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Lin S, Liu D, Liang T, Zhuang Y, Wang X, Ma S, Li Q, Hu K. Cryoablation-induced modulation of Treg cells and the TGF-β pathway in lung adenocarcinoma: implications for increased antitumor immunity. BMC Med 2025; 23:89. [PMID: 39948553 PMCID: PMC11827211 DOI: 10.1186/s12916-025-03926-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Accepted: 02/04/2025] [Indexed: 02/16/2025] Open
Abstract
BACKGROUND Cryoablation plays a key role in the comprehensive management of lung adenocarcinoma, characterized by its ability to activate antitumor immunity. This study aimed to explore the impact of cryoablation on the local immune microenvironment, focusing on regulatory T cells (Tregs) and the TGF-β pathway. METHODS Single-cell sequencing was employed to identify differences in immune cell populations and related pathway expression between lung adenocarcinoma tissues and adjacent noncancerous tissues. Prospective observations of changes in Tregs in the peripheral blood pre- and post-cryoablation for lung adenocarcinoma were conducted at Dongfang Hospital, Beijing University of Chinese Medicine. Bulk RNA-seq analysis of mouse tumor tissues was performed to predict the potential mechanisms underlying cryoablation-induced antitumor immunity. Finally, these predictions were validated through in vitro and in vivo experiments employing cell cryoablation and mouse subcutaneous tumor transplantation models. RESULTS Single-cell RNA sequencing analysis revealed intricate interactions between Tregs subpopulations and the regulation of the immune response in lung adenocarcinoma, highlighting the involvement of the TGF-β pathway. A significant decrease in the level of Tregs was noted at 30 days post-cryoablation compared to pre-surgical and 3-day post-surgery levels. The cellular and murine cryoablation models validated the inhibitory effect of cryoablation on Tregs and its potential to stimulate antitumor immunity. Additionally, the results of bulk RNA-seq demonstrated the role of cryoablation in regulating postoperative immunity via the TGF-β pathway. Cryoablation decreased the expression levels of TGF-β1, suppressed the phosphorylation of Smad2 and Smad3, and downregulated the expression of FOXP3, thereby inhibiting the conversion of CD4 + T cell precursors into Tregs. Moreover, cryoablation enhanced the expression of interferon-gamma (IFN-γ), thereby promoting its antitumor activity. CONCLUSIONS This study revealed the effective modification of the lung adenocarcinoma microenvironment by cryoablation through the suppression of Tregs and activation of antitumor immunity via the TGF-β pathway. These findings hold implications for optimizing cryoablation-based therapies and guiding future clinical trials on lung adenocarcinoma treatment. TRIAL REGISTRATION This trial was registered with the Chinese Clinical Trial Registry (Chictr.org.cn, ChiCTR2000038580, Sep 24, 2020).
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Affiliation(s)
- Shicheng Lin
- Graduate School, Beijing University of Chinese Medicine, Beijing, People's Republic of China
| | - Dianna Liu
- Oncology Department, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, People's Republic of China
| | - Tianyu Liang
- Graduate School, Beijing University of Chinese Medicine, Beijing, People's Republic of China
- Geriatric Department, Miyun Campus of the Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing, People's Republic of China
| | - Yaoxue Zhuang
- Graduate School, Beijing University of Chinese Medicine, Beijing, People's Republic of China
- Intensive Care Department, Tongxiang Hospital of Traditional Chinese Medicine, Zhejiang, People's Republic of China
| | - Xiaofan Wang
- Graduate School, Beijing University of Chinese Medicine, Beijing, People's Republic of China
| | - Shengmao Ma
- Department of Thoracic Surgery, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, People's Republic of China
| | - Quanwang Li
- Oncology Department, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, People's Republic of China.
| | - Kaiwen Hu
- Oncology Department, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, People's Republic of China.
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Chen Y, Xu C, Mou Z, Hu Y, Yang C, Hu J, Chen X, Luo J, Zou L, Jiang H. Endoscopic Cryoablation Versus Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma. Eur Urol Oncol 2024; 7:1453-1461. [PMID: 38693018 DOI: 10.1016/j.euo.2024.04.012] [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: 01/21/2024] [Revised: 02/25/2024] [Accepted: 04/09/2024] [Indexed: 05/03/2024]
Abstract
BACKGROUND AND OBJECTIVE Cryoablation is a traditional antitumor therapy with good prospects for development. The efficacy of endoscopic management as a kidney-sparing surgery for high-risk upper tract urothelial carcinoma (UTUC) remains controversial. Our aim was to evaluate the impact of endoscopic cryoablation (ECA) versus radical nephroureterectomy (RNU) on survival outcomes, renal function, and complications. METHODS We retrospectively analyzed data for 116 patients with newly diagnosed high-risk UTUC who underwent either ECA (n = 13) or RNU (n = 103) from March 25, 2019 to December 8, 2021. Propensity score matching (1:4) using the nearest neighbor method was performed before analysis. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), intravesical recurrence-free survival (RFS), the change in renal function, and treatment-emergent adverse events (TEAEs). KEY FINDINGS AND LIMITATIONS At median follow-up of 28.2 mo for the ECA group and 27.6 mo for the RNU group, 2-yr OS (82% vs 84%), PFS (73% vs 71%), and intravesical RFS (81% vs 83%) rates after matching did not significantly differ. A decline in renal function was observed after RNU, but not after ECA. Five (41.7%) patients in the ECA group reported six TEAEs, and 17 patients (35.4%) in the RNU group reported 20 TEAEs. CONCLUSIONS AND CLINICAL IMPLICATIONS In comparison to RNU, ECA for UTUC resulted in noninferior oncological outcomes and superior preservation of renal function. PATIENT SUMMARY Our study suggests that a treatment called endoscopic cryoablation for high-risk cancer in the upper urinary tract can help in preserving kidney function, with similar survival outcomes to those after more extensive surgery. This option can be considered for selected patients with a strong preference for kidney preservation.
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Affiliation(s)
- Yiling Chen
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China; Institute of Urology, Fudan University, Shanghai, China
| | - Chenyang Xu
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China; Institute of Urology, Fudan University, Shanghai, China
| | - Zezhong Mou
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China; Institute of Urology, Fudan University, Shanghai, China
| | - Yun Hu
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China; Institute of Urology, Fudan University, Shanghai, China
| | - Chen Yang
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China; Institute of Urology, Fudan University, Shanghai, China
| | - Jinzhong Hu
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China; Institute of Urology, Fudan University, Shanghai, China
| | - Xinan Chen
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China; Institute of Urology, Fudan University, Shanghai, China
| | - Jianfeng Luo
- Department of Biostatistics and Social Medicine, School of Public Health, Fudan University, Shanghai, China.
| | - Lujia Zou
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China; Institute of Urology, Fudan University, Shanghai, China.
| | - Haowen Jiang
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China; Institute of Urology, Fudan University, Shanghai, China; National Clinical Research Center for Aging and Medicine, Fudan University, Shanghai, China.
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Duan Y, Zhang H, Tan T, Ye W, Yin K, Yu Y, Kang M, Yang J, Liao R. The immune response of hepatocellular carcinoma after locoregional and systemic therapies: The available combination option for immunotherapy. Biosci Trends 2024; 17:427-444. [PMID: 37981319 DOI: 10.5582/bst.2023.01275] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2023]
Abstract
Hepatocellular carcinoma (HCC) is associated with a highly heterogeneous immune environment that produces an immune response to various locoregional treatments (LRTs), which in turn affects the effectiveness of immunotherapy. Although LRTs still dominate HCC therapies, 50-60% of patients will ultimately be treated with systemic therapies and might receive those treatments for the rest of their life. TACE, SIRT, and thermal ablation can dramatically increase the immunosuppressive state of HCC, a condition that can be addressed by combination with immunotherapy to restore the activity of lymphocytes and the secretion of cellular immune factors. Immune treatment with locoregional and systemic treatments has dramatically changed the management of HCC. In this review, we examine the research on the changes in the immune microenvironment after locoregional or systemic treatment. We also summarize the regulation of various immune cells and immune factors in the tumor microenvironment and discuss the different infiltration degrees of immune cells and factors on the prognosis of HCC to better compare the efficacy between different treatment methods from the perspective of the tumor microenvironment. This information can be used to help develop treatment options for the upcoming new era of HCC treatment in the future.
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Affiliation(s)
- Yuxin Duan
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hua Zhang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Tao Tan
- Chongqing Health Statistics Information Center, Chongqing, China
| | - Wentao Ye
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Kunli Yin
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yanxi Yu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Meiqing Kang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jian Yang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Rui Liao
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Chen Z, Meng L, Zhang J, Zhang X. Progress in the cryoablation and cryoimmunotherapy for tumor. Front Immunol 2023; 14:1094009. [PMID: 36761748 PMCID: PMC9907027 DOI: 10.3389/fimmu.2023.1094009] [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: 11/09/2022] [Accepted: 01/09/2023] [Indexed: 01/26/2023] Open
Abstract
With the rapid advancement of imaging equipment and minimally invasive technology, cryoablation technology is being used more frequently in minimally invasive treatment of tumors, primarily for patients with early tumors who voluntarily consent to ablation as well as those with advanced tumors that cannot be surgically removed or cannot be tolerated. Cryoablation is more effective and secure for target lesions than other thermal ablation methods like microwave and radiofrequency ablation (RFA). The study also discovered that cryoablation, in addition to causing tumor tissue necrosis and apoptosis, can facilitate the release of tumor-derived autoantigens into the bloodstream and activate the host immune system to elicit beneficial anti-tumor immunological responses against primary. This may result in regression of the primary tumor and distant metastasis. The additional effect called " Accompanying effects ". It is the basis of combined ablation and immunotherapy for tumor. At present, there is a lot of research on the mechanism of immune response induced by cryoablation. Trying to solve the question: how positively induce immune response. In this review, we focus on: 1. the immune effects induced by cryoablation. 2. the effect and mechanism of tumor immunotherapy combined with cryoablation. 3.The clinical research of this combination therapy in the treatment of tumors.
