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Lin X, Shao H, Tang Y, Wang Q, Yang Z, Wu H, Xing T. High expression of circulating exosomal PD-L1 contributes to immune escape of hepatocellular carcinoma and immune clearance of chronic hepatitis B. Aging (Albany NY) 2024; 16:11373-11384. [PMID: 39028365 PMCID: PMC11315384 DOI: 10.18632/aging.206020] [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: 01/02/2024] [Accepted: 04/09/2024] [Indexed: 07/20/2024]
Abstract
OBJECTIVE To investigate the expression of programmed death ligand-1 (PD-L1) in circulating exosomes, and to define the role of exosomal PD-L1 in promoting immune escape mechanism during chronic hepatitis B infection (CHB) and related liver diseases. METHODS The levels of PD-L1 expressed in exosomes were detected by ELISA. CD8+T cells were sorted and cytotoxicity test was assessed by flow cytometry. PD-L1 protein expression in hepatocellular carcinoma (HCC) and normal adjacent tissues were detected by immunohistochemistry. RESULTS Circulating exosomal PD-L1 levels were significantly higher in patients with CHB and HCC than in healthy controls (F =7.46, P=0.001). Levels of CD107a on CD8+T cells in patients with CHB receiving PD-L1 blocking antibody were significantly lower than in patients receiving isotype blocking antibody (t = 4.96, P < 0.01). Levels of TNF-α in cell culture supernatants of the PD-L1 blocking antibody group were significantly higher than in the isotype blocking antibody group (t =5.92, P < 0.01). Compared with patients receiving isotype blocking antibody, levels of CD107a on CD8+T cells significantly increased in patients with HCC receiving anti-PD-L1 antibody (t = 3.51, P<0.05). Compared with adjacent tissues, the levels of PD-L1 protein expression in HCC tissues were slightly higher; however, no significant difference between the two groups was observed. CONCLUSIONS PD-L1 blockade in exosomes might promote the cytotoxic function of CD8+T cells and inhibit immune evasion during progression of HCC. Blocking PD-L1 in exosomes reduced the cytotoxic function of CD8+T cells in patients with CHB while enhancing the production of proinflammatory cytokines.
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Affiliation(s)
- Xiaoqing Lin
- Wenzhou Central Hospital, Dingli Clinical College of Wenzhou Medical University, Wenzhou Sixth People’s Hospital, Wenzhou, Zhejiang, China
| | - Hui Shao
- Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Yongzhi Tang
- Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Qiupeng Wang
- Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Zhenyu Yang
- Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Hongwei Wu
- Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Tongjing Xing
- Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
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Zhang L, Liu Y, Song S, Makamure J, Shi H, Zheng C, Liang B. Hepatitis B virus reactivation in hepatocellular carcinoma patients after hepatic arterial infusion chemotherapy combined with and without immunotherapy. Infect Agent Cancer 2024; 19:19. [PMID: 38693564 PMCID: PMC11061977 DOI: 10.1186/s13027-024-00574-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 03/26/2024] [Indexed: 05/03/2024] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) reactivation (HBVr) is a major concern for hepatocellular carcinoma (HCC) patients undergoing hepatic arterial infusion chemotherapy (HAIC) using mFOLFOX6 regimen. There is insufficient evidence to support the routine use of HAIC combined with immunotherapy in HCC patients with HBVr. The aim of this study was to examine the adverse events (AEs) related to HBVr in HCC patients after HAIC, with or without immunotherapy, and to assess the effectiveness of antiviral prophylaxis for HBVr. METHODS Medical records of HCC patients receiving HAIC combined with and without immunotherapy between January 2021 and June 2023 were reviewed. The patients were divided into two groups based on whether they received immunotherapy or not. RESULTS Out of the 106 patients, 32 (30.2%) developed HBVr. Among these, 23 eligible patients with HBVr were included, with 14 patients (61%) receiving immunotherapy and nine patients (39%) not receiving immunotherapy. Prior to HAIC treatment, four patients in each group had detectable HBV DNA with median titre of 3.66 × 102 IU/ml (patients with immunotherapy) and 1.98 × 102 IU/ml (patients without immunotherapy), respectively. Fifteen patients did not show detectable HBV DNA. At HBVr occurrence, the median HBV DNA level was 6.95 × 102 IU/ml for all patients, 4.82 × 102 IU/ml in patients receiving immunotherapy and 1.3 × 103 IU/ml in patients not receiving immunotherapy. Grade 3 hepatitis developed in 12 cases of all patients (12/23, 48%), including five patients with immunotherapy (56%) and seven patients without immunotherapy (78%). At the 3-month follow-up, HBV DNA was detected in 10 patients, with a median HBV DNA level of 2.05 × 102 IU/ml (range, 1.5 × 102- 3.55 × 102 IU/ml) in patients (7/10) with immunotherapy and 4.28 × 102 IU/ml (range, 1.15 × 102- 5.88 × 102 IU/ml) in patients (3/10) without immunotherapy. Intensified antiviral treatment was administered to all patients. No HBVr-related fatal events occurred. CONCLUSION HBVr can occur after HAIC combined with or without immunotherapy. The degree of liver damage did not differ significantly in patients treated with or without immunotherapy. Intensified antiviral treatment was found to be crucial for HCC patients with HBVr.
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Affiliation(s)
- Lijie Zhang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Road, 430022, Wuhan, China
- Hubei Key Laboratory of Molecular Imaging, 430022, Wuhan, China
| | - Yiming Liu
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Road, 430022, Wuhan, China
- Hubei Key Laboratory of Molecular Imaging, 430022, Wuhan, China
| | - Songlin Song
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Road, 430022, Wuhan, China
- Hubei Key Laboratory of Molecular Imaging, 430022, Wuhan, China
| | - Joyman Makamure
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Road, 430022, Wuhan, China
- Hubei Key Laboratory of Molecular Imaging, 430022, Wuhan, China
| | - Heshui Shi
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Road, 430022, Wuhan, China
- Hubei Key Laboratory of Molecular Imaging, 430022, Wuhan, China
| | - Chuansheng Zheng
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Road, 430022, Wuhan, China.
- Hubei Key Laboratory of Molecular Imaging, 430022, Wuhan, China.
| | - Bin Liang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Road, 430022, Wuhan, China.
- Hubei Key Laboratory of Molecular Imaging, 430022, Wuhan, China.
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Zhou X, Hu Y, Sun H, Chen R, Huang G, Liu J. Relationship between SUVmax on 18F-FDG PET and PD-L1 expression in hepatocellular carcinoma. Eur J Nucl Med Mol Imaging 2023; 50:3107-3115. [PMID: 37147479 DOI: 10.1007/s00259-023-06251-y] [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: 12/15/2022] [Accepted: 04/24/2023] [Indexed: 05/07/2023]
Abstract
PURPOSE Our study was to investigate the correlation between 18F-FDG uptake in HCC and tumor PD-L1 expression in HCC, and assess the value of 18F-FDG PET/CT imaging for predicting PD-L1 expression in HCC. METHODS A total of 102 patients with confirmed HCC were included in this retrospective study. The PD-L1 expression and immune cell infiltrating of tumors were determined through immunohistochemistry staining. The SUVmax of HCC lesions were assessed using 18F-FDG PET/CT. The correlation between PD-L1 expression and the clinicopathological were evaluated by the Cox proportional hazards model and the Kaplan-Meier survival analysis. RESULTS The SUVmax of HCC primary tumors was higher in patients with poorly differentiated HCC, large tumor size, portal vein tumor thrombus, lymph node and distant metastases, and death. The SUVmax of HCC are correlated with the PD-L1 expression and the number of cytotoxic T cells and M2 macrophage infiltration. PD-L1 expression was significantly correlated with tumor SUVmax, tumor differentiation, tumor size, portal vein tumor thrombosis, and patient survival status and infiltrating M2 macrophages. Further, our results confirmed that SUVmax, portal vein tumor thrombosis, and the number of infiltrating M2 macrophages were closely related to PD-L1 expression and were independent risk factors by multivariate analysis. The combined assessment of SUVmax values and the presence of portal vein tumor thrombosis by 18F-FDG PET/CT imaging can help determine PD-L1 expression in HCC. CONCLUSIONS FDG uptake in HCC was positively correlated with the PD-L1 expression and the number of cytotoxic T cells and M2 macrophage infiltration. The combined use of SUVmax and portal vein tumor thrombosis by PET/CT imaging assess the PD-L1 expression better in HCC. These findings also provide a basis for clinical studies to assess the immune status of tumors by PET/CT.
