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Guo Z, Yao Z, Huang B, Wu D, Li Y, Chen X, Lu Y, Wang L, Lv W. MAFLD-related hepatocellular carcinoma: Exploring the potent combination of immunotherapy and molecular targeted therapy. Int Immunopharmacol 2024; 140:112821. [PMID: 39088919 DOI: 10.1016/j.intimp.2024.112821] [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: 05/23/2024] [Revised: 07/11/2024] [Accepted: 07/25/2024] [Indexed: 08/03/2024]
Abstract
Hepatocellular carcinoma (HCC) is a common cause of cancer-related mortality and morbidity globally, and with the prevalence of metabolic-related diseases, the incidence of metabolic dysfunction-associated fatty liver disease (MAFLD) related hepatocellular carcinoma (MAFLD-HCC) continues to rise with the limited efficacy of conventional treatments, which has created a major challenge for HCC surveillance. Immune checkpoint inhibitors (ICIs) and molecularly targeted drugs offer new hope for advanced MAFLD-HCC, but the evidence for the use of both types of therapy in this type of tumour is still insufficient. Theoretically, the combination of immunotherapy, which awakens the body's anti-tumour immunity, and targeted therapies, which directly block key molecular events driving malignant progression in HCC, is expected to produce synergistic effects. In this review, we will discuss the progress of immunotherapy and molecular targeted therapy in MAFLD-HCC and look forward to the opportunities and challenges of the combination therapy.
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Affiliation(s)
- Ziwei Guo
- Department of Infection, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Ziang Yao
- Department of Traditional Chinese Medicine, Peking University People 's Hospital, Beijing 100044, China
| | - Bohao Huang
- Beijing University of Chinese Medicine, Beijing 100105, China
| | - Dongjie Wu
- Department of Infection, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Yanbo Li
- Department of Infection, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Xiaohan Chen
- Department of Hematology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Yanping Lu
- Department of Hepatology, Shenzhen Bao'an Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen 518100, China.
| | - Li Wang
- Department of Infection, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China.
| | - Wenliang Lv
- Department of Infection, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China.
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Liu C, Tu YJ, Cai HY, Pan YY, Wu YY, Zhang L. Regulatory T cells inhibit FoxP3 to increase the population of tumor initiating cells in hepatocellular carcinoma. J Cancer Res Clin Oncol 2024; 150:373. [PMID: 39073490 PMCID: PMC11286637 DOI: 10.1007/s00432-024-05892-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 07/12/2024] [Indexed: 07/30/2024]
Abstract
PURPOSE Tumor initiating cells (TICs) or cancer stem cells (CSCs) are considered to be the main culprit of hepatocellular carcinoma (HCC) initiation and progression, nevertheless the mechanism by which tumor microenvironment maintains the HCC 'stemness' is not fully understood. This study aims to investigate the effect of regulatory T cells (Tregs) on the TICs characteristics of HCC. METHODS Immunocytochemistry, flow cytometry, real-time PCR, western blot, in vitro sphere-formation, and in vivo tumorigenesis assay were used to detect HCC 'stemness'. Additionally, after forced expression or inhibition of FoxP3, β-catenin expression and HCC 'stemness' were investigated. RESULTS Tregs enhanced the 'stemness' of HCC cells by upregulating TIC-related markers CD133, Oct3/4, Sox2, c-Myc, Klf4, Nanog, CD13, EpCAM, and inducting epithelial to mesenchymal transition (EMT), increasing TICs ratio, as well as promoting tumorigenic ability. Moreover, β-catenin and c-Myc were upregulated in HCC cells after co-cultured with Tregs. HCC 'stemness' was inhibited after treatment with Wnt/β-catenin pathway inhibitor. Furthermore, forced expression of FoxP3 resulted in increased GSK3β, decreased β-catenin and TIC ratio in HCC. In contrast, FoxP3 interference reduced GSK3β, enhanced β-catenin and TIC ratio of HCC. CONCLUSION This study, for the first time, demonstrated that Tregs increased the population of TICs in HCC by inhibiting FoxP3 as well as promoting β-catenin expression.