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Affiliation(s)
- Zenan Chen
- Department of Radiology, The First Medical Center, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Liangliang Meng
- Department of Radiology, The First Medical Center, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China.,Department of Radiology, Chinese People's Armed Police (PAP) Force Hospital of Beijing, Beijing, China
| | - Jing Zhang
- Department of Radiology, The First Medical Center, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Xiao Zhang
- Department of Radiology, The First Medical Center, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
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Zhang L, Zhang M, Wang J, Li Y, Wang T, Xia J, Feng B, Shen J. Immunogenic change after percutaneous microwave ablation in pulmonary malignancies: Variation in immune cell subsets and cytokines in peripheral blood. Front Immunol 2022; 13:1069192. [PMID: 36569954 PMCID: PMC9780363 DOI: 10.3389/fimmu.2022.1069192] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 11/28/2022] [Indexed: 12/14/2022] Open
Abstract
Introduction To investigate immunogenic changes after percutaneous microwave ablation (MWA) in pulmonary malignancies. Methods Twenty-two consecutive patients with pulmonary malignancies who underwent percutaneous lung tumor MWA were prospectively enrolled in this study. Peripheral blood samples were collected on the day before (D0) and one month (M1) after MWA. Changes in immune cell subsets (CD3+, CD4+, and CD8+ T cells, and B, natural killer, regulatory T (Treg), and CD3-CD20+ cells) and cytokines (interleukin [IL]-2, 4, 6, 10, 17A, tumor necrosis factor [TNF]-α, and interferon-γ) were noted and compared. Progression-free survival (PFS) and potentially related factors were analyzed. Results The proportion of CD8+ T cells increased from 22.95 ± 7.38% (D0) to 25.95 ± 9.16% (M1) (p = 0.031). The proportion of Treg cells decreased from 10.82 ± 4.52% (D0) to 8.77 ± 2.05% (M1) (p = 0.049). The IL-2 concentration was also decreased from 1.58 ± 0.46 pg/mL (D0) to 1.26 ± 0.60 pg/mL (M1) (p = 0.028). The reduction in Treg cells predicted PFS independently of clinical prognostic features in multivariate analysis (hazard ratio = 4.97, 95% confidence interval: 1.32-18.66, p = 0.018). A reduction in the proportion of Treg cells was observed in 15 patients (68.2%) and the average of the reduction was 2.05 ± 4.60%. Those patients with a reduction in the proportion of Treg cells that was more than average showed a significantly longer median PFS time than those with a reduction that was less than average (16 months vs. 8.5 months, p = 0.025). Discussion Percutaneous MWA of pulmonary malignancies leads to immunogenic changes. The reduction in the proportion of Treg cells was independently associated with PFS.
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Affiliation(s)
- Liang Zhang
- Department of Interventional Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Pudong, Shanghai, China
| | - Mingming Zhang
- School of Clinical Medicine, Jining Medical University, Jining, Shandong, China
| | - Jun Wang
- Department of Interventional Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Pudong, Shanghai, China
| | - Yang Li
- Department of Radiology, Shanghai Jiao Tong University School of Medicine, Pudong, Shanghai, China
| | - Taijie Wang
- Department of Radiology, People’s Hospital of Qintong, Taizhou, Jiangsu, China
| | - Jianguo Xia
- Department of Ultrasound, Shanghai Jiao Tong University School of Medicine, Pudong, Shanghai, China
| | - Bo Feng
- Department of Interventional Radiology, The First Hospital of China Medical University, Shenyang, Liaoning, China,*Correspondence: Jialin Shen, ; Bo Feng,
| | - Jialin Shen
- Department of Interventional Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Pudong, Shanghai, China,*Correspondence: Jialin Shen, ; Bo Feng,
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Garg T, Weiss CR, Sheth RA. Techniques for Profiling the Cellular Immune Response and Their Implications for Interventional Oncology. Cancers (Basel) 2022; 14:3628. [PMID: 35892890 PMCID: PMC9332307 DOI: 10.3390/cancers14153628] [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: 07/08/2022] [Revised: 07/19/2022] [Accepted: 07/20/2022] [Indexed: 12/07/2022] Open
Abstract
In recent years there has been increased interest in using the immune contexture of the primary tumors to predict the patient's prognosis. The tumor microenvironment of patients with cancers consists of different types of lymphocytes, tumor-infiltrating leukocytes, dendritic cells, and others. Different technologies can be used for the evaluation of the tumor microenvironment, all of which require a tissue or cell sample. Image-guided tissue sampling is a cornerstone in the diagnosis, stratification, and longitudinal evaluation of therapeutic efficacy for cancer patients receiving immunotherapies. Therefore, interventional radiologists (IRs) play an essential role in the evaluation of patients treated with systemically administered immunotherapies. This review provides a detailed description of different technologies used for immune assessment and analysis of the data collected from the use of these technologies. The detailed approach provided herein is intended to provide the reader with the knowledge necessary to not only interpret studies containing such data but also design and apply these tools for clinical practice and future research studies.
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Affiliation(s)
- Tushar Garg
- Division of Vascular and Interventional Radiology, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; (T.G.); (C.R.W.)
| | - Clifford R. Weiss
- Division of Vascular and Interventional Radiology, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; (T.G.); (C.R.W.)
| | - Rahul A. Sheth
- Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Hao X, Sun G, Zhang Y, Kong X, Rong D, Song J, Tang W, Wang X. Targeting Immune Cells in the Tumor Microenvironment of HCC: New Opportunities and Challenges. Front Cell Dev Biol 2021; 9:775462. [PMID: 34869376 PMCID: PMC8633569 DOI: 10.3389/fcell.2021.775462] [Citation(s) in RCA: 98] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 10/19/2021] [Indexed: 12/17/2022] Open
Abstract
Immune associated cells in the microenvironment have a significant impact on the development and progression of hepatocellular carcinoma (HCC) and have received more and more attention. Different types of immune-associated cells play different roles, including promoting/inhibiting HCC and several different types that are controversial. It is well known that immune escape of HCC has become a difficult problem in tumor therapy. Therefore, in recent years, a large number of studies have focused on the immune microenvironment of HCC, explored many mechanisms worth identifying tumor immunosuppression, and developed a variety of immunotherapy methods as targets, laying the foundation for the final victory in the fight against HCC. This paper reviews recent studies on the immune microenvironment of HCC that are more reliable and important, and provides a more comprehensive view of the investigation of the immune microenvironment of HCC and the development of more immunotherapeutic approaches based on the relevant summaries of different immune cells.
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Affiliation(s)
- Xiaopei Hao
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, China
| | - Guangshun Sun
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Yao Zhang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, China
| | - Xiangyi Kong
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, China
| | - Dawei Rong
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, China
| | - Jinhua Song
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, China
| | - Weiwei Tang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, China
| | - Xuehao Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, China
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Rangamuwa K, Leong T, Weeden C, Asselin-Labat ML, Bozinovski S, Christie M, John T, Antippa P, Irving L, Steinfort D. Thermal ablation in non-small cell lung cancer: a review of treatment modalities and the evidence for combination with immune checkpoint inhibitors. Transl Lung Cancer Res 2021; 10:2842-2857. [PMID: 34295682 PMCID: PMC8264311 DOI: 10.21037/tlcr-20-1075] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Accepted: 11/26/2020] [Indexed: 12/12/2022]
Abstract
Lung cancer is the leading cause of cancer death worldwide, with approximately 1.6 million cancer related deaths each year. Prognosis is best in patients with early stage disease, though even then five-year survival is only 55% in some groups. Median survival for advanced non-small cell lung cancer (NSCLC) is 8–12 months with conventional treatment. Immune checkpoint inhibitor (ICI) therapy has revolutionised the treatment of NSCLC with significant long-term improvements in survival demonstrated in some patients with advanced NSCLC. However, only a small proportion of patients respond to ICI, suggesting the need for further techniques to harness the potential of ICI therapy. Thermal ablation utilizes the extremes of temperature to cause tumour destruction. Commonly used modalities are radiofrequency ablation (RFA), cryoablation and microwave ablation (MWA). At present thermal ablation is reserved for curative-intent therapy in patients with localized NSCLC who are unable to undergo surgical resection or stereotactic ablative body radiotherapy (SABR). Limited evidence suggests that thermal ablative modalities can upregulate an anticancer immune response in NSCLC. It is postulated that thermal ablation can increase tumour antigen release, which would initiate and upregulated steps in the cancer immunity cycle required to elicit an anticancer immune response. This article will review the current thermal ablative techniques and their ability to modulate an anti-cancer immune response with a view of using thermal ablation in conjunction with ICI therapy.