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Affiliation(s)
- Xiang Zhou
- Department of Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Yongquan Hu
- Department of Nuclear Medicine, The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233004, Anhui, China
| | - Hong Sun
- Department of Clinical Laboratory Science, The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233004, China
| | - Ruohua Chen
- Department of Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Gang Huang
- Department of Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Jianjun Liu
- Department of Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
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Wang M, Sun L, Han X, Ren J, Li H, Wang W, Xu W, Liang C, Duan X. The addition of camrelizumab is effective and safe among unresectable hepatocellular carcinoma patients who progress after drug-eluting bead transarterial chemoembolization plus apatinib therapy. Clin Res Hepatol Gastroenterol 2023; 47:102060. [PMID: 36473631 DOI: 10.1016/j.clinre.2022.102060] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/22/2022] [Accepted: 12/02/2022] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Camrelizumab synergizes with apatinib or transarterial chemoembolization via tumor immunity and chemosensitivity. This study aimed to investigate the efficacy and safety of camrelizumab plus apatinib with or without drug-eluting bead transarterial chemoembolization (DEB-TACE) in unresectable hepatocellular carcinoma (HCC) patients after progression to DEB-TACE plus apatinib. METHODS Eighty-nine unresectable HCC patients accepted previous DEB-TACE plus apatinib therapy, then further received second-line camrelizumab plus apatinib with or without DEB-TACE treatment. Treatment responses were calculated at 3 months (M3) and 6 months (M6). Survival and treatment-related adverse events were documented. RESULTS Objective response rate and disease control rate were 39.3% and 80.9% at M3; meanwhile, they were 22.4% and 54.1% at M6. Furthermore, the median progression-free survival (PFS) (95% confidence interval (CI)) was 7.0 (6.2-7.8) months with a 1-year PFS rate of 18.4%; the median overall survival (OS) (95% CI) was 17.0 (15.3-18.7) months with a 1-year OS rate of 73.9%. Multivariable Cox's proportional hazards regression analysis presented that 3-4 times (vs. 0 time) of DEB-TACE, apatinib dose duration> 4 months, and camrelizumab dose duration> 5 months independently predicted longer PFS (all P<0.05); meanwhile, declined ECOG PS score, new lesions as progression pattern, 1-2 and 3-4 times (vs. 0 time) of DEB-TACE, apatinib dose duration> 4 months independently predicted prolonged OS (all P<0.05). Moreover, treatment-related adverse events mainly included grade 1-2 fever, gastrointestinal reaction, fatigue, hand-foot skin reaction, and hypertension. CONCLUSION After progression to DEB-TACE plus apatinib treatment, the addition of camrelizumab is effective and safe among unresectable HCC patients.
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Affiliation(s)
- Manzhou Wang
- Department of Interventional Radiology, The First Affiliated Hospital, Zhengzhou University, No. 1 Jianshe Road, Zhengzhou, Henan 450052, China
| | - Limin Sun
- Department of General ICU, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan, China
| | - Xinwei Han
- Department of Interventional Radiology, The First Affiliated Hospital, Zhengzhou University, No. 1 Jianshe Road, Zhengzhou, Henan 450052, China
| | - Jianzhuang Ren
- Department of Interventional Radiology, The First Affiliated Hospital, Zhengzhou University, No. 1 Jianshe Road, Zhengzhou, Henan 450052, China
| | - Hao Li
- Department of Interventional Radiology, The First Affiliated Hospital, Zhengzhou University, No. 1 Jianshe Road, Zhengzhou, Henan 450052, China
| | - Wenhui Wang
- Department of Interventional Radiology, The First Affiliated Hospital, Zhengzhou University, No. 1 Jianshe Road, Zhengzhou, Henan 450052, China
| | - Wenze Xu
- Department of Interventional Radiology, The First Affiliated Hospital, Zhengzhou University, No. 1 Jianshe Road, Zhengzhou, Henan 450052, China
| | - Chao Liang
- Department of Interventional Radiology, The First Affiliated Hospital, Zhengzhou University, No. 1 Jianshe Road, Zhengzhou, Henan 450052, China
| | - Xuhua Duan
- Department of Interventional Radiology, The First Affiliated Hospital, Zhengzhou University, No. 1 Jianshe Road, Zhengzhou, Henan 450052, China.
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Norcantharidin liposome emulsion hybrid delivery system enhances PD-1/PD-L1 immunotherapy by agonizing the non-canonical NF-κB pathway. Int J Pharm 2022; 628:122361. [DOI: 10.1016/j.ijpharm.2022.122361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 10/17/2022] [Accepted: 10/28/2022] [Indexed: 11/06/2022]
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Sharafi F, Hasani SA, Alesaeidi S, Kahrizi MS, Adili A, Ghoreishizadeh S, Shomali N, Tamjidifar R, Aslaminabad R, Akbari M. A comprehensive review about the utilization of immune checkpoint inhibitors and combination therapy in hepatocellular carcinoma: an updated review. Cancer Cell Int 2022; 22:269. [PMID: 35999569 PMCID: PMC9400240 DOI: 10.1186/s12935-022-02682-z] [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: 02/09/2022] [Accepted: 08/15/2022] [Indexed: 11/10/2022] Open
Abstract
A pharmacological class known as immune checkpoint inhibitors (ICIs) has been developed as a potential treatment option for various malignancies, including HCC. In HCC, ICIs have demonstrated clinically significant advantages as monotherapy or combination therapy. ICIs that target programmed cell death protein 1 (PD-1) and programmed cell death protein ligand 1 (PD-L1), as well as cytotoxic T lymphocyte antigen 4 (CTLA-4), have made significant advances in cancer treatment. In hepatocellular carcinoma (HCC), several ICIs are being tested in clinical trials, and the area is quickly developing. As immunotherapy-related adverse events (irAEs) linked with ICI therapy expands and gain worldwide access, up-to-date management guidelines become crucial to the safety profile of ICIs. This review aims to describe the evidence for ICIs in treating HCC, emphasizing the use of combination ICIs.
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Affiliation(s)
- Faezeh Sharafi
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sadegh Abaei Hasani
- Cancer Research Center, Department of General Surgery, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Samira Alesaeidi
- Department of Internal Medicine and Rheumatology, Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Ali Adili
- Senior Adult Oncology Department, Moffitt Cancer Center, University of South Florida, Tampa, Florida, USA
- Department of Oncology, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Navid Shomali
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Rozita Tamjidifar
- Department of Medical Biochemistry, Faculty of Medicine, Ege University, Izmir, 35100, Turkey
- Department of Stem Cell, Institute of Health Sciences, Ege University, Izmir, 35100, Turkey
| | - Ramin Aslaminabad
- Department of Medical Biochemistry, Faculty of Medicine, Ege University, Izmir, 35100, Turkey
| | - Morteza Akbari
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
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Risk of Hepatitis B Virus Reactivation in Patients Treated With Immunotherapy for Anti-cancer Treatment. Clin Gastroenterol Hepatol 2022; 20:898-907. [PMID: 34182151 DOI: 10.1016/j.cgh.2021.06.019] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 06/17/2021] [Accepted: 06/18/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Hepatitis B virus (HBV) reactivation is a well-known complication in patients with chronic hepatitis B treated with cytotoxic chemotherapy. However, the risk of HBV reactivation through use of immune checkpoint inhibitors (ICIs) is not well understood. Therefore, we aimed to evaluate the risk of HBV reactivation and hepatic adverse events in patients with cancer receiving ICIs according to cancer type and virologic serology. METHODS This historical cohort study included 3465 patients with cancer treated with ICIs between January 2015 and September 2020. The primary outcome was the occurrence of HBV reactivation, and the secondary outcome was presence of hepatic adverse events during ICI treatment. RESULTS The mean patient age was 62.2 years, and 68.8% of patients were men. Of the 3465 eligible patients, 511 (14.7%) showed hepatitis B surface antigen (HBsAg) positivity. The incidence rates of HBV reactivation of the total patients, HBsAg-positive patients, and HBsAg-negative patients were 0.14% (5/3465), 1.0% (5/511), and 0.0% (0/2954), respectively. Among HBsAg-positive patients, HBV reactivation occurred at a rate of 0.5% (2/409) and 2.9% (3/102) in patients with and without hepatocellular carcinoma, respectively. The HBV reactivation rates were 0.4% (2/464) and 6.4% (3/47) in patients with and without antiviral prophylaxis, respectively. Grade 3-4 hepatitis occurred in 23 (4.5%) HBsAg-positive, and 218 (7.4%) HBsAg-negative patients. No HBV-related fatality occurred. Only 2 patients (0.4%) experienced HBsAg seroclearance after ICI treatment among HBsAg-positive patients. CONCLUSIONS In general, HBV reactivation was rarely observed in patients with antiviral prophylaxis while undergoing ICI treatment. However, HBV reactivation may occur in HBsAg-positive patients without antiviral prophylaxis or noncompliant with antiviral prophylaxis.
