciences, The Catholic University Liver Research Center, College of Medicine, POSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul, South Korea
| | - Jaegyoon Ahn
- Department of Computer Science and Engineering, Incheon National University, Incheon, South Korea
| | - Seung Kew Yoon
- Department of Biomedicine and Health Sciences, The Catholic University Liver Research Center, College of Medicine, POSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul, South Korea
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, South Korea
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31
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Keber CU, Derigs M, Schultz C, Wegner M, Lingelbach S, Wischmann V, Hofmann R, Denkert C, Hegele A, Hänze J. Cellular and soluble immune checkpoint signaling forms PD-L1 and PD-1 in renal tumor tissue and in blood. Cancer Immunol Immunother 2022; 71:2381-2389. [PMID: 35184226 PMCID: PMC9463294 DOI: 10.1007/s00262-022-03166-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 01/31/2022] [Indexed: 01/15/2023]
Abstract
Immune checkpoint blockade therapy is a treatment option of various metastatic cancer diseases including renal cell carcinoma (RCC). Approved antibody drugs target the co-inhibitory signaling of Programmed Cell Death Ligand-1 (PD-L1) and its receptor Programmed Cell Death-1 (PD-1). The combined evaluation of PD-L1 and PD-1 at the mRNA and protein levels in tumor tissue with differentiation of tumor and immune cells as well as of soluble forms (sPD-L1) and (sPD-1) in blood is of basic interest in assessing biomarker surrogates. Here, we demonstrate that PD-L1 determined as fraction of stained tumor cells (TPS-score) correlates with PD-L1-mRNA in tumor tissue, reflecting the predominant expression of PD-L1 in tumor cells. Conversely, PD-1 in immune cells of tumor tissue (IC-score) correlated with PD-1-mRNA tissue levels reflecting the typical PD-1 expression in immune cells. Of note, sPD-L1 in blood did not correlate with either the TPS-score of PD-L1 or with PD-L1-mRNA in tumor tissue. sPD-L1 released into the supernatant of cultured RCC cells closely followed the cellular PD-L1 expression as tested by interferon γ (IFNG) induction and siRNA knockdown of PD-L1. Further analysis in patients revealed that sPD-L1 significantly increased in blood following renal tumor resection. In addition, sPD-L1 correlated significantly with inflammation marker C-reactive protein (CRP) and with PD-L1 mRNA level in whole blood. These results indicate that the major source of sPD-L1 in blood may be peripheral blood cells and not primarily tumor tissue PD-L1.
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Affiliation(s)
- Corinna U Keber
- Department of Pathology, Faculty of Medicine, Philipps-University Marburg, Marburg, Germany
| | - Marcus Derigs
- Clinic for Urology and Pediatric Urology, Faculty of Medicine, Philipps-University Marburg, Marburg, Germany
| | - Carolin Schultz
- Clinic for Urology and Pediatric Urology, Faculty of Medicine, Philipps-University Marburg, Marburg, Germany
| | - Moritz Wegner
- Department of Vascular and Endovascular Surgery, Faculty of Medicine, University of Cologne and University Hospital Cologne, Cologne, Germany
| | - Susanne Lingelbach
- Clinic for Urology and Pediatric Urology, Faculty of Medicine, Philipps-University Marburg, Marburg, Germany
| | - Viktoria Wischmann
- Department of Pathology, Faculty of Medicine, Philipps-University Marburg, Marburg, Germany
| | - Rainer Hofmann
- Clinic for Urology and Pediatric Urology, Faculty of Medicine, Philipps-University Marburg, Marburg, Germany
| | - Carsten Denkert
- Department of Pathology, Faculty of Medicine, Philipps-University Marburg, Marburg, Germany
| | - Axel Hegele
- Urological Center Mittelhessen, DRK Hospital Biedenkopf, Biedenkopf, Germany
| | - Jörg Hänze
- Clinic for Urology and Pediatric Urology, Faculty of Medicine, Philipps-University Marburg, Marburg, Germany.
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Tang Q, Chen Y, Li X, Long S, Shi Y, Yu Y, Wu W, Han L, Wang S. The role of PD-1/PD-L1 and application of immune-checkpoint inhibitors in human cancers. Front Immunol 2022; 13:964442. [PMID: 36177034 PMCID: PMC9513184 DOI: 10.3389/fimmu.2022.964442] [Citation(s) in RCA: 267] [Impact Index Per Article: 89.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 08/23/2022] [Indexed: 11/13/2022] Open
Abstract
Programmed cell death protein-1 (PD-1) is a checkpoint receptor expressed on the surface of various immune cells. PD-L1, the natural receptor for PD-1, is mainly expressed in tumor cells. Studies have indicated that PD-1 and PD-L1 are closely associated with the progression of human cancers and are promising biomarkers for cancer therapy. Moreover, the interaction of PD-1 and PD-L1 is one of the important mechanism by which human tumors generate immune escape. This article provides a review on the role of PD-L1/PD-1, mechanisms of immune response and resistance, as well as immune-related adverse events in the treatment of anti-PD-1/PD-L1 immunotherapy in human cancers. Moreover, we summarized a large number of clinical trials to successfully reveal that PD-1/PD-L1 Immune-checkpoint inhibitors have manifested promising therapeutic effects, which have been evaluated from different perspectives, including overall survival, objective effective rate and medium progression-free survival. Finally, we pointed out the current problems faced by PD-1/PD-L1 Immune-checkpoint inhibitors and its future prospects. Although PD-1/PD-L1 immune checkpoint inhibitors have been widely used in the treatment of human cancers, tough challenges still remain. Combination therapy and predictive models based on integrated biomarker determination theory may be the future directions for the application of PD-1/PD-L1 Immune-checkpoint inhibitors in treating human cancers.