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Affiliation(s)
- Kanishka Rangamuwa
- Department of Respiratory Medicine, Royal Melbourne Hospital, Melbourne, Australia.,Department of Medicine (RMH), University of Melbourne, Parkville, Australia
| | - Tracy Leong
- Department of Respiratory Medicine, Austin Hospital, Heidelberg, Victoria, Australia
| | - Clare Weeden
- Personalised Oncology Division, Walter Eliza Hall institute, Melbourne, Australia
| | | | - Steven Bozinovski
- School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
| | - Michael Christie
- Department of Pathology, Royal Melbourne Hospital, Melbourne, Australia
| | - Tom John
- Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Phillip Antippa
- Department of Thoracic Surgery, Royal Melbourne Hospital, Melbourne, Australia
| | - Louis Irving
- Department of Respiratory Medicine, Royal Melbourne Hospital, Melbourne, Australia
| | - Daniel Steinfort
- Department of Respiratory Medicine, Royal Melbourne Hospital, Melbourne, Australia.,Department of Medicine (RMH), University of Melbourne, Parkville, Australia
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Lin YM, Taiji R, Calandri M, Odisio BC. Tumor Biomarkers and Interventional Oncology: Impact on Local Outcomes for Liver and Lung Malignancy. Curr Oncol Rep 2021; 23:67. [PMID: 33855606 DOI: 10.1007/s11912-021-01056-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/11/2021] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW Interventional oncology (IO) loco-regional treatments are widely utilized in clinical practice. However, local tumor control rates are still widely variable. There is a need to identify and develop novel biomarkers prognosticators following IO therapies. Here, we review the current literature on molecular tumor biomarkers in IO, mainly focusing on patients with liver and lung cancers. RECENT FINDINGS RAS mutation is a prognosticator for patients with colorectal liver metastases. Several promising serum metabolites, gene signatures, circulating tumor nucleotides, and peptides are being evaluated for patients with hepatocellular carcinoma. Ki-67 and RAS mutation are independent risk factors for local tumor progression in the ablation of lung cancer. The relevant interplay between specific tumor biomarkers and IO loco-regional therapies outcomes has brought a new vision in the management of cancer. Further evolution of personalized interventional oncology accordingly to tumor biomarkers should improve oncologic outcomes for patients receiving IO therapies.
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Affiliation(s)
- Yuan-Mao Lin
- Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, 1400 Pressler St. FCT 14.5084, Houston, TX, 77030, USA
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Ryosuke Taiji
- Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, 1400 Pressler St. FCT 14.5084, Houston, TX, 77030, USA
- Department of Radiology, Nara Medical University, Nara, Japan
| | - Marco Calandri
- Radiology Unit, San Luigi Gonzaga University Hospital - Department of Oncology, University of Turin, Turin, Italy
| | - Bruno C Odisio
- Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, 1400 Pressler St. FCT 14.5084, Houston, TX, 77030, USA.
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Dumolard L, Ghelfi J, Roth G, Decaens T, Macek Jilkova Z. Percutaneous Ablation-Induced Immunomodulation in Hepatocellular Carcinoma. Int J Mol Sci 2020; 21:E4398. [PMID: 32575734 PMCID: PMC7352237 DOI: 10.3390/ijms21124398] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 06/17/2020] [Accepted: 06/19/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related deaths worldwide and its incidence is rising. Percutaneous locoregional therapies, such as radiofrequency ablation and microwave ablation, are widely used as curative treatment options for patients with small HCC, but their effectiveness remains restricted because of the associated high rate of recurrence, occurring in about 70% of patients at five years. These thermal ablation techniques have the particularity to induce immunomodulation by destroying tumours, although this is not sufficient to raise an effective antitumour immune response. Ablative therapies combined with immunotherapies could act synergistically to enhance antitumour immunity. This review aims to understand the different immune changes triggered by radiofrequency ablation and microwave ablation as well as the interest in using immunotherapies in combination with thermal ablation techniques as a tool for complementary immunomodulation.
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Affiliation(s)
- Lucile Dumolard
- Université Grenoble Alpes, 38000 Grenoble, France; (L.D.); (G.R.); (T.D.)
- Institute for Advanced Biosciences, Research Center UGA/Inserm U 1209/CNRS 5309, 38700 La Tronche, France
| | - Julien Ghelfi
- Service de Radiologie, Pôle Digidune, CHU Grenoble Alpes, 38700 La Tronche, France;
| | - Gael Roth
- Université Grenoble Alpes, 38000 Grenoble, France; (L.D.); (G.R.); (T.D.)
- Institute for Advanced Biosciences, Research Center UGA/Inserm U 1209/CNRS 5309, 38700 La Tronche, France
- Service d’Hépato-Gastroentérologie, Pôle Digidune, CHU Grenoble Alpes, 38700 La Tronche, France
| | - Thomas Decaens
- Université Grenoble Alpes, 38000 Grenoble, France; (L.D.); (G.R.); (T.D.)
- Institute for Advanced Biosciences, Research Center UGA/Inserm U 1209/CNRS 5309, 38700 La Tronche, France
- Service d’Hépato-Gastroentérologie, Pôle Digidune, CHU Grenoble Alpes, 38700 La Tronche, France
| | - Zuzana Macek Jilkova
- Université Grenoble Alpes, 38000 Grenoble, France; (L.D.); (G.R.); (T.D.)
- Institute for Advanced Biosciences, Research Center UGA/Inserm U 1209/CNRS 5309, 38700 La Tronche, France
- Service d’Hépato-Gastroentérologie, Pôle Digidune, CHU Grenoble Alpes, 38700 La Tronche, France
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11
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Effect of dendritic cell-based immunotherapy on hepatocellular carcinoma: A systematic review and meta-analysis. Cytotherapy 2018; 20:975-989. [PMID: 30072299 DOI: 10.1016/j.jcyt.2018.06.002] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Revised: 05/17/2018] [Accepted: 06/07/2018] [Indexed: 01/30/2023]
Abstract
BACKGROUND AIMS Dendritic cell (DC)-based immunotherapy has recently been reported frequently in the treatment of hepatocellular carcinoma (HCC); however, its efficacy remains controversial. In this study, we aimed to evaluate the clinical efficacy of DC-based immunotherapy on HCC by conducting a systematic review and meta-analysis. METHODS PubMed, Cochrane Library, Embase and Web of Science were searched to identify clinical trials on DC-based immunotherapy for HCC published up to January 31, 2018. The articles were selected according to pre-established inclusion criteria and methodologic quality, and publication bias were evaluated. RESULTS A total of 1276 cases from 19 clinical trials were included. Compared with traditional treatment, further DC-based therapy enhanced the CD4+ T/CD8+ T ratio (standardized mean difference: 0.68, 95% confidence interval [CI] 0.46-0.89, P < 0.001); increased the 1-year, 18-month and 5-year progression-free survival (PFS) rate and the 1-year, 18-month and 2-year overall survival (OS) rate (relative risk > 1, P < 0.05), prolonged the median PFS time (median survival ratio [MSR]: 1.98, 95% CI: 1.60-2.46, P < 0.001) and median OS time (MSR: 1.72, 95% CI: 1.51-1.96, P < 0.001). Adverse reactions were mild. CONCLUSIONS DC-based therapy not only enhanced anti-tumor immunity, improved the survival rate and prolonged the survival time of HCC patients, but it was also safe. These findings will provide encouraging information for further development of DC-based immunotherapy as an adjuvant treatment for HCC. However, the results must be interpreted with caution because of the small study numbers, publication bias and the various of study designs, pre-treatment and therapeutic processes of DCs.
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12
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Impact of Interventional Oncology Therapies on Tumor Microenvironment and Strategies to Enhance Their Efficacy. AJR Am J Roentgenol 2018; 210:648-656. [PMID: 29364726 DOI: 10.2214/ajr.16.17677] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE We provide a brief review of the tumor microenvironment, the impact of six interventional radiology treatments on the tumor microenvironment, and potential methods to improve treatment efficacy. CONCLUSION Interventional oncology plays a unique role in cancer therapy, contributing to both antitumorigenic and protumorigenic effects.
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Yan QH, Xu DG, Shen YF, Yuan DL, Bao JH, Li HB, Lv YG. Observation of the effect of targeted therapy of 64-slice spiral CT combined with cryoablation for liver cancer. World J Gastroenterol 2017; 23:4080-4089. [PMID: 28652661 PMCID: PMC5473127 DOI: 10.3748/wjg.v23.i22.4080] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2016] [Revised: 02/15/2017] [Accepted: 03/06/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To observe the effect of targeted therapy with 64-slice spiral computed tomography (CT) combined with cryoablation for liver cancer.
METHODS A total of 124 patients (142 tumors) were enrolled into this study. According to the use of dual-slice spiral CT or 64-slice spiral CT as a guide technology, patients were divided into two groups: dual-slice group (n = 56, 65 tumors) and 64-slice group (n = 8, 77 tumors). All patients were accepted and received targeted therapy by an argon-helium superconducting surgery system. The guided scan times of the two groups was recorded and compared. In the two groups, the lesion ice coverage in diameter of ≥ 3 cm and < 3 cm were recorded, and freezing effective rate was compared. Hepatic perfusion values [hepatic artery perfusion (HAP), portal vein perfusion (PVP), and the hepatic arterial perfusion index (HAPI)] of tumor tissues, adjacent tissues and normal liver tissues at preoperative and postoperative four weeks in the two groups were compared. Local tumor changes were recorded and efficiency was compared at four weeks post-operation. Adverse events were recorded and compared between the two groups, including fever, pain, frostbite, nausea, vomiting, pleural effusion and abdominal bleeding.