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Suresh A, Dhanasekaran R. Implications of genetic heterogeneity in hepatocellular cancer. Adv Cancer Res 2022; 156:103-135. [PMID: 35961697 PMCID: PMC10321863 DOI: 10.1016/bs.acr.2022.01.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Hepatocellular carcinoma (HCC) exhibits a remarkable degree of heterogeneity, not only at an inter-patient level but also between and within tumors in the same patient. The advent of next-generation sequencing (NGS)-based technologies has allowed the creation of high-resolution atlases of HCC. This review outlines recent findings from genomic, epigenomic, transcriptomic, and proteomic sequencing that have yielded valuable insights into the spatial and temporal heterogeneity of HCC. The high heterogeneity of HCC has both clinical and therapeutic implications. The challenges in prospectively validating molecular classifications for HCC either for prognostication or for prediction of therapeutic response are partly due to the immense heterogeneity in HCC. Moreover, the heterogeneity of HCC tumors combined with the lack of commonly mutated, druggable targets severely limits treatment options for HCC. Recently, immune checkpoint inhibitors and combination therapies have shown promise for advanced HCC, while T cell therapies and vaccines are currently being investigated. Yet, immunotherapies show benefit only in a limited subset of patients, making it imperative to decipher tumor heterogeneity in HCC in order to enable optimal patient selection. This review summarizes the cutting-edge research on heterogeneity in HCC and explores the implications of heterogeneity on stratifying patients and developing biomarkers and therapies for HCC.
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Affiliation(s)
- Akanksha Suresh
- Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, United States
| | - Renumathy Dhanasekaran
- Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, United States.
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Wang Z, He L, Li W, Xu C, Zhang J, Wang D, Dou K, Zhuang R, Jin B, Zhang W, Hao Q, Zhang K, Zhang W, Wang S, Gao Y, Gu J, Shang L, Tan Z, Su H, Zhang Y, Zhang C, Li M. GDF15 induces immunosuppression via CD48 on regulatory T cells in hepatocellular carcinoma. J Immunother Cancer 2021; 9:jitc-2021-002787. [PMID: 34489334 PMCID: PMC8422483 DOI: 10.1136/jitc-2021-002787] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/22/2021] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND A better understanding of the molecular mechanisms that manifest in the immunosuppressive tumor microenvironment (TME) is crucial for developing more efficacious immunotherapies for hepatocellular carcinoma (HCC), which has a poor response to current immunotherapies. Regulatory T (Treg) cells are key mediators of HCC-associated immunosuppression. We investigated the selective mechanism exploited by HCC that lead to Treg cells expansion and to find more efficacious immunotherapies. METHODS We used matched tumor tissues and blood samples from 150 patients with HCC to identify key factors of Treg cells expansion. We used mass cytometry (CyTOF) and orthotopic cancer mouse models to analyze overall immunological changes after growth differentiation factor 15 (GDF15) gene ablation in HCC. We used flow cytometry, coimmunoprecipitation, RNA sequencing, mass spectrum, chromatin immunoprecipitation and Gdf15 -/-, OT-I and GFP transgenic mice to demonstrate the effects of GDF15 on Treg cells and related molecular mechanism. We used hybridoma technology to generate monoclonal antibody to block GDF15 and evaluate its effects on HCC-associated immunosuppression. RESULTS GDF15 is positively associated with the elevation of Treg cell frequencies in patients wih HCC. Gene ablation of GDF15 in HCC can convert an immunosuppressive TME to an inflammatory state. GDF15 promotes the generation of peripherally derived inducible Treg (iTreg) cells and enhances the suppressive function of natural Treg (nTreg) cells by interacting with a previously unrecognized receptor CD48 on T cells and thus downregulates STUB1, an E3 ligase that mediates forkhead box P3 (FOXP3) protein degradation. GDF15 neutralizing antibody effectively eradicates HCC and augments the antitumor immunity in mouse. CONCLUSIONS Our results reveal the generation and function enhancement of Treg cells induced by GDF15 is a new mechanism for HCC-related immunosuppression. CD48 is the first discovered receptor of GDF15 in the immune system which provide the possibility to solve the molecular mechanism of the immunomodulatory function of GDF15. The therapeutic GDF15 blockade achieves HCC clearance without obvious adverse events.
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Affiliation(s)
- Zhaowei Wang
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Lei He
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Weina Li
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Chuanyang Xu
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Jieyu Zhang
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Desheng Wang
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Kefeng Dou
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Ran Zhuang
- Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Boquan Jin
- Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Wei Zhang
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Qiang Hao
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Kuo Zhang
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Wangqian Zhang
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Shuning Wang
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Yuan Gao
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Jintao Gu
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Lei Shang
- Department of Health Statistics, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Zhijun Tan
- Department of Health Statistics, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Haichuan Su
- Department of oncology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Yingqi Zhang
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Cun Zhang
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Meng Li
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
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Sukowati CHC, El-Khobar KE, Tiribelli C. Immunotherapy against programmed death-1/programmed death ligand 1 in hepatocellular carcinoma: Importance of molecular variations, cellular heterogeneity, and cancer stem cells. World J Stem Cells 2021; 13:795-824. [PMID: 34367478 PMCID: PMC8316870 DOI: 10.4252/wjsc.v13.i7.795] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/25/2021] [Accepted: 05/07/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a heterogeneous malignancy related to diverse etiological factors. Different oncogenic mechanisms and genetic variations lead to multiple HCC molecular classifications. Recently, an immune-based strategy using immune checkpoint inhibitors (ICIs) was presented in HCC therapy, especially with ICIs against the programmed death-1 (PD-1) and its ligand PD-L1. However, despite the success of anti-PD-1/PD-L1 in other cancers, a substantial proportion of HCC patients fail to respond. In this review, we gather current information on biomarkers of anti-PD-1/PD-L1 treatment and the contribution of HCC heterogeneity and hepatic cancer stem cells (CSCs). Genetic variations of PD-1 and PD-L1 are associated with chronic liver disease and progression to cancer. PD-L1 expression in tumoral tissues is differentially expressed in CSCs, particularly in those with a close association with the tumor microenvironment. This information will be beneficial for the selection of patients and the management of the ICIs against PD-1/PD-L1.