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Affiliation(s)
- Chang Liu
- Central Hospital of Dalian University of Technology, No. 826, Southwest Road, Dalian, 116033, China
| | - Yi-Jun Tu
- Central Hospital of Dalian University of Technology, No. 826, Southwest Road, Dalian, 116033, China
| | - Hong-Yang Cai
- Central Hospital of Dalian University of Technology, No. 826, Southwest Road, Dalian, 116033, China
| | - Yan-Yan Pan
- Central Hospital of Dalian University of Technology, No. 826, Southwest Road, Dalian, 116033, China
| | - Yuan-Yuan Wu
- Central Hospital of Dalian University of Technology, No. 826, Southwest Road, Dalian, 116033, China
| | - Li Zhang
- Central Hospital of Dalian University of Technology, No. 826, Southwest Road, Dalian, 116033, China.
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Xiang S, Li J, Zhang M. TGF-β1 inhibitor enhances the therapeutic effect of microwave ablation on hepatocellular carcinoma. Int J Hyperthermia 2024; 41:2359496. [PMID: 38909985 DOI: 10.1080/02656736.2024.2359496] [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: 09/18/2023] [Revised: 05/13/2024] [Accepted: 05/20/2024] [Indexed: 06/25/2024] Open
Abstract
BACKGROUND Microwave ablation (MWA) is a widely adopted treatment technique for hepatocellular carcinoma (HCC). However, MWA alone is of limited use and has a high recurrence rate. Transforming growth factor-β1 (TGF-β1) is recognized as a potential therapeutic target for HCC patients. Therefore, this study was designed to investigate whether the TGF-β1 inhibitor could increase the efficacy of MWA therapy for HCC treatment. METHODS In vitro, HCC cells challenged with TGF-β1 inhibitor (SB-525334), or normal saline were then heated by microwave. Methyl tetrazolium assays were performed to detect cell survival rate and half-maximal drug inhibitory concentration (IC50). Cell viability and apoptosis were detected by cell counting kit-8 assays, flow cytometry and western blotting. In vivo, the mice injected with HepG2 cells received oral gavage of SB-525334 (20 mg/kg) or normal saline and MWA at a power of 15 W. Tumor volume was recorded. Expression of Ki67 and apoptosis-related proteins were detected by immunohistochemistry and western blotting. TUNEL assays were used to detect cell death ratio. Histopathological changes were examined by hematoxylin and eosin staining. The mechanisms associated with the function of MWA combined with TGF-β1 inhibitor in HCC development were explored by western blotting. RESULTS Combination of MWA and SB-525334 decreased the survival rate and promoted the apoptosis of HCC cells compared with MWA alone. SB-525334 enhanced the suppressive effect of MWA on tumor growth and amplified cell apoptosis. Mechanistically, MWA collaborated with SB-525334 inhibitor inactivated the TGF-β1/Smad2/Smad3 pathway. CONCLUSION TGF-β1 inhibitor enhances the therapeutic effect of MWA on HCC.
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Affiliation(s)
- Shufang Xiang
- Department of Ultrasound, The First Affiliated Hospital of Yangtze University, Jingzhou City, P. R.China
| | - Juan Li
- Department of Ultrasound, The First Affiliated Hospital of Yangtze University, Jingzhou City, P. R.China
| | - Mei Zhang
- Department of Ultrasound, The First Affiliated Hospital of Yangtze University, Jingzhou City, P. R.China
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Wang W, Ding M, Wang Q, Song Y, Huo K, Chen X, Xiang Z, Liu L. Advances in Foxp3+ regulatory T cells (Foxp3+ Treg) and key factors in digestive malignancies. Front Immunol 2024; 15:1404974. [PMID: 38919615 PMCID: PMC11196412 DOI: 10.3389/fimmu.2024.1404974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 05/24/2024] [Indexed: 06/27/2024] Open
Abstract
Foxp3+ regulatory T cells (Foxp3+ Treg) play a role in regulating various types of tumors, but uncertainty still exists regarding the exact mechanism underlying Foxp3+ Treg activation in gastrointestinal malignancies. As of now, research has shown that Foxp3+ Treg expression, altered glucose metabolism, or a hypoxic tumor microenvironment all affect Foxp3+ Treg function in the bodies of tumor patients. Furthermore, it has been demonstrated that post-translational modifications are essential for mature Foxp3 to function properly. Additionally, a considerable number of non-coding RNAs (ncRNAs) have been implicated in the activation of the Foxp3 signaling pathway. These mechanisms regulating Foxp3 may one day serve as potential therapeutic targets for gastrointestinal malignancies. This review primarily focuses on the properties and capabilities of Foxp3 and Foxp3+Treg. It emphasizes the advancement of research on the regulatory mechanisms of Foxp3 in different malignant tumors of the digestive system, providing new insights for the exploration of anticancer treatments.