RESULTS Guided scan times in the dual-slice group was longer than that in the 64-slice group (t = 11.445, P = 0.000). The freezing effective rate for tumors < 3 cm in diameter in the dual-slice group (81.58%) was lower than that in the 64-slice group (92.86%) (χ2 = 5.707, P = 0.017). The HAP and HAPI of tumor tissues were lower at four weeks post-treatment than at pre-treatment in both groups (all P < 0.05), and those in the 64-slice group were lower than that in the dual-slice group (all P < 0.05). HAP and PVP were lower and HAPI was higher in tumor adjacent tissues at post-treatment than at pre-treatment (all P < 0.05). Furthermore, the treatment effect and therapeutic efficacy in the dual-slice group were lower than the 64-slice group at four weeks post-treatment (all P < 0.05). Moreover, pleural effusion and intraperitoneal hemorrhage occurred in patients in the dual-slice group, while no complications occurred in the 64-slice group (all P < 0.05).
CONCLUSION 64-slice spiral CT applied with cryoablation in targeted therapy for liver cancer can achieve a safe and effective freezing treatment, so it is worth being used.
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Sun L, Xu G, Liao W, Yang H, Xu H, Du S, Zhao H, Lu X, Sang X, Mao Y. Clinicopathologic and prognostic significance of regulatory T cells in patients with hepatocellular carcinoma: a meta-analysis. Oncotarget 2017; 8:39658-39672. [PMID: 28487498 PMCID: PMC5503641 DOI: 10.18632/oncotarget.17340] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2017] [Accepted: 04/12/2017] [Indexed: 01/10/2023] Open
Abstract
The clinicopathologic and prognostic significance of regulatory T cells (Tregs) in patients with hepatocellular carcinoma (HCC) remains controversial. We performed a meta-analysis to resolve this issue. PubMed, Embase, Cochrane library, and the Web of Science were searched to identify eligible studies performed up to November 2016. A total of 3,854 HCC patients from 27 cohort studies were included. The meta-analysis revealed that high levels of Tregs were associated with poor overall survival (OS; HR = 1.95, P < 0.00001) and disease-free survival (DFS; HR = 1.82, P < 0.00001). However, the prognostic effect varied greatly according to the site of the Tregs. Higher intratumoral and peripheral blood levels of Tregs were associated with shorter OS and DFS, whereas a high peritumoral Tregs level was not associated with decreased OS and DFS. Trial design, therapy and method of detection had no effect on prognosis of Tregs. Moreover, the patients with high Tregs infiltration had multiple tumors, high AFP level, poor differentiation, later TNM stage, and vascular invasion. The present study demonstrates that high levels of intratumoral and peripheral blood Tregs predict multiple tumors, high AFP level, poor differentiation, later TNM stage, and vascular invasion and might be a promising prognostic factor in patients with HCC.
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Affiliation(s)
- Lejia Sun
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC and Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Gang Xu
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC and Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Wenjun Liao
- Department of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Huayu Yang
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC and Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Haifeng Xu
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC and Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Shunda Du
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC and Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Haitao Zhao
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC and Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Xin Lu
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC and Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Xinting Sang
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC and Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Yilei Mao
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC and Chinese Academy of Medical Sciences, Beijing, 100730, China
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15
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Zhang AB, Qian YG, Zheng SS. Prognostic significance of regulatory T lymphocytes in patients with hepatocellular carcinoma. J Zhejiang Univ Sci B 2017; 17:984-991. [PMID: 27921403 DOI: 10.1631/jzus.b1600264] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
We investigated the prognostic role of regulatory T cells (Tregs) in patients with hepatocellular carcinoma (HCC). Relevant evidence regarding prognostic significance of Tregs was systematically searched in MEDLINE and Embase databases. A meta-analysis was performed to compare survival in patients with high or low Tregs level (either in peripheral blood or tumor). Eighteen studies were identified that fulfilled for the eligibility criteria and were included for data synthesis. Our pooled hazard ratios (HRs) demonstrated that increased Tregs intratumoral accumulation was significantly associated with worse overall survival (HR=2.04, 95% confidence interval (CI): 1.72-2.42) and disease-free survival (HR=1.82, 95% CI: 1.58-2.09). Three studies evaluated the role of Tregs in peripheral blood, and all of them showed that increased peripheral Tregs correlated with shortened disease-free and overall survival. Collectively, our results showed that the increased Tregs count is tightly associated with the shortened survivals. Its measurement in either primary tumor or even circulation might be a candidate marker of prognostic significance in HCC patients.
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Affiliation(s)
- Ai-Bin Zhang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.,Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou 310003, China.,Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou 310003, China.,Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Hangzhou 310003, China
| | - Yi-Gang Qian
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.,Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou 310003, China.,Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou 310003, China.,Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Hangzhou 310003, China
| | - Shu-Sen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.,Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou 310003, China.,Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou 310003, China.,Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Hangzhou 310003, China
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16
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Takaki H, Imai N, Contessa TT, Srimathveeravalli G, Covey AM, Getrajdman GI, Brown KT, Solomon SB, Erinjeri JP. Peripheral Blood Regulatory T-Cell and Type 1 Helper T-Cell Population Decrease after Hepatic Artery Embolization. J Vasc Interv Radiol 2016; 27:1561-8. [PMID: 27084711 PMCID: PMC5039109 DOI: 10.1016/j.jvir.2016.01.150] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2015] [Revised: 01/29/2016] [Accepted: 01/29/2016] [Indexed: 12/14/2022] Open
Abstract
PURPOSE To evaluate changes in T-cell populations in peripheral blood after bland hepatic artery embolization (HAE). MATERIALS AND METHODS Bland HAE was performed in 12 patients to treat primary (n = 5) or metastatic (n = 7) liver tumors, using microspheres and polyvinyl alcohol (n = 8) or microspheres alone (n = 4). Patient peripheral blood samples were collected within 1 month before HAE, within 1 week after HAE (early period after HAE), and 2-8 weeks after HAE (follow-up period). Peripheral blood populations of cytotoxic T lymphocytes, CD4(+) T cells, type 1 helper T cells (Th1) and type 2 helper T cells (Th2), and regulatory T cells (Treg) were evaluated using flow cytometry. Changes in T-cell populations before and after bland HAE were compared using paired t tests. RESULTS Peripheral blood CD4(+) T-cell populations decreased significantly in the early period after HAE (44.0% ± 2.2 to 34.4% ± 3.6, P < .01) and in the follow-up period (44.0% ± 2.2 to 36.3% ± 3.0, P < .01). Among the individual CD4(+) T-cell subtypes, Treg (2.5% ± 0.3 to 1.7% ± 0.2, P < .02) and Th1 (8.1% ± 1.8 to 5.6% ± 1.6, P < .02) decreased significantly in the early period after HAE only. The presence of extrahepatic disease was associated with decreasing Treg (P < .04). CONCLUSIONS After HAE, the peripheral blood T-cell environment is changed with decreases in Treg and Th1.
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Affiliation(s)
- Haruyuki Takaki
- Department of Radiology, Hyogo Collage of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan.
| | - Naoko Imai
- Division of Hematology/Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Thomas T Contessa
- Interventional Radiology Service, Memorial Sloan-Kettering Cancer Center, New York, New York
| | | | - Anne M Covey
- Interventional Radiology Service, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - George I Getrajdman
- Interventional Radiology Service, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Karen T Brown
- Interventional Radiology Service, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Stephen B Solomon
- Interventional Radiology Service, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Joseph P Erinjeri
- Interventional Radiology Service, Memorial Sloan-Kettering Cancer Center, New York, New York
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17
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Zhang X, Feng M, Liu X, Bai L, Kong M, Chen Y, Zheng S, Liu S, Wan YJY, Duan Z, Han YP. Persistence of cirrhosis is maintained by intrahepatic regulatory T cells that inhibit fibrosis resolution by regulating the balance of tissue inhibitors of metalloproteinases and matrix metalloproteinases. Transl Res 2016; 169:67-79.e792. [PMID: 26613891 DOI: 10.1016/j.trsl.2015.10.008] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Revised: 10/07/2015] [Accepted: 10/29/2015] [Indexed: 12/26/2022]
Abstract
Fibrosis is the result of the abnormal accumulation of the extracellular matrix and ineffective clearance of fibroplasia. CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) are immunosuppressive lymphocytes that are highly expressed in the fibrotic tissues and peripheral blood of patients with cirrhosis or hepatocellular carcinoma. The role of Tregs in the progression of liver fibrosis is not well understood. Our experiments reveal that abundant of Tregs was scattered around sites of fibroplasia. Conversely, the depletion of Tregs promoted the resolution of liver fibrosis. As a consequence of Tregs depletion, the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) was altered; mmp9 and timp1 were reduced, whereas mmp2 and mmp14 were enhanced. The mmp9/timp1, mmp13/timp1, and mmp14/timp2 ratios were significantly increased in association with fibrosis resolution. Kupffer cells (KCs) are the main source of MMP. We observed that when KCs were cocultured with Tregs, the Tregs were able to inhibit MMP expression of KCs even at a low ratio; and anti-transforming growth factor-β (TGF-β) significantly reversed the inhibition of Tregs on MMP. Meanwhile, we also found that after Tregs depletion, TGF-β levels decreased in the mice liver, unlike in fibrosis. Furthermore, double depletion of both KCs and Tregs did not cause fiber resolution in mice. Thus, our results demonstrate that the persistence of liver cirrhosis is maintained by increased Tregs in the sites of fibroplasia and the subsequent regulation of the MMP/TIMP balance and that the suppression of KC-mediated MMP expression contributed to the regulatory process.