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Affiliation(s)
| | | | - Claudio Tiribelli
- Centro Studi Fegato, Fondazione Italiana Fegato ONLUS, Trieste 34149, Italy
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Wang L, Yang Z, Cao Y. Regulatory T cell and activated natural killer cell infiltration in hepatocellular carcinoma: immune cell profiling using the CIBERSORT. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1483. [PMID: 33313228 PMCID: PMC7729330 DOI: 10.21037/atm-20-5830] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 10/29/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is understood to be an immunogenic tumor caused by chronic liver disease. Emerging research has indicated close interaction between various immune cells and tumor cells. Immunophenotyping, which has shown potential predictive value for the prognosis of various human malignancies, might allow responsive and non-responsive patients to be identified based on the extent and distribution of immune cell infiltration. Several novel immunotherapeutic approaches have been trialed and have shown promising efficacy. However, the efficacy of immunotherapies in HCC is limited by several factors. This study aimed to investigate tumor-infiltrating immune cells in HCC. METHODS Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) allows immune cell profiling analysis by deconvolution of gene expression microarray data. In this study, we analyzed the proportions of immune cells in 14 paired samples of HCC tissues obtained from GSE84402 in Gene Expression Omnibus (GEO) database. RESULTS In the 14 paired samples, HCC tissues showed significant infiltration by regulatory T cells (Tregs), activated natural killer (NK) cells, and M0 macrophages (P<0.001, P=0.007 and P=0.001, respectively), which were validated in CIBERSORT with the P value set at ≤0.05. In four paired samples identified from those selected by CIBERSORT, HCC tissues were found to have significant Treg and activated NK cell infiltration compared to non-tumor tissues (P=0.007 and P=0.015, respectively). Additionally, Pearson correlation analysis revealed Tregs to be positively correlated with activated NK cells (Correlation coefficient =0.41). CONCLUSIONS HCC tumor tissues were markedly infiltrated by Tregs and activated NK cells, which should be considered as candidate therapeutic targets in HCC multidisciplinary treatments.
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Affiliation(s)
- Lixin Wang
- Integrated TCM & Western Medicine Department, Shanghai Pulmonary Hospital Affiliated to Tongji University, Shanghai, China
| | - Zongguo Yang
- Department of Integrative Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Yajuan Cao
- Integrated TCM & Western Medicine Department, Shanghai Pulmonary Hospital Affiliated to Tongji University, Shanghai, China
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12
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Albukhaty S, Al-Musawi S, Abdul Mahdi S, Sulaiman GM, Alwahibi MS, Dewir YH, Soliman DA, Rizwana H. Investigation of Dextran-Coated Superparamagnetic Nanoparticles for Targeted Vinblastine Controlled Release, Delivery, Apoptosis Induction, and Gene Expression in Pancreatic Cancer Cells. Molecules 2020; 25:molecules25204721. [PMID: 33076247 PMCID: PMC7587551 DOI: 10.3390/molecules25204721] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 10/10/2020] [Accepted: 10/12/2020] [Indexed: 02/07/2023] Open
Abstract
In the current study, the surface of superparamagnetic iron oxide (SPION) was coated with dextran (DEX), and conjugated with folic acid (FA), to enhance the targeted delivery and uptake of vinblastine (VBL) in PANC-1 pancreatic cancer cells. Numerous analyses were performed to validate the prepared FA-DEX-VBL-SPION, such as field emission scanning transmission electron microscopy, high-resolution transmission electron microscopy, dynamic light scattering (DLS), Zeta Potential, Fourier transform infrared spectroscopy, and vibrating sample magnetometry (VSM). The delivery system capacity was evaluated by loading and release experiments. Moreover, in vitro biological studies, including a cytotoxicity study, cellular uptake assessment, apoptosis analysis, and real-time PCR, were carried out. The results revealed that the obtained nanocarrier was spherical with a suitable dispersion and without visible aggregation. Its average size, polydispersity, and zeta were 74 ± 13 nm, 0.080, and −45 mV, respectively. This dual functional nanocarrier also exhibited low cytotoxicity and a high apoptosis induction potential for successful VBL co-delivery. Real-time quantitative PCR analysis demonstrated the activation of caspase-3, NF-1, PDL-1, and H-ras inhibition, in PANC-1 cells treated with the FA-VBL-DEX-SPION nanostructure. Close inspection of the obtained data proved that the FA-VBL-DEX-SPION nanostructure possesses a noteworthy chemo-preventive effect on pancreatic cancer cells through the inhibition of cell proliferation and induction of apoptosis.
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Affiliation(s)
- Salim Albukhaty
- Department of Basic Sciences, College of Nursing, University of Misan, Maysan 62001, Iraq;
| | - Sharafaldin Al-Musawi
- Faculty of Biotechnology, Al-Qasim Green University, Babylon 51013, Iraq;
- Correspondence:
| | - Salih Abdul Mahdi
- Faculty of Biotechnology, Al-Qasim Green University, Babylon 51013, Iraq;
| | - Ghassan M. Sulaiman
- Department of Applied Sciences, University of Technology, Baghdad 10066, Iraq;
| | - Mona S. Alwahibi
- Department of Botany and Microbiology, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia; (M.S.A.); (D.A.S.); (H.R.)
| | - Yaser Hassan Dewir
- College of Food and Agriculture Sciences, King Saud University, Riyadh 11451, Saudi Arabia;
- Faculty of Agriculture, Kafrelsheikh University, Kafr El-Sheikh 33516, Egypt
| | - Dina A. Soliman
- Department of Botany and Microbiology, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia; (M.S.A.); (D.A.S.); (H.R.)
| | - Humaira Rizwana
- Department of Botany and Microbiology, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia; (M.S.A.); (D.A.S.); (H.R.)
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13
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Chan SL, Yip TC, Wong VW, Tse Y, Yuen BW, Luk HW, Lui RN, Chan HL, Mok TS, Wong GL. Pattern and impact of hepatic adverse events encountered during immune checkpoint inhibitors - A territory-wide cohort study. Cancer Med 2020; 9:7052-7061. [PMID: 32780516 PMCID: PMC7541136 DOI: 10.1002/cam4.3378] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Revised: 07/08/2020] [Accepted: 07/27/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) are increasingly used in the treatment of cancers. We aimed to evaluate the incidence and prognostic impact of hepatic adverse events (AEs) in a territory-wide cohort of patients who received ICIs. METHODS Patients were identified from a territory-wide database who received ICIs in 2014-2018. Hepatic AEs were defined as any elevation of liver biochemistries including serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin levels. Hepatic AEs were graded according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0. RESULTS Total of 1480 patients were identified (mean age 60 years, male 65.5%) and the commonest malignancies being lung cancer (39.6%), liver cancer (16.5%), and gastrointestinal cancer (10.0%). Grade 1-2 and grade 3-4 hepatic AEs occurred in 41.3% and 14.9% of patients during ICI treatment, respectively. Patients with liver cancer had the highest rate of hepatic AEs (grade 1-2:54.1%; grade 3-4:32.8%). Among 711 patients with hepatic AEs, 383 (53.9%) had raised ALT/AST only, and 328 (46.1%) had concomitant raised ALT/AST and bilirubin levels. In the whole cohort, median overall survival of patients without any hepatic AEs, grade 1-2 and grade 3-4 hepatic AEs during ICI treatment was 9.0 months, 7.2 months, and 3.3 months (P < .001), respectively. Similar results on overall survival were obtained among different types of cancers. CONCLUSIONS Hepatic AEs occur in more than half of patients receiving ICIs for cancer treatment, with approximately 15% being grade 3-4 AEs. Occurrence of hepatic AEs is associated with worse prognosis.