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Affiliation(s)
- Qing Tang
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Clinical and Basic Research Team of Traditional Chinese Medicine (TCM) Prevention and Treatment of Non small cell lung cancer (NSCLC), Department of Oncology, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yun Chen
- Department of Organ Transplantation, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xiaojuan Li
- Institute of Rehabilitation Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Shunqin Long
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Clinical and Basic Research Team of Traditional Chinese Medicine (TCM) Prevention and Treatment of Non small cell lung cancer (NSCLC), Department of Oncology, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yao Shi
- Department of Cerebrovascular Disease, Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yaya Yu
- Department of Oncology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - Wanyin Wu
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Clinical and Basic Research Team of Traditional Chinese Medicine (TCM) Prevention and Treatment of Non small cell lung cancer (NSCLC), Department of Oncology, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Wanyin Wu, ; Ling Han, ; Sumei Wang,
| | - Ling Han
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Wanyin Wu, ; Ling Han, ; Sumei Wang,
| | - Sumei Wang
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Clinical and Basic Research Team of Traditional Chinese Medicine (TCM) Prevention and Treatment of Non small cell lung cancer (NSCLC), Department of Oncology, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Wanyin Wu, ; Ling Han, ; Sumei Wang,
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Recombinant programmed cell death protein 1 functions as an immune check point blockade and enhances anti-cancer immunity. Biomaterials 2022; 285:121550. [DOI: 10.1016/j.biomaterials.2022.121550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 03/22/2022] [Accepted: 04/25/2022] [Indexed: 11/21/2022]
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Wang T, Denman D, Bacot SM, Feldman GM. Challenges and the Evolving Landscape of Assessing Blood-Based PD-L1 Expression as a Biomarker for Anti-PD-(L)1 Immunotherapy. Biomedicines 2022; 10:1181. [PMID: 35625917 PMCID: PMC9138337 DOI: 10.3390/biomedicines10051181] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/16/2022] [Accepted: 05/17/2022] [Indexed: 02/05/2023] Open
Abstract
While promising, PD-L1 expression on tumor tissues as assessed by immunohistochemistry has been shown to be an imperfect biomarker that only applies to a limited number of cancers, whereas many patients with PD-L1-negative tumors still respond to anti-PD-(L)1 immunotherapy. Recent studies using patient blood samples to assess immunotherapeutic responsiveness suggests a promising approach to the identification of novel and/or improved biomarkers for anti-PD-(L)1 immunotherapy. In this review, we discuss the advances in our evolving understanding of the regulation and function of PD-L1 expression, which is the foundation for developing blood-based PD-L1 as a biomarker for anti-PD-(L)1 immunotherapy. We further discuss current knowledge and clinical study results for biomarker identification using PD-L1 expression on tumor and immune cells, exosomes, and soluble forms of PD-L1 in the peripheral blood. Finally, we discuss key challenges for the successful development of the potential use of blood-based PD-L1 as a biomarker for anti-PD-(L)1 immunotherapy.
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Affiliation(s)
- Tao Wang
- Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA; (D.D.); (S.M.B.); (G.M.F.)
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Liao G, Liu Z, Xia M, Chen H, Wu H, Li B, Yu T, Cai S, Zhang X, Peng J. Soluble Programmed Cell Death-1 is a Novel Predictor of HBsAg Loss in Chronic Hepatitis B Patients When Long-Term Nucleos(t)ide Analog Treatment is Discontinued. Infect Drug Resist 2022; 15:2347-2357. [PMID: 35517900 PMCID: PMC9065130 DOI: 10.2147/idr.s360202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Accepted: 04/23/2022] [Indexed: 11/23/2022] Open
Affiliation(s)
- Guichan Liao
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Ziying Liu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Muye Xia
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Hongjie Chen
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Houji Wu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Bing Li
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Tao Yu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Shaohang Cai
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Xiaoyong Zhang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Jie Peng
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
- Correspondence: Jie Peng, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China, Tel +86 20 6278 7428, Fax +86 20 8771 9653, Email
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36
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Niu M, Liu Y, Yi M, Jiao D, Wu K. Biological Characteristics and Clinical Significance of Soluble PD-1/PD-L1 and Exosomal PD-L1 in Cancer. Front Immunol 2022; 13:827921. [PMID: 35386715 PMCID: PMC8977417 DOI: 10.3389/fimmu.2022.827921] [Citation(s) in RCA: 83] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 02/21/2022] [Indexed: 12/12/2022] Open
Abstract
The immune checkpoint pathway consisting of the cell membrane-bound molecule programmed death protein 1 (PD-1) and its ligand PD-L1 has been found to mediate negative regulatory signals that effectively inhibit T-cell proliferation and function and impair antitumor immune responses. Considerable evidence suggests that the PD-1/PD-L1 pathway is responsible for tumor immune tolerance and immune escape. Blockage of this pathway has been found to reverse T lymphocyte depletion and restore antitumor immunity. Antagonists targeting this pathway have shown significant clinical activity in specific cancer types. Although originally identified as membrane-type molecules, several other forms of PD-1/PD-L1 have been detected in the blood of cancer patients, including soluble PD-1/PD-L1 (sPD-1/sPD-L1) and exosomal PD-L1 (exoPD-L1), increasing the composition and functional complications of the PD-1/PD-L1 signaling pathway. For example, sPD-1 has been shown to block the PD-1/PD-L immunosuppressive pathway by binding to PD-L1 and PD-L2, whereas the role of sPD-L1 and its mechanism of action in cancer remain unclear. In addition, many studies have investigated the roles of exoPD-L1 in immunosuppression, as a biomarker for tumor progression and as a predictive biomarker for response to immunotherapy. This review describes the molecular mechanisms underlying the generation of sPD-1/sPD-L1 and exoPD-L1, along with their biological activities and methods of detection. In addition, this review discusses the clinical importance of sPD-1/sPD-L1 and exoPD-L1 in cancer, including their predictive and prognostic roles and the effects of treatments that target these molecules.
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Affiliation(s)
- Mengke Niu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yiming Liu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ming Yi
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dechao Jiao
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- *Correspondence: Kongming Wu, ; Dechao Jiao,
| | - Kongming Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- *Correspondence: Kongming Wu, ; Dechao Jiao,
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Xing Y, Liu J, Luo J, Ming T, Yang G, Sun S, Xu S, Li X, He E, Kong F, Yan S, Yang Y, Cai X. A Dual-Channel Intelligent Point-of-Care Testing System for Soluble Programmed Death-1 and Programmed Death-Ligand 1 Detection Based on Folding Paper-Based Immunosensors. ACS Sens 2022; 7:584-592. [PMID: 35060694 DOI: 10.1021/acssensors.1c02486] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Both programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) are important proteins in cancer immunotherapy. Soluble forms (sPD-1 and sPD-L1) have potential for determining treatment and prognosis monitoring. However, there is a lack of detection methods for point-of-care testing (POCT) of these two proteins, so a low-cost rapid detection platform is urgently needed. To solve this problem, a dual-channel electrochemical platform, including a folding paper-based immunosensor and a POCT system for rapid simultaneous detection of these two proteins was designed and fabricated. The immunosensor consists of a three-electrode system and a reaction cell. The surface of the working electrode was modified with nanocomposites synthesized from amine-functionalized single-walled carbon nanotubes, new methylene blue, and gold nanoparticles. Antibodies to sPD-1 and sPD-L1 were also immobilized on the working electrode surface. A differential pulse voltammetry electrochemical method was adopted. The immunosensor was able to detect sPD-1 and sPD-L1 in the ranges of 50 pg/mL to 50 ng/mL and 5 pg/mL to 5 ng/mL, respectively. The limits of detection were 10 and 5 pg/mL. Using this detection platform, sPD-1 and sPD-L1 in plasma were detected by both enzyme-linked immunosorbent assay and the immunosensor, which has good application potential.