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Affiliation(s)
- Xiaohui Zhang
- Artificial Liver Treatment Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Min Feng
- Department of Liver Transplantation, First Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | - Xin Liu
- Artificial Liver Treatment Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Li Bai
- Artificial Liver Treatment Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Ming Kong
- Artificial Liver Treatment Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Yu Chen
- Artificial Liver Treatment Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Sujun Zheng
- Artificial Liver Treatment Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Shuang Liu
- Artificial Liver Treatment Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Yu-Jui Yvonne Wan
- Department of Medical Pathology and Laboratory Medicine, University of California, Davis Health Systems, Sacramento, Calif
| | - Zhongping Duan
- Artificial Liver Treatment Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China.
| | - Yuan-Ping Han
- The Center for Growth, Metabolism and Aging, The Key Laboratory for Bio-Resource and Eco-Environment, College of Life Science, and The National Key Laboratory of Biotherapy, Sichuan University, Chengdu, China.
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18
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Tampaki M, Doumba PP, Deutsch M, Koskinas J. Circulating biomarkers of hepatocellular carcinoma response after locoregional treatments: New insights. World J Hepatol 2015; 7:1834-1842. [PMID: 26207165 PMCID: PMC4506941 DOI: 10.4254/wjh.v7.i14.1834] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Revised: 06/24/2015] [Accepted: 07/11/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular cancer is the 5(th) most common cancer in the world and the third cause of death by malignant disease. Locoregional therapies are the most usual treatment of choice for patients with early or intermediate stage of disease. The main diagnostic tools for the detection of recurrence are the radiological techniques such as 4-phase computed tomography or dynamic contrast enhanced magnetic resonance imaging. However, in order to achieve best evaluation of treatment outcome and recurrence rates, there is a great need for the identification of specific and easily measured circulating biomarkers. The aim of this review is to analyze the existing data considering the prognostic significance of changes of serum diagnostic markers such as alpha-fetoprotein, des-gamma-carboxy prothrombin, alpha-fetoprotein-L3, angiogenetic factors (vascular endothelial growth factor, hypoxia inducible factor-1a) and immune parameters before and after radiofrequency ablation or transarterial chemoembolization.
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Affiliation(s)
- Maria Tampaki
- Maria Tampaki, Polyxeni P Doumba, Melanie Deutsch, John Koskinas, Academic Department of Medicine, Medical School of Athens, Hippokration General Hospital, 11527 Athens, Greece
| | - Polyxeni P Doumba
- Maria Tampaki, Polyxeni P Doumba, Melanie Deutsch, John Koskinas, Academic Department of Medicine, Medical School of Athens, Hippokration General Hospital, 11527 Athens, Greece
| | - Melanie Deutsch
- Maria Tampaki, Polyxeni P Doumba, Melanie Deutsch, John Koskinas, Academic Department of Medicine, Medical School of Athens, Hippokration General Hospital, 11527 Athens, Greece
| | - John Koskinas
- Maria Tampaki, Polyxeni P Doumba, Melanie Deutsch, John Koskinas, Academic Department of Medicine, Medical School of Athens, Hippokration General Hospital, 11527 Athens, Greece
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19
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Ding ZY, Wei YQ. Immunopathology of Hepatobiliary Tumors and Immunotherapy of Liver Cancers. CANCER IMMUNOLOGY 2015:199-215. [DOI: 10.1007/978-3-662-46410-6_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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20
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Hu KQ. Advances in clinical application of cryoablation therapy for hepatocellular carcinoma and metastatic liver tumor. J Clin Gastroenterol 2014; 48:830-836. [PMID: 25148553 DOI: 10.1097/mcg.0000000000000201] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Although surgical resection and liver transplantation are the curative treatments, many of HCC patients do not qualify for these curative therapies at the presentation. Thus, ablation therapies are currently important modalities in HCC treatment. Among currently available ablation therapies, cryoablation (ie, cryotherapy) is a novel local therapeutic modality. However, cryoablation has not been widely used as one of ablation therapies for HCC, because of historical concerns about risk of bleeding when cryotherapy is delivered by early generation of the argon-helium device. Nevertheless, with technological advances and increased clinical experience in the past decade, clinical application of cryoablation for HCC management has significantly increased. Accumulating data have demonstrated that cryoablation is highly effective in local tumor control with well-acceptable safety profile, and the overall survival is comparable with that of radiofrequency ablation in patients with tumors <5 cm. Compared with radiofrequency ablation and other thermal-based modalities, cryoablation has several advantages, such as the ability to produce larger and precise zones of ablation. This article systemically reviews the advances in clinical application of cryoablation therapy for HCC, including the related mechanisms and technology, clinical indications, efficacy and safety profiles, and future research directions.
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Affiliation(s)
- Ke-Qin Hu
- Division of Gastroenterology/Hepatology, Irvine Medical Center, University of California, Irvine, Orange, CA
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21
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Cryotherapy for cirrhosis-based hepatocellular carcinoma: a single center experience from 1595 treated cases. Front Med 2014; 9:63-71. [DOI: 10.1007/s11684-014-0342-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2014] [Accepted: 05/22/2014] [Indexed: 12/24/2022]
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22
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Bai JF, Liu P, Xu LX. Recent Advances in Thermal Treatment Techniques and Thermally Induced Immune Responses Against Cancer. IEEE Trans Biomed Eng 2014; 61:1497-505. [DOI: 10.1109/tbme.2014.2314357] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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23
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Yang Y, Hou J, Lin Z, Zhuo H, Chen D, Zhang X, Chen Y, Sun B. Attenuated Listeria monocytogenes as a cancer vaccine vector for the delivery of CD24, a biomarker for hepatic cancer stem cells. Cell Mol Immunol 2014; 11:184-96. [PMID: 24488178 DOI: 10.1038/cmi.2013.64] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2013] [Revised: 12/01/2013] [Accepted: 12/05/2013] [Indexed: 01/14/2023] Open
Abstract
Attenuated Listeria monocytogenes (LM) is a promising candidate vector for the delivery of cancer vaccines. After phagocytosis by antigen-presenting cells, this bacterium stimulates the major histocompatibility complex (MHC)-I and MHC-II pathways and induces the proliferation of antigen-specific T lymphocytes. A new strategy involving genetic modification of the replication-deficient LM strain ΔdalΔdat (Lmdd) to express and secrete human CD24 protein has been developed. CD24 is a hepatic cancer stem cell biomarker that is closely associated with apoptosis, metastasis and recurrence of hepatocellular carcinoma (HCC). After intravenous administration in mice, Lmdd-CD24 was distributed primarily in the spleen and liver and did not cause severe organ injury. Lmdd-CD24 effectively increased the number of interferon (IFN)-γ-producing CD8(+) T cells and IFN-γ secretion. Lmdd-CD24 also enhanced the number of IL-4- and IL-10-producing T helper 2 cells. The efficacy of the Lmdd-CD24 vaccine was further investigated against Hepa1-6-CD24 tumors, which were inguinally inoculated into mice. Lmdd-CD24 significantly reduced the tumor size in mice and increased their survival. Notably, a reduction of T regulatory cell (Treg) numbers and an enhancement of specific CD8(+) T-cell activity were observed in the tumor-infiltrating lymphocytes (TILs). These results suggest a potential application of the Lmdd-CD24 vaccine against HCC.
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Affiliation(s)
- Yu Yang
- Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jiajie Hou
- Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zhe Lin
- Department of Microbiology and Immunology, Nanjing Medical University, Nanjing, China
| | - Han Zhuo
- Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Dianyu Chen
- Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xudong Zhang
- Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yun Chen
- Department of Microbiology and Immunology, Nanjing Medical University, Nanjing, China
| | - Beicheng Sun
- Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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24
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Lu L, Feng M, Gu J, Xia Z, Zhang H, Zheng S, Duan Z, Hu R, Wang J, Shi W, Ji C, Shen Y, Chen G, Zheng SG, Han YP. Restoration of intrahepatic regulatory T cells through MMP-9/13-dependent activation of TGF-β is critical for immune homeostasis following acute liver injury. J Mol Cell Biol 2013; 5:369-379. [PMID: 24280647 PMCID: PMC3841112 DOI: 10.1093/jmcb/mjt042] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2012] [Revised: 07/24/2013] [Accepted: 08/08/2013] [Indexed: 12/24/2022] Open
Abstract
During the acute liver injury, immune responses are provoked into eliciting inflammation in the acute phase. In the healing phase, the inflammation is terminated for wound healing and restoration of immune homeostasis. In this study, we sought to address how regulatory T cells (Tregs) are involved in the progression of liver injury and repair. In the acute phase, intrahepatic Tregs (CD4(+)FoxP3(+)Helios(+)) diminished promptly through apoptosis, which was followed by inflammation and tissue injury. In the healing phase, a new subset of Tregs (CD4(+)Foxp3(+)Helios(-)) was generated in correlation with the matrix metalloproteinase (MMP) cascade and transforming growth factor-beta (TGF-β) activation that were manifested mainly by hepatic stellate cells. Moreover, the induction of induced Tregs and wound healing were both impaired in mice lacking TGF-β signaling or MMPs. The depletion of induced Tregs also impeded wound healing for tissue repair. Together, this study demonstrates the mechanism that the loss of nTregs through apoptosis in the acute phase may facilitate inflammation, while regenerated Tregs through MMP9/13-dependent activation of TGF-β in the healing phase are critical to terminate inflammation and allow for wound healing.