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Affiliation(s)
- Stephen Lam Chan
- Department of Clinical OncologyThe Chinese University of Hong KongHong Kong SARChina
| | - Terry Cheuk‐Fung Yip
- Institute of Digestive DiseaseThe Chinese University of Hong KongHong Kong SARChina
- Department of Medicine and TherapeuticsThe Chinese University of Hong KongHong Kong SARChina
- Medical Data Analytics CentrePathologyThe Chinese University of Hong KongHong Kong SARChina
| | - Vincent Wai‐Sun Wong
- Institute of Digestive DiseaseThe Chinese University of Hong KongHong Kong SARChina
- Department of Medicine and TherapeuticsThe Chinese University of Hong KongHong Kong SARChina
- Medical Data Analytics CentrePathologyThe Chinese University of Hong KongHong Kong SARChina
| | - Yee‐Kit Tse
- Institute of Digestive DiseaseThe Chinese University of Hong KongHong Kong SARChina
- Department of Medicine and TherapeuticsThe Chinese University of Hong KongHong Kong SARChina
- Medical Data Analytics CentrePathologyThe Chinese University of Hong KongHong Kong SARChina
| | - Becky Wing‐Yan Yuen
- Institute of Digestive DiseaseThe Chinese University of Hong KongHong Kong SARChina
- Department of Medicine and TherapeuticsThe Chinese University of Hong KongHong Kong SARChina
| | - Hester Wing‐Sum Luk
- Department of Medicine and TherapeuticsThe Chinese University of Hong KongHong Kong SARChina
| | - Rashid Nok‐Shun Lui
- Institute of Digestive DiseaseThe Chinese University of Hong KongHong Kong SARChina
- Department of Medicine and TherapeuticsThe Chinese University of Hong KongHong Kong SARChina
- Medical Data Analytics CentrePathologyThe Chinese University of Hong KongHong Kong SARChina
| | - Henry Lik‐Yuen Chan
- Institute of Digestive DiseaseThe Chinese University of Hong KongHong Kong SARChina
- Department of Medicine and TherapeuticsThe Chinese University of Hong KongHong Kong SARChina
- Medical Data Analytics CentrePathologyThe Chinese University of Hong KongHong Kong SARChina
| | - Tony Shu‐Kam Mok
- Department of Clinical OncologyThe Chinese University of Hong KongHong Kong SARChina
| | - Grace Lai‐Hung Wong
- Institute of Digestive DiseaseThe Chinese University of Hong KongHong Kong SARChina
- Department of Medicine and TherapeuticsThe Chinese University of Hong KongHong Kong SARChina
- Medical Data Analytics CentrePathologyThe Chinese University of Hong KongHong Kong SARChina
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Zhao W, Qiu L, Liu H, Xu Y, Zhan M, Zhang W, Xin Y, He X, Yang X, Bai J, Xiao J, Guan Y, Li Q, Chang L, Yi X, Li Y, Chen X, Lu L. Circulating tumor DNA as a potential prognostic and predictive biomarker during interventional therapy of unresectable primary liver cancer. J Gastrointest Oncol 2020; 11:1065-1077. [PMID: 33209498 PMCID: PMC7657842 DOI: 10.21037/jgo-20-409] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Accepted: 10/09/2020] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Imaging and alpha fetoprotein (AFP) measurement are used as surveillance methods during interventional therapy in patients with unresectable liver cancer, but their accuracy has been challenged in patients receiving drug perfusion therapy. Circulating tumor DNA (ctDNA) can reflect tumor load and treatment efficacy. Studies of the prognostic value of ctDNA in unresectable liver cancer are needed. METHODS Forty-two patients with unresectable liver cancer were prospective enrolled in this study. Pre-treatment, in-treatment plasma samples and available matched tissue samples were collected. Targeted-capture sequencing of 1,021 genes that are frequently mutated in solid tumors. RESULTS Targeted-capture sequencing of 1,021 genes that are frequently mutated in solid tumors revealed that the most frequently mutated genes in ctDNA were TP53 (52.4%) and TERT (35.7%). The ctDNA abundance was more closely correlated with tumor size than the AFP level and was also related to BCLC stage (P<0.001). Gene mutations profile in ctDNA with progressed disease. PD patients were enriched in TP53 mutation group compared with TP53 wildtype group (P=0.0221). Moreover, interventional therapy was more effective in patients without TP53 mutation (OS: P=0.0589; PFS: 0.0411). The dynamic change of ctDNA showed consistent or more sensitivity than imaging for evaluating treatment response. The tumor mutation burden was highly consistent between tissue and blood samples (P<0.0001). CONCLUSIONS ctDNA was a reliable biomarker to assist in diagnosis and evaluation of prognosis and treatment efficacy in advanced liver cancer. Considering that biopsy is unnecessary when advanced liver cancer is diagnosed, ctDNA may be an ideal biomarker for evaluating tumor mutation burden prior to immunotherapy.
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Affiliation(s)
- Wei Zhao
- Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People’s Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, China
| | - Lige Qiu
- Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People’s Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, China
- 2 Clinical Medical College of Jinan University, Shenzhen People’s Hospital, Shenzhen, China
| | - Huajiang Liu
- Department of Intervention Therapy, The First Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Ying Xu
- Department of Computer Science and Technology, School of Electronic and Information Engineering, Xi’an Jiaotong University, Xi’an, China
| | - Meixiao Zhan
- Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People’s Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, China
| | - Wei Zhang
- 2 Clinical Medical College of Jinan University, Shenzhen People’s Hospital, Shenzhen, China
| | - Yongjie Xin
- Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People’s Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, China
| | - Xu He
- Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People’s Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, China
| | - Xiangyu Yang
- Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People’s Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, China
| | - Jing Bai
- Geneplus-Beijing Institute, Beijing, China
| | - Jing Xiao
- Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People’s Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, China
| | - Yanfang Guan
- Department of Computer Science and Technology, School of Electronic and Information Engineering, Xi’an Jiaotong University, Xi’an, China
- Geneplus-Beijing Institute, Beijing, China
| | - Qiyang Li
- 2 Clinical Medical College of Jinan University, Shenzhen People’s Hospital, Shenzhen, China
| | | | - Xin Yi
- Geneplus-Beijing Institute, Beijing, China
| | - Yong Li
- Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People’s Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, China
| | - Xudong Chen
- 2 Clinical Medical College of Jinan University, Shenzhen People’s Hospital, Shenzhen, China
| | - Ligong Lu
- Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People’s Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, China
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15
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Galati G, Massimo Vainieri AF, Maria Fulgenzi CA, Di Donato S, Silletta M, Gallo P, Onorato A, Vespasiani-Gentilucci U, Picardi A. Current Treatment Options for HCC: From Pharmacokinetics to Efficacy and Adverse Events in Liver Cirrhosis. Curr Drug Metab 2020; 21:866-884. [PMID: 32957880 DOI: 10.2174/1389200221999200918141239] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 06/09/2020] [Accepted: 07/27/2020] [Indexed: 12/28/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is among the world's most common cancers. For over ten years, the only medical treatment for it has been the multikinase inhibitor Sorafenib. Currently, however, other first or second-line therapeutic options have also shown efficacy against HCC, such as multikinase inhibitors (Regorafenib, Lenvatinib, and Cabozantinib), a monoclonal antibody against the vascular endothelial growth factor receptor 2 (Ramucirumab), and immune-checkpoint inhibitors (Nivolumab, Pembrolizumab, Ipilimumab). AIM The aim of this paper is to review the metabolic pathways of drugs that have been tested for the treatment of HCC and the potential influence of liver failure over those pathways. METHODS The Food and Drug Administration (FDA)'s and European Medicines Agency (EMA)'s datasheets, results from clinical trials and observational studies have been reviewed. RESULTS This review summarizes the current knowledge regarding targets, metabolic pathways, drug interactions, and adverse events of medical treatments for HCC in cirrhotic patients. CONCLUSION The new scenario of systemic HCC therapy includes more active drugs with different metabolic pathways and different liver adverse events. Clinical and pharmacological studies providing more data on the safety of these molecules are urgently needed.