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Affiliation(s)
- Yu Xing
- State Key Laboratory of Transducer Technology, Aerospace Information Research Institute, Chinese Academy of Sciences, Beijing 100190, P.R. China
- School of Electronic, Electrical and Communication Engineering, University of Chinese Academy of Sciences, Beijing 100049, P.R. China
| | - Juntao Liu
- State Key Laboratory of Transducer Technology, Aerospace Information Research Institute, Chinese Academy of Sciences, Beijing 100190, P.R. China
- School of Electronic, Electrical and Communication Engineering, University of Chinese Academy of Sciences, Beijing 100049, P.R. China
| | - Jinping Luo
- State Key Laboratory of Transducer Technology, Aerospace Information Research Institute, Chinese Academy of Sciences, Beijing 100190, P.R. China
- School of Electronic, Electrical and Communication Engineering, University of Chinese Academy of Sciences, Beijing 100049, P.R. China
| | - Tao Ming
- State Key Laboratory of Transducer Technology, Aerospace Information Research Institute, Chinese Academy of Sciences, Beijing 100190, P.R. China
- School of Electronic, Electrical and Communication Engineering, University of Chinese Academy of Sciences, Beijing 100049, P.R. China
| | - Gucheng Yang
- State Key Laboratory of Transducer Technology, Aerospace Information Research Institute, Chinese Academy of Sciences, Beijing 100190, P.R. China
- School of Electronic, Electrical and Communication Engineering, University of Chinese Academy of Sciences, Beijing 100049, P.R. China
| | - Shuai Sun
- State Key Laboratory of Transducer Technology, Aerospace Information Research Institute, Chinese Academy of Sciences, Beijing 100190, P.R. China
- School of Electronic, Electrical and Communication Engineering, University of Chinese Academy of Sciences, Beijing 100049, P.R. China
| | - Shengwei Xu
- State Key Laboratory of Transducer Technology, Aerospace Information Research Institute, Chinese Academy of Sciences, Beijing 100190, P.R. China
- School of Electronic, Electrical and Communication Engineering, University of Chinese Academy of Sciences, Beijing 100049, P.R. China
| | - Xinrong Li
- State Key Laboratory of Transducer Technology, Aerospace Information Research Institute, Chinese Academy of Sciences, Beijing 100190, P.R. China
- School of Electronic, Electrical and Communication Engineering, University of Chinese Academy of Sciences, Beijing 100049, P.R. China
| | - Enhui He
- State Key Laboratory of Transducer Technology, Aerospace Information Research Institute, Chinese Academy of Sciences, Beijing 100190, P.R. China
- School of Electronic, Electrical and Communication Engineering, University of Chinese Academy of Sciences, Beijing 100049, P.R. China
| | - Fanli Kong
- State Key Laboratory of Transducer Technology, Aerospace Information Research Institute, Chinese Academy of Sciences, Beijing 100190, P.R. China
- School of Electronic, Electrical and Communication Engineering, University of Chinese Academy of Sciences, Beijing 100049, P.R. China
| | - Shi Yan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Surgery II, Peking University Cancer Hospital & Institute, Beijing 100142, P.R. China
| | - Yue Yang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Surgery II, Peking University Cancer Hospital & Institute, Beijing 100142, P.R. China
| | - Xinxia Cai
- State Key Laboratory of Transducer Technology, Aerospace Information Research Institute, Chinese Academy of Sciences, Beijing 100190, P.R. China
- School of Electronic, Electrical and Communication Engineering, University of Chinese Academy of Sciences, Beijing 100049, P.R. China
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Liao G, Zhao Z, Qian Y, Ling X, Chen S, Li X, Kong FMS. Prognostic Role of Soluble Programmed Death Ligand 1 in Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis. Front Oncol 2022; 11:774131. [PMID: 35004295 PMCID: PMC8732757 DOI: 10.3389/fonc.2021.774131] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Accepted: 11/17/2021] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVE The objective of this study was to explore whether soluble programmed death ligand 1 (sPD-L1) is a potential prognostic biomarker in patients with non-small cell lung cancer (NSCLC). METHODS A comprehensive search of electronic databases was carried out. Original studies with inclusion of sPD-L1, progression-free survival, and overall survival in NSCLC were eligible. The primary endpoints were overall survival and progression-free survival. Hazard ratios (HRs) and 95% confidence intervals (CIs) were applied for data analysis. RESULTS Eight studies involving 710 patients with NSCLC were included in the analysis. A pooled data analysis revealed that high levels of sPD-L1 were correlated with poorer overall survival (HR = 2.34; 95% CI = 1.82-3.00; P < 0.001) and progression-free survival (HR = 2.35; 95% CI = 1.62-3.40, P < 0.001). A subgroup analysis revealed that high levels of sPD-L1 were correlated with poor overall survival in patients treated with immunotherapy (HR = 2.40; 95% CI = 1.79-3.22; P < 0.001). CONCLUSION This pooled analysis of published data suggests that sPD-L1 may serve as a readily available biomarker for survival in NSCLC patients treated with ICI based treatment. Prospective studies with well-designed standard assessment methods should be conducted to validate the prognostic role of sPD-L1 in NSCLC. SYSTEMATIC REVIEW REGISTRATION https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021283177.