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Affiliation(s)
- Ling Lu
- Department of Liver Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Min Feng
- Department of General Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China
| | - Jia Gu
- Department of Liver Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Zanxian Xia
- School of Biological Sciences and Technology, Central South University, Changsha 410013, China
| | - Hongjun Zhang
- Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Sujun Zheng
- Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Zhongping Duan
- Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Richard Hu
- Olive View-UCLA Medical Center, Los Angeles, CA 91342, USA
| | - Julie Wang
- Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Wei Shi
- Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Cheng Ji
- Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Yi Shen
- Penn State University Hershey College of Medicine, Hershey, PA 17033, USA
| | - Guihua Chen
- Department of Liver Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Song Guo Zheng
- Penn State University Hershey College of Medicine, Hershey, PA 17033, USA
- Tongji University Shanghai East Hospital, Institute of Immunology, Shanghai 200120, China
| | - Yuan-Ping Han
- The Center for Growth, Metabolism and Aging, the Key Laboratory for Bio-Resource and Eco-Environment, and the National Key Laboratory of Biotherapy, Sichuan University, Chengdu 610064, China
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Buonaguro L, Petrizzo A, Tagliamonte M, Tornesello ML, Buonaguro FM. Challenges in cancer vaccine development for hepatocellular carcinoma. J Hepatol 2013; 59:897-903. [PMID: 23714157 DOI: 10.1016/j.jhep.2013.05.031] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2013] [Revised: 05/16/2013] [Accepted: 05/21/2013] [Indexed: 12/17/2022]
Abstract
Hepatocellular carcinoma (HCC) is the most common liver malignancy, representing the third and fifth leading cause of death from cancer worldwide in men and women, respectively. The main risk factor for the development of HCC is the hepatitis B and C virus (HBV and HCV) infection; non-viral causes (e.g., alcoholism and aflatoxin) are additional risk factors. HCC prognosis is generally poor because of the low effectiveness of available treatments and the overall 5-year survival rate is approximately 5-6%. In this framework, immunotherapeutic interventions, including cancer vaccines, may represent a novel and effective therapeutic tool. However, only few immunotherapy trials for HCC have been conducted so far with contrasting results, suggesting that improvements in several aspects of the immunotherapy approaches need to be implemented. In particular, identification of novel specific tumor antigens and evaluation of most advanced combinatorial strategies could result in unprecedented clinical outcomes with great beneficial effect for HCC patients. The state of the art in immunotherapy strategies for HCC and future perspectives are reported in the present review.
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Affiliation(s)
- Luigi Buonaguro
- Laboratory of Molecular Biology and Viral Oncology, Department of Experimental Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Pascale" - IRCCS, Naples, Italy.
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EASL and mRECIST responses are independent predictors of survival in hepatocellular carcinoma patients treated with cryoablation. Eur J Gastroenterol Hepatol 2013; 25:620-7. [PMID: 23325276 DOI: 10.1097/meg.0b013e32835ced13] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE The aim of this study was to determine which response evaluation criteria will best help predict the treatment efficacy of cryoablation for hepatocellular carcinoma. MATERIALS AND METHODS We retrospectively analyzed clinical data of 64 patients with hepatocellular carcinoma treated with cryoablation. Triphasic helical computed tomography scans were analyzed on the basis of WHO, Response Evaluation Criteria In Solid Tumors 1.1 (RECIST 1.1), modified RECIST (mRECIST), and European Association for the Study of the Liver (EASL) guidelines. We assessed the concordance among response guidelines and selected the most reliable model depending upon the correlation with overall survival. RESULTS Both objective response rates and disease control rates were higher for mRECIST and EASL than for WHO and RECIST 1.1 for both overall responses and target responses. The κ-value of comparisons between WHO and RECIST 1.1 and mRECIST and EASL was not more than 0.20 for both overall responses and target responses. There was consistency between WHO and RECIST 1.1 [κ=0.82, 95% confidence interval (CI): 0.72-0.91 for overall responses and κ=0.87; 95% CI, 0.76-0.94 for target responses], the same as that between mRECIST and EASL (κ=0.91, 95% CI, 0.73-0.98 for overall responses and κ=0.88, 95% CI, 0.72-0.95 for target responses). There was no significant association with survival for WHO and RECIST 1.1 responses or all target responses. The Cox-regression model showed that both mRECIST and EASL were independent predictors of overall survival, with a 51% risk reduction for mRECIST and a 61% risk reduction for EASL. CONCLUSION The enhancement models including mRECIST and EASL guidelines should be used in preference to WHO, RECIST 1.1, or target responses to assess the efficacy of cryotherapy.
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Yang YP, Qu JH, Chang XJ, Lu YY, Bai WL, Dong Z, Wang H, An LJ, Xu ZX, Wang CP, Zeng Z, Hu KQ. High intratumoral metastasis-associated in colon cancer-1 expression predicts poor outcomes of cryoablation therapy for advanced hepatocellular carcinoma. J Transl Med 2013; 11:41. [PMID: 23414367 PMCID: PMC3599141 DOI: 10.1186/1479-5876-11-41] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2012] [Accepted: 02/07/2013] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Cryoablation is one of the local therapies for hepatocellular carcinoma (HCC), but its safety and effect has not been studied in patients with Child class A or B and Barcelona Clinic Liver Cancer (BCLC) stage C HCC. Metastasis-associated in colon cancer-1 (MACC1) overexpression has been associated with poor prognosis of HCC, but its predictive value to post-cryoablation outcomes remains unknown in patients with BCLC stage C HCC. METHODS This study assessed the safety and outcomes of cryoablation measured by time to progression (TTP) and overall survival (OS), and predictive value of MACC1 mRNA and protein overexpression in tumorous tissue to post-cryoablation outcomes in 120 advanced HCC patients with child-pugh class A or B by quantitative polymerase chain reaction and immunohistochemical staining. The potenial correlation of MACC1 and c-Met expression to tumor cell proliferation and apoptosis was also analyzed. RESULTS The cryoablation in patients with advanced unresectable HCC resulted in a median TTP and OS of 5.5 (4.2- 6.7) months and 10.5 (9.0-12.0) months, respectively and no significant complications, comparable to the historical report for RFA therapy. The MACC1 mRNA and nuclear protein expression was significantly increased in tumorous tissues in these patients than that in normal liver tissue controls. Higher expression of MACC1 mRNA and nuclear protein in tumorous tissues in these patients was associated with shorter post cryoablation median TTP and OS than that with lower MACC1 expression. CONCLUSIONS Cryoablation is a safe and effective therapeutic option for patients with advanced HCC and Child-pugh class A or B cirrhosis; and a higher intratumoral expression of MACC1 or nuclear translocation predicts poor outcomes of cryotherapy in these patients.
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Affiliation(s)
- Yong-Ping Yang
- Center of Therapeutic Research for Liver Cancer, the 302nd Hospital, 100 Xi Si Huan Middle Road, Beijing 100039, China
- Beijing Institute for Infectious Disease, Beijing, China
| | - Jian-Hui Qu
- Center of Therapeutic Research for Liver Cancer, the 302nd Hospital, 100 Xi Si Huan Middle Road, Beijing 100039, China
| | - Xiu-Juan Chang
- Center of Therapeutic Research for Liver Cancer, the 302nd Hospital, 100 Xi Si Huan Middle Road, Beijing 100039, China
| | - Yin-Ying Lu
- Center of Therapeutic Research for Liver Cancer, the 302nd Hospital, 100 Xi Si Huan Middle Road, Beijing 100039, China
| | - Wen-Lin Bai
- Center of Therapeutic Research for Liver Cancer, the 302nd Hospital, 100 Xi Si Huan Middle Road, Beijing 100039, China
| | - Zheng Dong
- Center of Therapeutic Research for Liver Cancer, the 302nd Hospital, 100 Xi Si Huan Middle Road, Beijing 100039, China
| | - Hong Wang
- Center of Therapeutic Research for Liver Cancer, the 302nd Hospital, 100 Xi Si Huan Middle Road, Beijing 100039, China
| | - Lin-Jing An
- Center of Therapeutic Research for Liver Cancer, the 302nd Hospital, 100 Xi Si Huan Middle Road, Beijing 100039, China
| | - Zhong-Xian Xu
- Center of Therapeutic Research for Liver Cancer, the 302nd Hospital, 100 Xi Si Huan Middle Road, Beijing 100039, China
| | - Chun-Ping Wang
- Center of Therapeutic Research for Liver Cancer, the 302nd Hospital, 100 Xi Si Huan Middle Road, Beijing 100039, China
| | - Zhen Zeng
- Center of Therapeutic Research for Liver Cancer, the 302nd Hospital, 100 Xi Si Huan Middle Road, Beijing 100039, China
| | - Ke-Qin Hu
- Division of Gastroenterology/Hepatology, University of California, 101 the City Dr., Building 56, Ste. 237, Irvine, CA 92868, USA
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Wang CP, Wang H, Qu JH, Lu YY, Bai WL, Dong Z, Gao XD, Rong GH, Zeng Z, Yang YP. Tumour seeding after percutaneous cryoablation for hepatocellular carcinoma. World J Gastroenterol 2012; 18:6587-96. [PMID: 23236233 PMCID: PMC3516217 DOI: 10.3748/wjg.v18.i45.6587] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2012] [Revised: 07/30/2012] [Accepted: 08/14/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the rate and risk factors for tumour seeding in a large cohort of patients.