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Affiliation(s)
- Giovanni Galati
- Unit of Clinical Medicine and Hepatology, University Campus Bio-Medico, Rome, Italy
| | | | | | - Stefano Di Donato
- Unit of Clinical Medicine and Hepatology, University Campus Bio-Medico, Rome, Italy
| | | | - Paolo Gallo
- Unit of Clinical Medicine and Hepatology, University Campus Bio-Medico, Rome, Italy
| | - Angelo Onorato
- Medical Oncology Unit, University Campus Bio-Medico, Rome, Italy
| | | | - Antonio Picardi
- Unit of Clinical Medicine and Hepatology, University Campus Bio-Medico, Rome, Italy
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16
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Wang Y, Xie Y, Ma J, Wang Y, Gong R. Development and validation of a prognostic and immunotherapeutically relevant model in hepatocellular carcinoma. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1177. [PMID: 33241026 PMCID: PMC7576066 DOI: 10.21037/atm-20-6112] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Background The tumor immune microenvironment is pivotal in predicting clinical outcomes and therapeutic efficacy in cancer patients. This study aims to develop an immune prediction model (IPM) to effectively predict prognosis and immunotherapeutic response in patients with hepatocellular carcinoma (HCC). Methods An IPM was constructed and validated based on immune-related genes. The influence of IPM on the HCC immune microenvironment, as well as the possible mechanism, was comprehensively analyzed. The value of the model in predicting the response of HCC patients to immunotherapy was also evaluated. Results A novel IPM based on eight genes was developed and validated to predict the prognosis of HCC patients. These genes are matrix metalloproteinase 12 (MMP12), heme oxygenase 1 (HMOX1), C-X-C motif chemokine receptor 6 (CXCR6), hepatoma-derived growth factor (HDGF), placental growth factor (PGF), tyrosine kinase 2 (TYK2), retinoid X receptor beta (RXRB), and cyclin-dependent kinase 4 (CDK4). High-risk patients showed significantly poorer survival than low-risk patients. A nomogram was also established based on the IPM and tumor, node, metastasis (TNM) classification, which showed some net clinical benefit. Gene set enrichment analysis (GSEA) revealed several significantly enriched oncological signatures and immunologic signatures. Furthermore, high-risk patients were characterized by severe clinicopathological characteristics and immune cell infiltration. Finally, we found the that the IPM showed a significant positive correlation with programmed cell death 1 (PDCD1), cluster of differentiation 274 (CD274), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) expression, suggesting a potentially enhanced effects of immunotherapy antibodies in HCC patients with a high risk score. Conclusions A novel IPM that could predict clinical prognosis and immunotherapeutic response in HCC patients was developed. Our findings not only provide new insights into the identification of HCC patients with poor survival, but also deepen our understanding of the immune microenvironment, as well as the mechanism of immunotherapy, in HCC.
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Affiliation(s)
- Yu Wang
- Department of Hepatic Surgery, Shanghai Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, Shanghai, China
| | - Yanting Xie
- Department of Hepatic Surgery, Shanghai Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, Shanghai, China
| | - Junyong Ma
- Department of Hepatic Surgery, Shanghai Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, Shanghai, China
| | - Yizhou Wang
- Department of Hepatic Surgery, Shanghai Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, Shanghai, China
| | - Renyan Gong
- Department of Hepatic Surgery, Shanghai Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, Shanghai, China
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Dal Bo M, De Mattia E, Baboci L, Mezzalira S, Cecchin E, Assaraf YG, Toffoli G. New insights into the pharmacological, immunological, and CAR-T-cell approaches in the treatment of hepatocellular carcinoma. Drug Resist Updat 2020; 51:100702. [DOI: 10.1016/j.drup.2020.100702] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 04/06/2020] [Accepted: 04/13/2020] [Indexed: 02/07/2023]
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Yang Y, Liu F, Liu W, Ma M, Gao J, Lu Y, Huang L, Li X, Shi Y, Wang X, Wu D. Analysis of single-cell RNAseq identifies transitional states of T cells associated with hepatocellular carcinoma. Clin Transl Med 2020; 10:e133. [PMID: 32659053 PMCID: PMC7418813 DOI: 10.1002/ctm2.133] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 07/04/2020] [Accepted: 07/05/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Exhausted T cells and regulatory T cells (Tregs) comprise diverse subsets of tumor immunosuppressive microenvironment that play key roles in tumor progress. Understanding subset diversity in T cells is a critical question for developing cancer immunotherapy. METHODS A total of 235 specimens from surgical resections of hepatocellular carcinoma (HCC) patients were examined for infiltration of exhausted T cell (Tex) in tumor and adjacent tissue. We conducted deep single-cell targeted immune profiling on CD3+ cells collected from tumor tissues, adjacent normal tissues (ANTs) and peripheral blood of HCC patients. Total 10 cell clusters were identified with distinct distributions and characteristics. RESULTS We observed transitional differentiation of exhausted CD8+ T cells and Tregs increasingly enriched in tumor tissue. The accumulation and location of Tex were related to the differences in the long-term clinical outcome of HCC. Furthermore, data of single-cell RNA-seq showed that (1) cells transforming from effector CD8+ T cells to exhausted CD8+ T cells simultaneously expressed upregulated effector molecules and inhibitory receptors, (2) indicated alteration of gene expression related to stress response and cell cycle at early exhaustion stage, and (3) immunosuppressive Treg had profound activation in comparison to resting Tregs. CONCLUSIONS T cell exhaustion is a progressive process, and the gene-expression profiling displayed T cell exhaustion and anergy are different. Accordingly, it is possible that functional exhaustion is caused by the combination effects of passive defects and overactivation in stress response. The results help to understand the dynamic framework of T cells function in cancer which is important for designing rational cancer immunotherapies.
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Affiliation(s)
- Yanying Yang
- Department of Endocrinology and MetabolismZhongshan HospitalKey Laboratory of Metabolism and Molecular Medicinethe Ministry of EducationFudan UniversityShanghaiChina
| | - Fangming Liu
- Institute of Clinical ScienceZhongshan HospitalFudan UniversityShanghaiChina
| | - Weiren Liu
- Liver Surgery Department of Zhongshan HospitalFudan UniversityShanghaiChina
| | - Mingyue Ma
- Department of Endocrinology and MetabolismZhongshan HospitalKey Laboratory of Metabolism and Molecular Medicinethe Ministry of EducationFudan UniversityShanghaiChina
| | - Jie Gao
- Institute of Clinical ScienceZhongshan HospitalFudan UniversityShanghaiChina
| | - Yan Lu
- Department of Endocrinology and MetabolismZhongshan HospitalKey Laboratory of Metabolism and Molecular Medicinethe Ministry of EducationFudan UniversityShanghaiChina
| | - Li‐Hao Huang
- Department of Pathology & ImmunologyWashington University School of MedicineSaint LouisMissouri
| | - Xiaoying Li
- Department of Endocrinology and MetabolismZhongshan HospitalKey Laboratory of Metabolism and Molecular Medicinethe Ministry of EducationFudan UniversityShanghaiChina
| | - Yinghong Shi
- Liver Surgery Department of Zhongshan HospitalFudan UniversityShanghaiChina
| | - Xiangdong Wang
- Institute of Clinical ScienceZhongshan HospitalFudan UniversityShanghaiChina
| | - Duojiao Wu
- Institute of Clinical ScienceZhongshan HospitalFudan UniversityShanghaiChina
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19
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Schonfeld M, Zhao J, Komatz A, Weinman SA, Tikhanovich I. The polymorphism rs975484 in the protein arginine methyltransferase 1 gene modulates expression of immune checkpoint genes in hepatocellular carcinoma. J Biol Chem 2020; 295:7126-7137. [PMID: 32245889 DOI: 10.1074/jbc.ra120.013401] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 03/31/2020] [Indexed: 12/31/2022] Open
Abstract
Protein arginine methyltransferase 1 (PRMT1) is a key regulator of hepatic immune responses. Recently, we reported that PRMT1 regulates the tumor immune response in hepatocellular carcinoma (HCC). Here we found that PRMT1 expression in human HCC correlates with that of programmed cell death 1 ligand 1 (PD-L1), PD-L2, and other checkpoint genes. PRMT1 deletion in mice reduced PD-L1 and PD-L2 expression in tumors and reduced the efficiency of PD-1 antibody treatment in a diethylnitrosamine-induced HCC mouse model, suggesting that PRMT1 regulates the hepatic immune checkpoint. Mice had reduced PD-L1 and PD-L2 expression when PRMT1 was specifically deleted in tumor cells or macrophages, but PRMT1 deletion in dendritic cells did not alter PD-L1 and PD-L2 expression. rs975484 is a common polymorphism in the human PRMT1 gene promoter, and we found that it alters PRMT1 expression in blood monocytes and tumor-associated macrophages in human HCC. PRMT1 expression was higher in individuals with a GG genotype than in individuals with a CC genotype, and heterozygous carriers had intermediate expression. Luciferase reporter assays indicated that this differential expression is due to an extra C/EBPβ-binding site in the PRMT1 promoter of individuals carrying the minor G allele. The rs975484 genotype also correlated with PRMT1 target expression in HCC. Individuals with the GG genotype had significantly higher levels of the PRMT1 targets PD-L1, PD-L2, and VISTA than those with the CC genotype. We conclude that PRMT1 critically controls immune checkpoints in mice and humans and that the PRMT1 polymorphism rs975484 affects checkpoint gene expression in HCC.