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Affiliation(s)
- Guixiang Liao
- Department of Radiation Oncology, Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University, Shenzhen, China
| | - Zhihong Zhao
- Department of Nephrology, Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University, Shenzhen, China
| | - Yuting Qian
- Department of Radiation Oncology, Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University, Shenzhen, China
| | - Xiean Ling
- Department of Thoracic Surgery, Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University, Shenzhen, China
| | - Shanyi Chen
- Department of Radiation Oncology, Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University, Shenzhen, China
| | - Xianming Li
- Department of Radiation Oncology, Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University, Shenzhen, China
| | - Feng-Ming Spring Kong
- Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.,Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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Kozuka R, Enomoto M, Dong MP, Hai H, Thuy LTT, Odagiri N, Yoshida K, Kotani K, Motoyama H, Kawamura E, Hagihara A, Fujii H, Uchida-Kobayashi S, Tamori A, Kawada N. Soluble programmed cell death-1 predicts hepatocellular carcinoma development during nucleoside analogue treatment. Sci Rep 2022; 12:105. [PMID: 34996935 PMCID: PMC8741806 DOI: 10.1038/s41598-021-03706-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Accepted: 12/01/2021] [Indexed: 12/13/2022] Open
Abstract
Soluble immune checkpoint molecules are emerging novel mediators of immune regulation. However, it is unclear whether soluble immune checkpoint proteins affect the development of hepatocellular carcinoma (HCC) during nucleos(t)ide analogue (NA) treatment in patients with chronic hepatitis B virus infection. This study included 122 NA-naïve patients who received NA therapy. We assessed the associations of clinical factors, including soluble immune checkpoint proteins, with HCC development during NA treatment. The baseline serum concentrations of 16 soluble immune checkpoint proteins were measured using multiplexed fluorescent bead-based immunoassay. In total, 13 patients developed HCC during the follow-up period (median duration, 4.3 years). Of the 16 proteins, soluble inducible T-cell co-stimulator (≥ 164.71 pg/mL; p = 0.014), soluble programmed cell death-1 (sPD-1) (≤ 447.27 pg/mL; p = 0.031), soluble CD40 (≤ 493.68 pg/mL; p = 0.032), and soluble herpes virus entry mediator (≤ 2470.83 pg/mL; p = 0.038) were significantly associated with HCC development (log-rank test). In multivariate analysis, an sPD-1 level ≤ 447.27 pg/mL (p = 0.014; hazard ratio [HR], 4.537) and α-fetoprotein level ≥ 6.4 ng/mL (p = 0.040; HR, 5.524) were independently and significantly associated with HCC development. Pre-treatment sPD-1 is a novel predictive biomarker for HCC development during NA treatment.
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Affiliation(s)
- Ritsuzo Kozuka
- Department of Hepatology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8585, Japan
| | - Masaru Enomoto
- Department of Hepatology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8585, Japan.
| | - Minh Phuong Dong
- Department of Hepatology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8585, Japan
| | - Hoang Hai
- Department of Hepatology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8585, Japan
| | - Le Thi Thanh Thuy
- Department of Hepatology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8585, Japan
| | - Naoshi Odagiri
- Department of Hepatology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8585, Japan
| | - Kanako Yoshida
- Department of Hepatology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8585, Japan
| | - Kohei Kotani
- Department of Hepatology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8585, Japan
| | - Hiroyuki Motoyama
- Department of Hepatology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8585, Japan
| | - Etsushi Kawamura
- Department of Hepatology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8585, Japan
| | - Atsushi Hagihara
- Department of Hepatology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8585, Japan
| | - Hideki Fujii
- Department of Hepatology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8585, Japan
| | - Sawako Uchida-Kobayashi
- Department of Hepatology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8585, Japan
| | - Akihiro Tamori
- Department of Hepatology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8585, Japan
| | - Norifumi Kawada
- Department of Hepatology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8585, Japan
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Association of PD-L1 gene polymorphisms and circulating sPD-L1 levels with HBV infection susceptibility and related liver disease progression. Gene 2022; 806:145935. [PMID: 34478821 DOI: 10.1016/j.gene.2021.145935] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 08/24/2021] [Accepted: 08/27/2021] [Indexed: 02/08/2023]
Abstract
Soluble molecules of programmed death ligand 1 (sPD-L1) are known to modulate T-cell depletion, an important mechanism of hepatitis B virus (HBV) persistence and liver disease progression. In addition, PD-L1 polymorphisms in the 3'-UTR can influence PD-L1 expression and have been associated with cancer risk, although not definitively. The purpose of this study was to investigate the association of PD-L1 polymorphisms and circulating levels of sPD-L1 in HBV infection and live disease progression. In this study, five hundred fifty-one HBV infected patients of the three clinically well-defined subgroups chronic hepatitis B (CHB, n = 186), liver cirrhosis (LC, n = 142) and hepatocellular carcinoma (HCC, n = 223) and 240 healthy individuals (HC) were enrolled. PD-L1 polymorphisms (rs2297136 and rs4143815) were genotyped by in-house validated ARMS assays. Logistic regression models were applied in order to determine the association of PD-L1 polymorphisms with HBV infection as well as with progression of related liver diseases. Plasma sPD-L1 levels were quantified by ELISA assays. The PD-L1 rs2297136 AA genotype was associated with HBV infection susceptibility (HBV vs. HC: OR = 1.6; 95%CI = 1.1-2.3; p = 0.0087) and disease progression (LC vs. CHB: OR = 1.8; 95%CI = 1.1-2.9; p = 0.018). Whereas, the rs2297136 GG genotype was a protective factor for HCC development. Plasma sPD-L1 levels were significantly high in HBV patients (p < 0.0001) and higher in the LC followed by CHB and HCC groups. High sPD-L1 levels correlated with increased liver enzymes and with advanced liver disease progression (Child-pugh C > B > A, p < 0.0001) and BCLC classification (BCLC D > C > B > A, p = 0.031). We could, for the first time, conclude that PD-L1 rs2297136 polymorphism and plasma sPD-L1 protein levels associate with HBV infection and HBV-related liver disease progression.