METHODS: Over an 8-year period, 1436 hepatocellular carcinoma (HCC) patients with 2423 tumour nodules underwent 3015 image-guided percutaneous cryoablation sessions [1215 guided by ultrasonography and 221 by spiral computed tomography (CT)]. Follow-up CT or magnetic resonance imaging was performed every 3 mo. The detailed clinical data were recorded to analyse the risk factors for seeding.
RESULTS: The median follow-up time was 18 (range 1-90) mo. Seeding was detected in 11 patients (0.76%) at 1-24 (median 6.0) mo after cryoablation. Seeding occurred along the needle tract in 10 patients and at a distant location in 1 patient. Seeded tumours usually showed similar imaging and histopathological features to the primary HCCs. Univariate analyses identified subcapsular tumour location and direct subcapsular needle insertion as risk factors for seeding. Multivariate analysis showed that only direct subcapsular needle insertion was an independent risk factor for seeding (P = 0.017; odds ratio 2.57; 95%CI: 1.47-3.65). Seeding after cryoablation occurred earlier in patients with poorly differentiated HCC than those with well or moderately differentiated HCC [1.33 ± 0.577 mo vs 11.12 ± 6.896 mo; P = 0.042; 95%CI: (-19.115)-(-0.468)].
CONCLUSION: The risk of seeding after cryoablation for HCC is small. Direct puncture of subcapsular tumours should be avoided to minimise seeding.
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Zhang GL, Zhao W. Recent progress in understanding the effect of interventional therapy for hepatic carcinoma on immune function. Shijie Huaren Xiaohua Zazhi 2012; 20:3225-3230. [DOI: 10.11569/wcjd.v20.i33.3225] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Liver cancer is a common highly malignant tumor in China, with a high rate of recurrence and metastasis. The body's immune function is closely related with the occurrence and development of liver cancer, and low immunological function is an important reason why hepatic carcinoma is hard to cure and tend to recur and metastasize. At present, surgery-based comprehensive therapy plays a dominant role in the treatment of hepatic carcinoma; however, the majority of patients had lost their opportunities for surgical treatment when a definitive diagnosis was established. Interventional therapy is regarded as the first choice of nonsurgical treatment for hepatic carcinoma. Interventional therapy can not only result in coagulative tumor necrosis but also promote apoptosis of tumor cells. The body's immune function can be enhanced to improve the anti-tumor ability by interventional therapy, especially the cellular immune function. As a result, the metastasis and recurrence of hepatic carcinoma may be inhibited. The purpose of this article is to review the progress in understanding the effect of interventional therapy for hepatic carcinoma on immune function.
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Li X, Xu K, Li W, Qiu X, Ma B, Fan Q, Li Z. Immunologic response to tumor ablation with irreversible electroporation. PLoS One 2012; 7:e48749. [PMID: 23139816 PMCID: PMC3490901 DOI: 10.1371/journal.pone.0048749] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2012] [Accepted: 10/01/2012] [Indexed: 12/14/2022] Open
Abstract
Background Irreversible electroporation (IRE) is a promising technique for the focal treatment of pathologic tissues, which involves placing minimally invasive electrodes within the targeted region. However, the knowledge about the therapeutic efficacy and immune reactions in response to IRE remains in its infancy. Methods In this work, to detect whether tumor ablation with IRE could trigger the immunologic response, we developed an osteosarcoma rat model and applied IRE directly to ablate the tumor. In the experiment, 118 SD rats were randomized into 4 groups: the control, sham operation, surgical resection, and IRE groups. Another 28 rats without tumor cell implantation served as the normal non-tumor-bearing group. We analyzed the changes in T lymphocyte subsets, sIL-2R and IL-10 levels in the peripheral blood one day before operation, as well as at 1, 3, 7,14 and 21 days after the operation. Moreover, splenocytes were assayed for IFN-γ and IL-4 production using intracellular cytokine staining one day before the operation, as well as at 7 and 21 days after operation. Results We found that direct IRE completely ablated the tumor cells. A significant increase in peripheral lymphocytes, especially CD3+ and CD4+ cells, as well as an increased ratio of CD4+/CD8+ were detectable 7 days after operation in both the IRE and surgical resection groups. Compared with the surgical resection group, the IRE group exhibited a stronger cellular immune response. The sIL-2R level of the peripheral blood in the IRE group decreased with time and was significantly different from that in the surgical resection group. Moreover, ablation with IRE significantly increased the percentage of IFN-γ-positive splenocytes. Conclusion These findings indicated that IRE could not only locally destroy the tumor but also change the status of cellular immunity in osteosarcoma-bearing rats. This provides experimental evidence for the clinical application of IRE in osteosarcoma treatment.
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Affiliation(s)
- Xiaoxiang Li
- Orthopedics Oncology Institute of Chinese PLA, Tangdu Hospital, the Fourth Military Medical University, Xi’an, Shannxi, China
| | - Kui Xu
- Orthopedics Oncology Institute of Chinese PLA, Tangdu Hospital, the Fourth Military Medical University, Xi’an, Shannxi, China
| | - Wei Li
- Orthopedics Oncology Institute of Chinese PLA, Tangdu Hospital, the Fourth Military Medical University, Xi’an, Shannxi, China
| | - Xiuchun Qiu
- Orthopedics Oncology Institute of Chinese PLA, Tangdu Hospital, the Fourth Military Medical University, Xi’an, Shannxi, China
| | - Baoan Ma
- Orthopedics Oncology Institute of Chinese PLA, Tangdu Hospital, the Fourth Military Medical University, Xi’an, Shannxi, China
| | - Qingyu Fan
- Orthopedics Oncology Institute of Chinese PLA, Tangdu Hospital, the Fourth Military Medical University, Xi’an, Shannxi, China
- * E-mail: (ZL); (QF)
| | - Zhao Li
- Orthopedics Oncology Institute of Chinese PLA, Tangdu Hospital, the Fourth Military Medical University, Xi’an, Shannxi, China
- * E-mail: (ZL); (QF)
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Li H, Wu K, Tao K, Chen L, Zheng Q, Lu X, Liu J, Shi L, Liu C, Wang G, Zou W. Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma. Hepatology 2012; 56:1342-51. [PMID: 22505239 DOI: 10.1002/hep.25777] [Citation(s) in RCA: 383] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
UNLABELLED The interaction between T cell immunoglobulin- and mucin-domain-containing molecule (Tim-3) expressed on T helper 1 (Th1) cells, and its ligand, galectin-9, negatively regulates Th1-mediated immune responses. However, it is poorly understood if and how the Tim-3/galectin-9 signaling pathway is involved in immune escape in patients with hepatocellular carcinoma (HCC). Here we studied the expression, function, and regulation of the Tim-3/galectin-9 pathway in patients with hepatitis B virus (HBV)-associated HCC. We detected different levels of galectin-9 expression on antigen-presenting cell (APC) subsets including Kupffer cells (KCs), myeloid dendritic cells (DCs), and plasmacytoid DCs in HCC. The highest galectin-9 expression was on KCs in HCC islets, not in the adjacent tissues. Furthermore, Tim-3 expression was increased on CD4(+) and CD8(+) T cells in HCC as compared to the adjacent tissues, and Tim-3(+) T cells were replicative senescent and expressed surface and genetic markers for senescence. Interestingly, tumor-infiltrating T-cell-derived interferon (IFN)-γ stimulated the expression of galectin-9 on APCs in the HCC microenvironment. Immunofluorescence staining revealed a colocalization of Tim-3(+) T cells and galectin-9(+) KCs in HCC. Functional studies demonstrated that blockade of the Tim-3/galectin-9 signaling pathway importantly increased the functionality of tumor-infiltrating Tim-3(+) T cells as shown by increased T-cell proliferation and effector cytokine production. Finally, we show that the numbers of Tim-3(+) tumor-infiltrating cells were negatively associated with patient survival. CONCLUSION Our work demonstrates that the Tim-3/galectin-9 signaling pathway mediates T-cell senescence in HBV-associated HCC. The data suggest that this pathway could be an immunotherapeutic target in patients with HBV-associated HCC.