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Affiliation(s)
- Michael Schonfeld
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160-1018
| | - Jie Zhao
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160-1018
| | - Amberly Komatz
- Liver Center, University of Kansas Medical Center, Kansas City, Kansas 66160-1018
| | - Steven A Weinman
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160-1018.,Liver Center, University of Kansas Medical Center, Kansas City, Kansas 66160-1018
| | - Irina Tikhanovich
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160-1018
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20
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Liao Y. Obstacles and opportunities in the prevention and treatment of HBV-related hepatocellular carcinoma. Genes Dis 2020; 7:291-298. [PMID: 32884983 PMCID: PMC7452511 DOI: 10.1016/j.gendis.2019.12.014] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 12/31/2019] [Indexed: 12/25/2022] Open
Abstract
Despite the tremendous progresses toward our understanding of the mechanisms of how liver cancer was developed, the therapeutic outcomes of liver cancer in the clinic have very limited improvement within the past three decades or so. In addition, both the incidence and mortality of liver cancer worldwide are not dropping, but increasing steadily, in the last decade. Thus, it is time for us to rethink what has been wrong and how could we do better in the upcoming years, in order to achieve our goal of improving the therapeutic outcomes of patients with liver cancer in the clinic, and at the meantime, effectively reducing the incidence of liver cancer by blocking malignant transformation of hepatocytes from chronic viral infection. This is also one of the main reasons why we try to organize this special issue on primary liver cancer in the journal of Genes & Diseases. In this perspective, I will summarize the major obstacles confronted with in the prevention and management of patients with chronic hepatitis B infection and subsequent development of liver cirrhosis and liver cancer. Next, I will delineate the pitfalls and underlying mechanisms of why the current anti-viral strategies and therapeutic agents are not as effective as one expected in terms of successful reduction or prevention chronic hepatitis B infection associated liver cirrhosis and liver cancer. I will then provide my personal perspectives on potential approaches and strategies for effective prevention and management of hepatitis B-related liver cancer.
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Affiliation(s)
- Yong Liao
- Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Chongqing, PR China.,Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, PR China.,Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China
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21
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Niu C, Li M, Zhu S, Chen Y, Zhou L, Xu D, Xu J, Li Z, Li W, Cui J. PD-1-positive Natural Killer Cells have a weaker antitumor function than that of PD-1-negative Natural Killer Cells in Lung Cancer. Int J Med Sci 2020; 17:1964-1973. [PMID: 32788875 PMCID: PMC7415385 DOI: 10.7150/ijms.47701] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Accepted: 07/07/2020] [Indexed: 12/14/2022] Open
Abstract
Antibodies targeting the immune checkpoint inhibitor, programmed cell death 1 (PD-1), have provided a breakthrough in the treatment of lung cancer. However, the function of PD-1 in natural killer (NK) cells of cancer patients remains unclear. Herein, we analyzed the expression of PD-1 on the NK cells in the peripheral blood of patients with lung cancer and found that the level of PD-1+ NK cells in patients was significantly higher than that in healthy individuals. Moreover, these PD-1+ NK cells demonstrated a weaker ability to secrete interferon-gamma (INF-γ), granzyme B, and perforin, and exhibited lower CD107a expression. Importantly, in patients with lung cancer, the percentage of PD-1+ NK cells was significantly positively correlated with the concentration of IL-2 in the plasma, which was also higher than that in healthy individuals. In addition, IL-2 could increase the expression of PD-1 on NK cells in vitro, indicating that high IL-2 level in the plasma is largely responsible for the abundance of PD-1+ NK cells in patients with lung cancer. These findings demonstrate intriguing mechanisms for understanding the expression of PD-1 on NK cells and the function of PD-1+ NK cells in lung cancer. This study confirms and extends previous studies demonstrating that PD-1 can negatively regulate the antitumor function of NK cells.
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Affiliation(s)
- Chao Niu
- Department of Cancer Center, The First Hospital of Jilin University, Changchun 130021, China
| | - Min Li
- Department of Cancer Center, The First Hospital of Jilin University, Changchun 130021, China
| | - Shan Zhu
- Department of Translational Medicine, The First Hospital of Jilin University, Changchun 130021, China
| | - Yongchong Chen
- Department of Cancer Center, The First Hospital of Jilin University, Changchun 130021, China
| | - Lei Zhou
- Department of Cancer Center, The First Hospital of Jilin University, Changchun 130021, China
| | - Dongsheng Xu
- Department of Cancer Center, The First Hospital of Jilin University, Changchun 130021, China
| | - Jianting Xu
- Department of Cancer Center, The First Hospital of Jilin University, Changchun 130021, China
| | - Zhaozhi Li
- Department of Cancer Center, The First Hospital of Jilin University, Changchun 130021, China
| | - Wei Li
- Department of Cancer Center, The First Hospital of Jilin University, Changchun 130021, China
| | - Jiuwei Cui
- Department of Cancer Center, The First Hospital of Jilin University, Changchun 130021, China
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22
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Listeria-based hepatocellular carcinoma vaccine facilitates anti-PD-1 therapy by regulating macrophage polarization. Oncogene 2019; 39:1429-1444. [PMID: 31659256 DOI: 10.1038/s41388-019-1072-3] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 10/05/2019] [Accepted: 10/11/2019] [Indexed: 12/24/2022]
Abstract
Recently, patients with advanced cancers have been benefited greatly from immune checkpoint blockade immunotherapy. However, immune checkpoint blockade is still suboptimal in HCC treatment and more immune modifications are needed to achieve an efficient therapeutic goal. Here, we investigated the combined administration of a Listeria-based HCC vaccine, Lmdd-MPFG, and the anti-PD-1 immune checkpoint blockade antibody. We found that Lmdd-MPFG promoted the expression of PD-L1 in HCC cells but resensitized the tumor local T cell to respond to the anti-PD-1 immunotherapy. Mechanistically, the Lmdd-MPFG vaccine activates the NF-κB pathway in the tumor-associated macrophages (TAMs) through the TLR2 and MyD88 pathway, and recruits p62 to activate the autophagy pathway. The overall effect is skewing the TAMs from M2-polarized TAMs into the M1-polarized TAMs. Most importantly, it skewed the cytokine profiles into antitumor one in the tumor microenvironment (TME). This change restores the T-cell reactivity to the anti-PD-1 blockade. Our results suggested that Lmdd-MPFG combined with PD-1 blockade exerted synergistic antitumor effects through modifying TAMs in the TME and removing T-cell inhibitory signals, thereby providing a new potential strategy for HCC treatment.
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23
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Lai Q, Vitale A, Manzia TM, Foschi FG, Levi Sandri GB, Gambato M, Melandro F, Russo FP, Miele L, Viganò L, Burra P, Giannini EG. Platelets and Hepatocellular Cancer: Bridging the Bench to the Clinics. Cancers (Basel) 2019; 11:1568. [PMID: 31618961 PMCID: PMC6826649 DOI: 10.3390/cancers11101568] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Revised: 10/10/2019] [Accepted: 10/14/2019] [Indexed: 02/06/2023] Open
Abstract
Growing interest is recently being focused on the role played by the platelets in favoring hepatocellular cancer (HCC) growth and dissemination. The present review reports in detail both the experimental and clinical evidence published on this topic. Several growth factors and angiogenic molecules specifically secreted by platelets are directly connected with tumor progression and neo-angiogenesis. Among them, we can list the platelet-derived growth factor, the vascular endothelial growth factor, the endothelial growth factor, and serotonin. Platelets are also involved in tumor spread, favoring endothelium permeabilization and tumor cells' extravasation and survival in the bloodstream. From the bench to the clinics, all of these aspects were also investigated in clinical series, showing an evident correlation between platelet count and size of HCC, tumor biological behavior, metastatic spread, and overall survival rates. Moreover, a better understanding of the mechanisms involved in the platelet-tumor axis represents a paramount aspect for optimizing both current tumor treatment and development of new therapeutic strategies against HCC.