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Hwang S, Lee KJ, Moon DB, Song GW, Jung DH, Kim YK, Yang H, An DE, Lee S, Lee SG. Prognostic impact of serum soluble PD-1 and ADV score for living donor liver transplantation in patients with previously untreated hepatocellular carcinoma. Ann Surg Treat Res 2022; 102:46-54. [PMID: 35071119 PMCID: PMC8753378 DOI: 10.4174/astr.2022.102.1.46] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 11/25/2021] [Accepted: 12/03/2021] [Indexed: 11/30/2022] Open
Affiliation(s)
- Shin Hwang
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kyung Jin Lee
- Asan Institute of Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Deok-Bog Moon
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Gi-Won Song
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Dong-Hwan Jung
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Yun Kyu Kim
- Asan Institute of Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hunji Yang
- Asan Institute of Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Da Eun An
- Asan Institute of Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Sion Lee
- Asan Institute of Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Sung-Gyu Lee
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Increased Plasma Soluble PD-1 Concentration Correlates with Disease Progression in Patients with Cancer Treated with Anti-PD-1 Antibodies. Biomedicines 2021; 9:biomedicines9121929. [PMID: 34944745 PMCID: PMC8698555 DOI: 10.3390/biomedicines9121929] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 12/09/2021] [Accepted: 12/14/2021] [Indexed: 12/21/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs) confer remarkable therapeutic benefits to patients with various cancers. However, many patients are non-responders or develop resistance following an initial response to ICIs. There are no reliable biomarkers to predict the therapeutic effect of ICIs. Therefore, this study investigated the clinical implications of plasma levels of soluble anti-programmed death-1 (sPD-1) in patients with cancer treated with ICIs. In total, 22 patients (13 with non-small-cell lung carcinoma, 8 with gastric cancer, and 1 with bladder cancer) were evaluated for sPD-1 concentration using enzyme-linked immunosorbent assays for diagnostic and anti-PD-1 antibody analyses. sPD-1 levels were low before the administration of anti-PD-1 antibodies. After two and four cycles of anti-PD-1 antibody therapy, sPD-1 levels significantly increased compared with pretreatment levels (p = 0.0348 vs. 0.0232). We observed an increased rate of change in plasma sPD-1 concentrations after two and four cycles of anti-PD-1 antibody therapy that significantly correlated with tumor size progression (p = 0.024). sPD-1 may be involved in resistance to anti-PD-1 antibody therapy, suggesting that changes in sPD-1 levels can identify primary ICI non-responders early in treatment. Detailed analysis of each cancer type revealed the potential of sPD-1 as a predictive biomarker of response to ICI treatment in patients with cancer.
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Huyen PTM, Dung DTN, Weiß PJ, Hoan PQ, Giang DP, Uyen NT, Van Tuan N, Trung NT, Velavan TP, Song LH, Hoan NX. Circulating levels of sPD-1 and PD-1 genetic variants are associated with hepatitis B infection and related liver disease progression. Int J Infect Dis 2021; 115:229-236. [PMID: 34910956 DOI: 10.1016/j.ijid.2021.12.325] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 12/07/2021] [Accepted: 12/09/2021] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Programmed cell death-1 (PD-1) variants and circulating levels of soluble PD-1 are associated with susceptibility to malignant and infectious disease. This study aimed to examine the association of PD-1.5 and PD-1.9 variants, and plasma sPD-1 levels with HBV infection and disease progression. METHODS The study cohort consists of HBV-infected adults (n=513) stratified by clinical course, including chronic hepatitis B (CHB, n=173), liver cirrhosis (LC, n=134), hepatocellular carcinoma (HCC, n=206), and matched healthy controls (HC, n=196). The PD-1.5 (rs2227981 C/T) and PD-1.9 (rs2227982 C/T) genetic variants were genotyped by Sanger sequencing, and plasma sPD-1 levels were quantified by enzyme immunoassay. RESULTS The plasma sPD-1 levels were significantly high among HBV patients. The highest plasma sPD-1 levels were observed in CHB patients, followed by the LC and HCC groups. In addition, the plasma sPD-1 levels correlated positively with liver inflammation (aspartate transaminase, AST: rho=0.57, P<0.0001 and alanine aminotransferase, ALT: rho=0.57, P<0.0001) and were positively correlated with liver fibrosis (AST to Platelet Ratio Index, APRI score: rho=0.53, P<0.0001). The PD-1.9 TT genotype was less frequent in CHB patients compared to LC, HCC and HCC+LC patients in both codominant and recessive models (P<0.01) and was found to be a risk factor for HCC predisposition [HCC vs. non-HCC: OR=2.0 (95% CI: 1.13-3.7), Padj=0.017]. The PD-1.5 CT genotype was associated with a reduced risk of acquiring HCC [OR=0.6 (95%CI: 0.4-0.9), Padj=0.031]. CONCLUSION Our study concludes that sPD-1 levels are associated with liver inflammation and progression of liver fibrosis and the PD-1.5 and PD-1.9 variants are associated with HBV infection and progression of liver disease.
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Affiliation(s)
- Pham Thi Minh Huyen
- Department of Biochemistry, 108 Institute of Clinical Medical and Pharmaceutical Sciences, Hanoi, Vietnam; Faculty of Biochemistry, Hanoi Medical University, Hanoi, Vietnam; Faculty of Infectious Diseases, 108 Institute of Clinical Medical and Pharmaceutical Sciences, Hanoi, Vietnam
| | - Dang Thi Ngoc Dung
- Faculty of Biochemistry, Hanoi Medical University, Hanoi, Vietnam; Faculty of Infectious Diseases, 108 Institute of Clinical Medical and Pharmaceutical Sciences, Hanoi, Vietnam
| | - Peter Johann Weiß
- Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany
| | - Phan Quoc Hoan
- Department of Molecular Biology, 108 Institute of Clinical Medical and Pharmaceutical Sciences, Hanoi, Vietnam
| | - Dao Phuong Giang
- Centre for Genetic Consultation and Cancer Screening, 108 Institute of Clinical Medical and Pharmaceutical Sciences, Hanoi, Vietnam; Vietnamese-German Center for Medical Research (VG-CARE), Hanoi, Vietnam
| | - Ngo Thi Uyen
- Faculty of Biochemistry, Hanoi Medical University, Hanoi, Vietnam
| | | | - Ngo Tat Trung
- Centre for Genetic Consultation and Cancer Screening, 108 Institute of Clinical Medical and Pharmaceutical Sciences, Hanoi, Vietnam; Vietnamese-German Center for Medical Research (VG-CARE), Hanoi, Vietnam
| | - Thirumalaisamy P Velavan
- Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany; Centre for Genetic Consultation and Cancer Screening, 108 Institute of Clinical Medical and Pharmaceutical Sciences, Hanoi, Vietnam
| | - Le Huu Song
- Vietnamese-German Center for Medical Research (VG-CARE), Hanoi, Vietnam; Faculty of Infectious Diseases, 108 Institute of Clinical Medical and Pharmaceutical Sciences, Hanoi, Vietnam
| | - Nghiem Xuan Hoan
- Department of Molecular Biology, 108 Institute of Clinical Medical and Pharmaceutical Sciences, Hanoi, Vietnam; Vietnamese-German Center for Medical Research (VG-CARE), Hanoi, Vietnam.