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Affiliation(s)
- Hang Li
- Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Wang F, Jing X, Li G, Wang T, Yang B, Zhu Z, Gao Y, Zhang Q, Yang Y, Wang Y, Wang P, Du Z. Foxp3+ regulatory T cells are associated with the natural history of chronic hepatitis B and poor prognosis of hepatocellular carcinoma. Liver Int 2012; 32:644-655. [PMID: 22118340 DOI: 10.1111/j.1478-3231.2011.02675.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2011] [Accepted: 10/13/2011] [Indexed: 12/31/2022]
Abstract
BACKGROUND Recent studies have focused on regulatory T cells (Tregs) in chronic hepatitis B (CHB) and hepatocellular carcinoma (HCC) and they were also conducted independently of each other. AIMS This study tried to characterize Tregs in blood and tumour infiltration, and to explore the correlations between Tregs and the context of chronic hepatitis B in HCC patients. METHODS The liver-resident Tregs and CD8(+) T cells on core biopsy were investigated using immunohistochemistry staining in individuals (n = 209) with CHB (n = 47), HCC (n = 137) or healthy controls (n = 25). Circulating Tregs were detected in the above patients with CHB (n = 27) or HCC (n = 101) by flow cytometry. RESULTS The number of tumour-infiltrating and circulating FoxP3(+) Tregs was significantly high in patients with CHB (P < 0.001). However, there were fewer intratumoural Tregs in patients with advanced HCC than those in patients with early stage HCC (P = 0.043); In contrast, the circulating Tregs frequency increased during the progression of HCC (P = 0.024). Increased tumour-infiltrating and circulating FoxP3(+) Tregs were associated with poor overall survival (P = 0.041, 0.002 respectively) and a shorter time to recurrence (P = 0.049, 0.002 respectively) in patients with early stage HCC. Tumour-infiltrating Foxp3 + Tregs were related to chronic hepatitis B natural history in HCC (P = 0.012). Neither tumour-infiltrating CD8(+) T cells nor balance of intratumoural Tregs and CD8(+) T cells correlated with prognosis of HCC. CONCLUSIONS Increased Foxp3(+) Tregs may represent a prognostic predictor in patients with early stage HCC. The CHB natural history influenced density of tumour-infiltrating Tregs in hepatocellular carcinoma patients with chronic hepatitis B viruses infection.
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Affiliation(s)
- Fengmei Wang
- Department of Gastroenterology and Hepatology, The Third Central Clinical College of Tianjin Medical University, Tianjin, China
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More than just tumor destruction: immunomodulation by thermal ablation of cancer. Clin Dev Immunol 2011; 2011:160250. [PMID: 22242035 PMCID: PMC3254009 DOI: 10.1155/2011/160250] [Citation(s) in RCA: 156] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2011] [Accepted: 08/25/2011] [Indexed: 02/07/2023]
Abstract
Over the past decades, thermoablative techniques for the therapy of localized tumors have gained importance in the treatment of patients not eligible for surgical resection. Anecdotal reports have described spontaneous distant tumor regression after thermal ablation, indicating a possible involvement of the immune system, hence an induction of antitumor immunity after thermoinduced therapy. In recent years, a growing body of evidence for modulation of both adaptive and innate immunity, as well as for the induction of danger signals through thermoablation, has emerged. Induced immune responses, however, are mostly weak and not sufficient for the complete eradication of established tumors or durable prevention of disease progression, and combination therapies with immunomodulating drugs are being evaluated with promising results. This article aims to summarize published findings on immune modulation through radiofrequency ablation, cryoablation, microwave ablation therapy, high-intensity focused ultrasound, and laser-induced thermotherapy.
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Development of a Listeria monocytogenes-based vaccine against hepatocellular carcinoma. Oncogene 2011; 31:2140-52. [PMID: 21927025 DOI: 10.1038/onc.2011.395] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Live attenuated Listeria monocytogenes (LM) is a promising bacterial vector able to induce a T-cell response to tumor-associated antigens and demonstrates great potential for use in vaccine development. A novel recombinant LM-based vaccine (Lmdd (LM ΔdalΔdat)-MPFG (multiple peptide fusing genes)) was developed with the ability to express and secrete hepatocellular carcinoma (HCC)-related tumor-associated antigens fragments due to the insertion of hepatitis B virus (HBV)-X protein (HBx)-derived epitopes HBx(52-60) and HBx(140-148), the universal T-helper epitope, alpha-fetoprotein (AFP) epitope AFP(158-166), and melanoma antigen gene (MAGE)-3(271-279) into the HBV core protein. Following immunization with the Lmdd-MPFG vaccine, macrophages exhibited uptake of the bacteria; the vaccine was then nearly cleared 3 days after the first administration. It disappeared even more quickly following subsequent vaccinations. However, recombinant Lmdd-MPFG allowed for the full development of an antitumor response towards the human leukocyte antigen (HLA)-A0201 epitopes of MPFG. Each epitope stimulated an augmented T-cell proliferation and enhanced the supernatant level of interferon (IFN)-γ in vitro. In addition, IFN-γ-producing CD8(+) T cells as well as in vivo cytolytic activity were significantly increased in HLA-A2 transgenic mice. Additionally, the Lmdd-MPFG developed a strong antitumor response, as indicated by the significant resistance of immunized mice to MPFG-positive Hepa1-6 cell challenge in both a prophylactic and therapeutic setting. Tumor regression was accompanied by an enhanced cytotoxic T lymphocyte response and a decrease of regulatory T cells in the tumor. Collectively, these results suggest that utilizing attenuated LM as a vaccine vector, able to carry the MPFG gene, presents a potentially feasible strategy for prevention of HCC.
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Zeng Z, Shi F, Zhou L, Zhang MN, Chen Y, Chang XJ, Lu YY, Bai WL, Qu JH, Wang CP, Wang H, Lou M, Wang FS, Lv JY, Yang YP. Upregulation of circulating PD-L1/PD-1 is associated with poor post-cryoablation prognosis in patients with HBV-related hepatocellular carcinoma. PLoS One 2011; 6:e23621. [PMID: 21912640 PMCID: PMC3164659 DOI: 10.1371/journal.pone.0023621] [Citation(s) in RCA: 142] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2011] [Accepted: 07/21/2011] [Indexed: 02/06/2023] Open
Abstract
Background The programmed cell death-1 receptor/programmed cell death-1 ligand (PD-1/PD-L1) pathway plays a crucial role in tumor evasion from host immunity. This study was designed to evaluate the association between circulating PD-L1/PD-1 and prognosis after cryoablation in patients with HBV-related hepatocellular carcinoma (HCC). Methodology/Principal Findings In the present study, 141 HBV-related HCC patients were enrolled and of those 109 patients received cryoablation. Circulating PD-L1/PD-1 expression was tested by flow cytometry, and 23 patients were simultaneously evaluated for intratumoral PD-L1 expression by immunohistochemical staining. Circulating PD-1/PD-L1 expression was associated with severity of diseases in patients with HCC, and the circulating PD-L1 expression was closely correlated with intratumoral PD-L1 expression. Of the clinical parameters, PD-1/PD-L1 expression was associated with tumor size, blood vessel invasion and BCLC staging. Moreover, PD-1/PD-L1 expression dropped after cryoablation while being elevated at the time of tumor recurrence. Patients with higher expression of circulating PD-L1, as well as circulating PD-1, had a significantly shorter overall survival and tumor-free survival than those with lower expression. Multivariate analysis confirmed that circulating PD-L1 could serve as an independent predictor of overall survival and tumor-recurrence survival in HCC patients after cryoablation. Conclusions/Significance Upregulation of circulating PD-L1/PD-1 is associated with poor post-cryoablation prognosis in patients with HBV-related hepatocellular carcinoma.
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Affiliation(s)
- Zhen Zeng
- Center of Therapeutic Research for Hepatocellular Carcinoma, Beijing 302 Hospital, Beijing, China
| | - Feng Shi
- Research Center for Biological Therapy, Beijing 302 Hospital, Beijing, China
- Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
| | - Lin Zhou
- Center of Therapeutic Research for Hepatocellular Carcinoma, Beijing 302 Hospital, Beijing, China
| | - Min-Na Zhang
- Center of Therapeutic Research for Hepatocellular Carcinoma, Beijing 302 Hospital, Beijing, China
| | - Yan Chen
- Center of Therapeutic Research for Hepatocellular Carcinoma, Beijing 302 Hospital, Beijing, China
| | - Xiu-Juan Chang
- Center of Therapeutic Research for Hepatocellular Carcinoma, Beijing 302 Hospital, Beijing, China
| | - Yin-Ying Lu
- Center of Therapeutic Research for Hepatocellular Carcinoma, Beijing 302 Hospital, Beijing, China
| | - Wen-Lin Bai
- Center of Therapeutic Research for Hepatocellular Carcinoma, Beijing 302 Hospital, Beijing, China
| | - Jian-Hui Qu
- Center of Therapeutic Research for Hepatocellular Carcinoma, Beijing 302 Hospital, Beijing, China
| | - Chun-Ping Wang
- Center of Therapeutic Research for Hepatocellular Carcinoma, Beijing 302 Hospital, Beijing, China
| | - Hong Wang
- Center of Therapeutic Research for Hepatocellular Carcinoma, Beijing 302 Hospital, Beijing, China
| | - Min Lou
- Center of Therapeutic Research for Hepatocellular Carcinoma, Beijing 302 Hospital, Beijing, China
| | - Fu-Sheng Wang
- Research Center for Biological Therapy, Beijing 302 Hospital, Beijing, China
| | - Ji-Yun Lv
- Center of Therapeutic Research for Hepatocellular Carcinoma, Beijing 302 Hospital, Beijing, China
- Research Center for Biological Therapy, Beijing 302 Hospital, Beijing, China
| | - Yong-Ping Yang
- Center of Therapeutic Research for Hepatocellular Carcinoma, Beijing 302 Hospital, Beijing, China
- * E-mail:
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