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Affiliation(s)
- Quirino Lai
- Department of General Surgery and Organ Transplantation, Umberto I Hospital, Sapienza University, 00161 Rome, Italy.
| | - Alessandro Vitale
- Department of Surgery, Oncology, and Gastroenterology, University of Padua, 35122 Padua, Italy.
| | - Tommaso M Manzia
- Department of Transplant Surgery, Polyclinic Tor Vergata Foundation, Tor Vergata University, 00133 Rome, Italy.
| | - Francesco G Foschi
- Department of Internal Medicine, Ospedale per gli Infermi di Faenza, 48018 Faenza, Italy.
| | | | - Martina Gambato
- Department of Surgery, Oncology, and Gastroenterology, University of Padua, 35122 Padua, Italy.
| | - Fabio Melandro
- Hepatobiliary Surgery and Liver Transplantation Unit, University of Pisa Medical School Hospital, 56126 Pisa, Italy.
| | - Francesco P Russo
- Department of Surgery, Oncology, and Gastroenterology, University of Padua, 35122 Padua, Italy.
| | - Luca Miele
- Internal Medicine, Gastroenterology and Liver Unit, A. Gemelli Polyclinic, Sacro Cuore Catholic University, 20123 Rome, Italy.
| | - Luca Viganò
- Division of Hepatobiliary and General Surgery, Department of Surgery, Humanitas Clinical and Research Center, Rozzano, 20089 Milan, Italy.
| | - Patrizia Burra
- Department of Surgery, Oncology, and Gastroenterology, University of Padua, 35122 Padua, Italy.
| | - Edoardo G Giannini
- Gastroenterology Unit, Department of Internal Medicine, Università di Genova, IRCCS-Ospedale Policlinico San Martino, 16132 Genoa, Italy.
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24
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De Mattia E, Cecchin E, Guardascione M, Foltran L, Di Raimo T, Angelini F, D’Andrea M, Toffoli G. Pharmacogenetics of the systemic treatment in advanced hepatocellular carcinoma. World J Gastroenterol 2019; 25:3870-3896. [PMID: 31413525 PMCID: PMC6689804 DOI: 10.3748/wjg.v25.i29.3870] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 05/23/2019] [Accepted: 07/03/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. To date, most patients with HCC are diagnosed at an advanced tumor stage, excluding them from potentially curative therapies (i.e., resection, liver transplantation, percutaneous ablation). Treatments with palliative intent include chemoembolization and systemic therapy. Among systemic treatments, the small-molecule multikinase inhibitor sorafenib has been the only systemic treatment available for advanced HCC over 10 years. More recently, other small-molecule multikinase inhibitors (e.g., regorafenib, lenvatinib, cabozantinib) have been approved for HCC treatment. The promising immune checkpoint inhibitors (e.g., nivolumab, pembrolizumab) are still under investigation in Europe while in the US nivolumab has already been approved by FDA in sorafenib refractory or resistant patients. Other molecules, such as the selective CDK4/6inhibitors (e.g., palbociclib, ribociclib), are in earlier stages of clinical development, and the c-MET inhibitor tivantinib did not show positive results in a phase III study. However, even if the introduction of targeted agents has led to great advances in patient response and survival with an acceptable toxicity profile, a remarkable inter-individual heterogeneity in therapy outcome persists and constitutes a significant problem in disease management. Thus, the identification of biomarkers that predict which patients will benefit from a specific intervention could significantly affect decision-making and therapy planning. Germ-line variants have been suggested to play an important role in determining outcomes of HCC systemic therapy in terms of both toxicity and treatment efficacy. Particularly, a number of studies have focused on the role of genetic polymorphisms impacting the drug metabolic pathway and membrane translocation as well as the drug mechanism of action as predictive/prognostic markers of HCC treatment. The aim of this review is to summarize and critically discuss the pharmacogenetic literature evidences, with particular attention to sorafenib and regorafenib, which have been used longer than the others in HCC treatment.
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Affiliation(s)
- Elena De Mattia
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
| | - Erika Cecchin
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
| | - Michela Guardascione
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
| | - Luisa Foltran
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
| | - Tania Di Raimo
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
- Medical Oncology and Anatomic Pathology Unit, “San Filippo Neri Hospital”, Rome 00135, Italy
| | - Francesco Angelini
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
- Medical Oncology and Anatomic Pathology Unit, “San Filippo Neri Hospital”, Rome 00135, Italy
| | - Mario D’Andrea
- Department of Oncology, “San Filippo Neri Hospital”, Rome 00135, Italy
| | - Giuseppe Toffoli
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
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25
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Cheung TT. Management of hepatocellular carcinoma: from bench to bedside and beyond. Transl Gastroenterol Hepatol 2019; 4:54. [PMID: 31463413 DOI: 10.21037/tgh.2019.07.01] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Affiliation(s)
- Tan To Cheung
- Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
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26
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PD-L1 Expression in Mastocytosis. Int J Mol Sci 2019; 20:ijms20092362. [PMID: 31086024 PMCID: PMC6539475 DOI: 10.3390/ijms20092362] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 05/01/2019] [Accepted: 05/04/2019] [Indexed: 01/14/2023] Open
Abstract
Programmed death 1 (PD-1), when activated by its ligands PD-L1 and PD-L2, suppresses active immune cells in normal immune regulation to limit autoimmunity and, in tumors, as a mechanism of immune evasion. PD-L1 expression has been described as both a prognostic and predictive marker in many solid and hematologic neoplasms, as targeted therapies against the PD-1/PD-L1 interaction have gained clinical importance. PD-L1 expression has been assessed in a few studies on mastocytosis. We review this literature and the need for further investigation of the tumor-immune interaction in mastocytosis.
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27
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Bioinformatics analysis to identify the key genes affecting the progression and prognosis of hepatocellular carcinoma. Biosci Rep 2019; 39:BSR20181845. [PMID: 30705088 PMCID: PMC6386764 DOI: 10.1042/bsr20181845] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2018] [Revised: 01/28/2019] [Accepted: 01/30/2019] [Indexed: 12/20/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, which has poor outcome. The present study aimed to investigate the key genes implicated in the progression and prognosis of HCC. The RNA-sequencing data of HCC was extracted from The Cancer Genome Atlas (TCGA) database. Using the R package (DESeq), the differentially expressed genes (DEGs) were analyzed. Based on the Cluepedia plug-in in Cytoscape software, enrichment analysis for the protein-coding genes amongst the DEGs was conducted. Subsequently, protein–protein interaction (PPI) network was built by Cytoscape software. Using survival package, the genes that could distinguish the survival differences of the HCC samples were explored. Moreover, quantitative real-time reverse transcription-PCR (qRT-PCR) experiments were used to detect the expression of key genes. There were 2193 DEGs in HCC samples. For the protein-coding genes amongst the DEGs, multiple functional terms and pathways were enriched. In the PPI network, cyclin-dependent kinase 1 (CDK1), polo-like kinase 1 (PLK1), Fos proto-oncogene, AP-1 transcription factor subunit (FOS), serum amyloid A1 (SAA1), and lysophosphatidic acid receptor 3 (LPAR3) were hub nodes. CDK1 interacting with PLK1 and FOS, and LPAR3 interacting with FOS and SAA1 were found in the PPI network. Amongst the 40 network modules, 4 modules were with scores not less than 10. Survival analysis showed that anterior gradient 2 (AGR2) and RLN3 could differentiate the high- and low-risk groups, which were confirmed by qRT-PCR. CDK1, PLK1, FOS, SAA1, and LPAR3 might be key genes affecting the progression of HCC. Besides, AGR2 and RLN3 might be implicated in the prognosis of HCC.
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