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Ebeling Barbier C, Heindryckx F, Lennernäs H. Limitations and Possibilities of Transarterial Chemotherapeutic Treatment of Hepatocellular Carcinoma. Int J Mol Sci 2021; 22:ijms222313051. [PMID: 34884853 PMCID: PMC8658005 DOI: 10.3390/ijms222313051] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 11/26/2021] [Accepted: 11/29/2021] [Indexed: 02/07/2023] Open
Abstract
Because diagnostic tools for discriminating between hepatocellular carcinoma (HCC) and advanced cirrhosis are poor, HCC is often detected in a stage where transarterial chemoembolization (TACE) is the best treatment option, even though it provides a poor survival gain. Despite having been used worldwide for several decades, TACE still has many limitations. First, there is a vast heterogeneity in the cellular composition and metabolism of HCCs as well as in the patient population, which renders it difficult to identify patients who would benefit from TACE. Often the delivered drug does not penetrate sufficiently selectively and deeply into the tumour and the drug delivery system is not releasing the drug at an optimal clinical rate. In addition, therapeutic effectiveness is limited by the crosstalk between the tumour cells and components of the cirrhotic tumour microenvironment. To improve this widely used treatment of one of our most common and deadly cancers, we need to better understand the complex interactions between drug delivery, local pharmacology, tumour targeting mechanisms, liver pathophysiology, patient and tumour heterogeneity, and resistance mechanisms. This review provides a novel and important overview of clinical data and discusses the role of the tumour microenvironment and lymphatic system in the cirrhotic liver, its potential response to TACE, and current and possible novel DDSs for locoregional treatment.
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Affiliation(s)
| | - Femke Heindryckx
- Department of Medical Cell Biology, Uppsala University, 751 23 Uppsala, Sweden;
| | - Hans Lennernäs
- Department of Pharmaceutical Biosciences, Uppsala University, 751 23 Uppsala, Sweden
- Correspondence: ; Tel.: +46-18-471-4317; Fax: +46-18-471-4223
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Xue JS, Liu H, Meng GX, Ding ZN, Yan LJ, Yao SY, Li HC, Dong ZR, Chen ZQ, Hong JG, Li T. Prognostic value of soluble programmed cell death-1 (sPD-1) and soluble programmed cell death ligand-1 (sPD-L1) for hepatocellular carcinoma: a systematic review and meta-analysis. Cancer Immunol Immunother 2021; 71:1633-1644. [PMID: 34750662 DOI: 10.1007/s00262-021-03103-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 10/28/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND Preliminary studies have suggested that soluble programmed death-1 (sPD-1) and soluble programmed cell death ligand-1 (sPD-L1) have prognostic implications in many malignant tumors. However, the correlation between sPD-1/sPD-L1 level and prognosis of hepatocellular carcinoma (HCC) is still unclear. METHODS We searched several electronic databases from database inception to October 7, 2021. Meta-analyses were performed separately for overall survival (OS), disease-free survival (DFS), recurrence-free survival (RFS), time to progression (TTP), and tumor-free survival (TFS). Random effects were introduced to this meta-analysis. The correlation between sPD-1/sPD-L1 level and prognosis was evaluated using hazard ratios (HRs) with 95% confidence intervals (95%CIs). RESULTS A total of 11 studies (1291 patients) were incorporated into this meta-analysis, including seven on sPD-L1, two on sPD-1, and two about both factors. The pooled results showed that high sPD-L1 level was associated with worse OS (HR = 2.46, 95%CI 1.74-3.49, P < 0.001; I2 = 31.4, P = 0.177) and poorer DFS/RFS/TTP/TFS of patients with HCC (HR = 2.22, 95%CI 1.47-3.35, P < 0.001; I2 = 66.1, P = 0.011), irrespective of method of detection, study type, treatment, cut-off value and follow-up time. In contrast, the level of sPD-1 was not correlated to the OS (HR = 1.19, 95%CI 0.55-2.56, P = 0.657) and DFS/TFS of patients with HCC (HR = 0.94, 95%CI 0.36-2.49, P = 0.906). CONCLUSION sPD-L1 rather than sPD-1 could be a good predictor for recurrence and survival after treatment for HCC. More high-quality prospective studies are warranted to assess the prognostic value of sPD-1 or sPD-L1 for HCC.
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Affiliation(s)
- Jun-Shuai Xue
- Department of General Surgery, Qilu Hospital, Shandong University, 107 West Wen Hua Road, Jinan, 250012, China
| | - Hui Liu
- Department of General Surgery, Qilu Hospital, Shandong University, 107 West Wen Hua Road, Jinan, 250012, China
| | - Guang-Xiao Meng
- Department of General Surgery, Qilu Hospital, Shandong University, 107 West Wen Hua Road, Jinan, 250012, China
| | - Zi-Niu Ding
- Department of General Surgery, Qilu Hospital, Shandong University, 107 West Wen Hua Road, Jinan, 250012, China
| | - Lun-Jie Yan
- Department of General Surgery, Qilu Hospital, Shandong University, 107 West Wen Hua Road, Jinan, 250012, China
| | - Sheng-Yu Yao
- Department of General Surgery, Qilu Hospital, Shandong University, 107 West Wen Hua Road, Jinan, 250012, China
| | - Hai-Chao Li
- Department of General Surgery, Qilu Hospital, Shandong University, 107 West Wen Hua Road, Jinan, 250012, China
| | - Zhao-Ru Dong
- Department of General Surgery, Qilu Hospital, Shandong University, 107 West Wen Hua Road, Jinan, 250012, China
| | - Zhi-Qiang Chen
- Department of General Surgery, Qilu Hospital, Shandong University, 107 West Wen Hua Road, Jinan, 250012, China
| | - Jian-Guo Hong
- Department of General Surgery, Qilu Hospital, Shandong University, 107 West Wen Hua Road, Jinan, 250012, China
| | - Tao Li
- Department of General Surgery, Qilu Hospital, Shandong University, 107 West Wen Hua Road, Jinan, 250012, China. .,Department of Hepatobiliary Surgery, The Second Hospital of Shandong University, Jinan, 250012, China.
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Pan SW, Su WJ, Chan YJ, Ho ML, Feng JY, Shu CC, Wang JY, Wang HC, Yu CJ, Chen YM. Disease progression in patients with nontuberculous mycobacterial lung disease of nodular bronchiectatic (NB) pattern: the role of cavitary NB and soluble programmed death protein-1. Clin Infect Dis 2021; 75:239-247. [PMID: 34726741 DOI: 10.1093/cid/ciab929] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND In patients with nodular bronchiectatic (NB) nontuberculous mycobacterial-lung disease (NTM-LD), risk factors for disease progression have not been clearly investigated. The roles of cavitary NB and soluble programmed death protein-1 (sPD-1), an immune-related biomarker, in the disease course of NB NTM-LD remain unknown. METHODS Patients with NB NTM-LD were enrolled from two medical centers in 2014-2020. We identified cavitary NB, measured sPD-1 levels, and analyzed factors associated with cavitary NB and predictors for disease progression of NB NTM-LD. RESULTS Of 120 cases of NB NTM-LD, 87 (72.5%) were caused by Mycobacterium avium complex. sPD-1 levels were lower in 13 (10.8%) patients with cavitary NB than in non-cavitary patients (P = 0.020). Over 1.41 ± 1.43 years of follow-up, 12 (92.3%) patients in the cavitary and 66 (61.7%) in the non-cavitary group developed disease progression (P = 0.032). In multivariate analysis, body mass index (BMI) (Kg/m 2, adjusted hazard ratio [aHR], 0.895 [95% CI, 0.811-0.988]), sputum smear grade (aHR, 1.247 [1.014-1.534), cavitary NB (aHR, 2.008 [1.052-3.834]) and sPD-1 (per 10-pg/mL increase, aHR, 0.889 [0.816-0.967]) were predictive for disease progression. Notably, sPD-1 showed a dose-dependent association with disease progression (sPD-1 ≤ 23.5 pg/ml; aHR, 3.306 [1.664-6.567], and sPD-1: 23.6-53.7 pg/ml; aHR, 2.496 [1.390-4.483]) compared with the reference (sPD-1 > 53.7 pg/ml). CONCLUSIONS Patients with NB NTM-LD and low sPD-1, low BMI, high smear grade and cavitary NB were at high risk for disease progression. sPD-1 was low in patients with cavitary NB phenotype and dose-responsively associated with disease progression.
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Affiliation(s)
- Sheng-Wei Pan
- Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Institute of Public Health, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Wei-Juin Su
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Division of Chest Medicine, China Medical University Hospital, Taipei Branch, Taipei, Taiwan
| | - Yu-Jiun Chan
- Institute of Public Health, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Division of Infectious Diseases, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,Division of Microbiology, Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Mei-Lin Ho
- Department of Chemistry, Soochow University, Taipei, Taiwan
| | - Jia-Yih Feng
- Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chin-Chung Shu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Jann-Yuan Wang
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Hao-Chien Wang
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Departmnet of Medicine, National Taiwan University Cancer Center, Taipei, Taiwan
| | - Chong-Jen Yu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University Hospital, Hsin-Chu Branch, Hsin-Chu, Taiwan
| | - Yuh-Min Chen
- Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
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47
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Lawal G, Xiao Y, Rahnemai-Azar AA, Tsilimigras DI, Kuang M, Bakopoulos A, Pawlik TM. The Immunology of Hepatocellular Carcinoma. Vaccines (Basel) 2021; 9:vaccines9101184. [PMID: 34696292 PMCID: PMC8538643 DOI: 10.3390/vaccines9101184] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 09/20/2021] [Accepted: 10/08/2021] [Indexed: 12/13/2022] Open
Abstract
Liver cancer is the third leading cause of cancer death worldwide. Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver. Liver resection or transplantation offer the only potentially curative options for HCC; however, many patients are not candidates for surgical resection, either due to presentation at advanced stages or poor liver function and portal hypertension. Liver transplantation is also limited to patients with certain characteristics, such as those that meet the Milan criteria (one tumor ≤ 5 cm, or up to three tumors no larger than 3 cm, along with the absence of gross vascular invasion or extrahepatic spread). Locoregional therapies, such as ablation (radiofrequency, ethanol, cryoablation, microwave), trans-arterial therapies like chemoembolization (TACE) or radioembolization (TARE), and external beam radiation therapy, have been used mainly as palliative measures with poor prognosis. Therefore, emerging novel systemic treatments, such as immunotherapy, have increasingly become popular. HCC is immunogenic, containing infiltrating tumor-specific T-cell lymphocytes and other immune cells. Immunotherapy may provide a more effective and discriminatory targeting of tumor cells through induction of a tumor-specific immune response in cancer cells and can improve post-surgical recurrence-free survival in HCC. We herein review evidence supporting different immunomodulating cell-based technology relative to cancer therapy in vaccines and targeted therapies, such as immune checkpoint inhibitors, in the management of hepatocellular carcinoma among patients with advanced disease.
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Affiliation(s)
- Gbemisola Lawal
- Division of Surgical Oncology, Department of Surgery, Arrowhead Regional Cancer Center, California University of Science and Medicine, Colton, CA 92324, USA; (G.L.); (A.A.R.-A.)
| | - Yao Xiao
- Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China; (Y.X.); (M.K.)
| | - Amir A. Rahnemai-Azar
- Division of Surgical Oncology, Department of Surgery, Arrowhead Regional Cancer Center, California University of Science and Medicine, Colton, CA 92324, USA; (G.L.); (A.A.R.-A.)
| | - Diamantis I. Tsilimigras
- Department of Surgery, The Ohio State Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH 43210, USA;
- Correspondence: ; Tel.: +1-215-987-9177
| | - Ming Kuang
- Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China; (Y.X.); (M.K.)
| | - Anargyros Bakopoulos
- Department of Surgery, Attikon University Hospital, University of Athens, 12462 Athens, Greece;
| | - Timothy M. Pawlik
- Department of Surgery, The Ohio State Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH 43210, USA;
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48
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Moldogazieva NT, Zavadskiy SP, Sologova SS, Mokhosoev IM, Terentiev AA. Predictive biomarkers for systemic therapy of hepatocellular carcinoma. Expert Rev Mol Diagn 2021; 21:1147-1164. [PMID: 34582293 DOI: 10.1080/14737159.2021.1987217] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Introduction: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the third cancer-related cause of death worldwide. In recent years, several systemic therapy drugs including sorafenib, lenvatinib, regorafenib, cabozantinib, ramucicurab, nivilumab, and pembrolizumab have been approved by FDA for advanced HCC. However, their insufficient efficacy, toxicity, and drug resistance require clinically applicable and validated predictive biomarkers.Areas covered: Our review covers the recent advancements in the identification of proteomic/genomic/epigenomic/transcriptomic biomarkers for predicting HCC treatment efficacy with the use of multi-kinase inhibitors (MKIs), CDK4/6 inhibitors, and immune checkpoint inhibitors (ICIs). Alpha-fetoprotein, des-carboxyprothrombin, vascular endothelial growth factor, angiopoietin-2, and dysregulated MTOR, VEGFR2, c-KIT, RAF1, PDGFRβ have the potential of proteomic/genomic biomarkers for sorafenib treatment. Alanine aminotransferase, aspartate aminotransferase, and albumin-bilirubin grade can predict the efficacy of other MKIs. Rb, p16, and Ki-67, and genes involved in cell cycle regulation, CDK1-4, CCND1, CDKN1A, and CDKN2A have been proposed for CD4/6 inhibitors, while dysregulated TERT, CTNNB1, TP53 FGF19, and TP53 are found to be predictors for ICI efficacy.Expert opinion: There are still limited clinically applicable and validated predictive biomarkers to identify HCC patients who benefit from systemic therapy. Further prospective biomarker validation studies for HCC personalized systemic therapy are required.
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Affiliation(s)
- Nurbubu T Moldogazieva
- Laboratory of Bioinformatics, Institute of Translational Medicine and Biotechnology, I.m. Sechenov First Moscow State Medical University (Sechenov University);, Moscow, Russia
| | - Sergey P Zavadskiy
- Department of Pharmacology, Nelyubin Institute of Pharmacy, I.m. Sechenov First Moscow State Medical University (Sechenov University), Russia, Russia
| | - Susanna S Sologova
- Department of Pharmacology, Nelyubin Institute of Pharmacy, I.m. Sechenov First Moscow State Medical University (Sechenov University), Russia, Russia
| | - Innokenty M Mokhosoev
- Department of Biochemistry and Molecular Biology, N.i. Pirogov Russian National Research Medical University, Moscow, Russia
| | - Alexander A Terentiev
- Department of Biochemistry and Molecular Biology, N.i. Pirogov Russian National Research Medical University, Moscow, Russia
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49
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He Y, Lu M, Che J, Chu Q, Zhang P, Chen Y. Biomarkers and Future Perspectives for Hepatocellular Carcinoma Immunotherapy. Front Oncol 2021; 11:716844. [PMID: 34552872 PMCID: PMC8450565 DOI: 10.3389/fonc.2021.716844] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Accepted: 08/18/2021] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular cancer is the sixth most frequently diagnosed malignant disease worldwide, and was responsible for tens of millions of deaths in 2020; however, treatment options for patients with advanced hepatocellular carcinoma remain limited. Immunotherapy has undergone rapid development over recent years, especially in the field of immune checkpoint inhibitors (ICIs). These drugs aim to activate and enhance antitumor immunity and represent a new prospect for the treatment of patients with advanced cancer. Nevertheless, only a small proportion of liver cancer patients currently benefit from ICI-based treatment, highlighting the need to better understand how ICIs and tumors interact, as well as identify predictive biomarkers for immunotherapeutic responses. In this review, we highlight clinical trials and basic research in hepatocellular carcinoma, with a particular focus on predictive biomarkers for the therapeutic efficacy of ICIs. Predictive biomarkers for immune-related adverse events are also discussed.
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Affiliation(s)
- Yuqing He
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mengyao Lu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jing Che
- College of Life Sciences, Wuhan University, Wuhan, China
| | - Qian Chu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Peng Zhang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuan Chen
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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50
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Mattos ÂZ, Debes JD, Boonstra A, Vogel A, Mattos AA. Immune aspects of hepatocellular carcinoma: From immune markers for early detection to immunotherapy. World J Gastrointest Oncol 2021; 13:1132-1143. [PMID: 34616518 PMCID: PMC8465446 DOI: 10.4251/wjgo.v13.i9.1132] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 05/02/2021] [Accepted: 07/05/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent cancers and one of the main causes of cancer-related deaths worldwide. Most HCCs develop in an inflammatory microenvironment, and mounting evidence emphasizes the importance of immune aspects in hepatocarcinogenesis. In normal physiology, both innate and adaptive immune responses are responsible for eliminating malignantly transformed cells, thus preventing the development of liver cancer. However, in the setting of impaired natural killer cells and exhaustion of T cells, HCC can develop. The immunogenic features of HCC have relevant clinical implications. There is a large number of immune markers currently being studied for the early detection of liver cancer, which would be critical in order to improve surveillance programs. Moreover, novel immunotherapies have recently been proven to be effective, and the combination of atezolizumab and bevacizumab is currently the most effective treatment for advanced HCC. It is expected that in the near future different subgroups of patients will benefit from specific immunotherapy. The better we understand the immune aspects of HCC, the greater the benefit to patients through surveillance aiming for early detection of liver cancer, which allows for curative treatments, and, in cases of advanced disease, through the selection of the best possible therapy for each individual.
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Affiliation(s)
- Ângelo Z Mattos
- Graduate Program in Medicine: Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, Brazil
- Gastroenterology and Hepatology Unit, Irmandade Santa Casa de Misericórdia de Porto Alegre, Porto Alegre 90020-090, Brazil
| | - Jose D Debes
- Department of Medicine, Division of Gastroenterology and Infectious Diseases, University of Minnesota, Minneapolis, MN 55812, United States
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam NL-3015, The Netherlands
| | - Andre Boonstra
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam NL-3015, The Netherlands
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover 30625, Germany
| | - Angelo A Mattos
- Graduate Program in Medicine: Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, Brazil
- Gastroenterology and Hepatology Unit, Irmandade Santa Casa de Misericórdia de Porto Alegre, Porto Alegre 90020-090, Brazil
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