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Affiliation(s)
- Wanyao Wang
- School of Basic Medicine, Mudanjiang Medical University, Mudanjiang, Heilongjiang, China
| | - Minglu Ding
- Mudanjiang Medical University, Mudanjiang, Heilongjiang, China
| | - Qiuhong Wang
- Mudanjiang Hospital for Cardiovascular Diseases, Department of Anesthesiology, Mudanjiang, Heilongjiang, China
| | - Yidan Song
- School of Basic Medicine, Mudanjiang Medical University, Mudanjiang, Heilongjiang, China
| | - Keyuan Huo
- School of Basic Medicine, Mudanjiang Medical University, Mudanjiang, Heilongjiang, China
| | - Xiaojie Chen
- School of Basic Medicine, Mudanjiang Medical University, Mudanjiang, Heilongjiang, China
| | - Zihan Xiang
- School of Basic Medicine, Mudanjiang Medical University, Mudanjiang, Heilongjiang, China
| | - Lantao Liu
- School of Basic Medicine, Mudanjiang Medical University, Mudanjiang, Heilongjiang, China
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Ajith A, Merimi M, Arki MK, Hossein-khannazer N, Najar M, Vosough M, Sokal EM, Najimi M. Immune regulation and therapeutic application of T regulatory cells in liver diseases. Front Immunol 2024; 15:1371089. [PMID: 38571964 PMCID: PMC10987744 DOI: 10.3389/fimmu.2024.1371089] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 02/28/2024] [Indexed: 04/05/2024] Open
Abstract
CD4+ CD25+ FOXP3+ T regulatory cells (Tregs) are a subset of the immunomodulatory cell population that can inhibit both innate and adaptive immunity by various regulatory mechanisms. In hepatic microenvironment, proliferation, plasticity, migration, and function of Tregs are interrelated to the remaining immune cells and their secreted cytokines and chemokines. In normal conditions, Tregs protect the liver from inflammatory and auto-immune responses, while disruption of this crosstalk between Tregs and other immune cells may result in the progression of chronic liver diseases and the development of hepatic malignancy. In this review, we analyze the deviance of this protective nature of Tregs in response to chronic inflammation and its involvement in inducing liver fibrosis, cirrhosis, and hepatocellular carcinoma. We will also provide a detailed emphasis on the relevance of Tregs as an effective immunotherapeutic option for autoimmune diseases, liver transplantation, and chronic liver diseases including liver cancer.
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Affiliation(s)
- Ananya Ajith
- Laboratory of Pediatric Hepatology and Cell Therapy, Institute of Experimental and Clinical Research (IREC), UCLouvain, Brussels, Belgium
| | - Makram Merimi
- Genetics and Immune Cell Therapy Unit, LBBES Laboratory, Faculty of Sciences, University Mohammed Premier, Oujda, Morocco
| | - Mandana Kazem Arki
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nikoo Hossein-khannazer
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehdi Najar
- Osteoarthritis Research Unit, Department of Medicine, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC, Canada
- Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Centre, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Huddinge, Sweden
| | - Etienne Marc Sokal
- Laboratory of Pediatric Hepatology and Cell Therapy, Institute of Experimental and Clinical Research (IREC), UCLouvain, Brussels, Belgium
| | - Mustapha Najimi
- Laboratory of Pediatric Hepatology and Cell Therapy, Institute of Experimental and Clinical Research (IREC), UCLouvain, Brussels, Belgium
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Chen X, Mohammed AF, Li C. Assessment of the Clinical Value of Platelet-to-Lymphocyte Ratio in Patients with Hepatocellular Carcinoma. Clin Appl Thromb Hemost 2024; 30:10760296231221535. [PMID: 38591958 PMCID: PMC11005495 DOI: 10.1177/10760296231221535] [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: 10/16/2023] [Revised: 11/30/2023] [Accepted: 12/03/2023] [Indexed: 04/10/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is associated with higher mortality as a result of poor prognosis and unavailability of effective treatment options. This study retrospectively analyzed the clinical value of platelet-to-lymphocyte ratio (PLR) to aid in differentiating early hepatocellular carcinoma from liver cirrhosis patients. Three hundred and nine (309) patients including 155 patients with hepatocellular carcinoma (HCC) and 154 patients with liver cirrhosis were enrolled in this study. General clinical characteristics and blood parameters of each patient were collected, calculated, and retrospectively analyzed. Mann-Whitney U test was calculated to compare the two groups. Receiver operating characteristics (ROC) curve was performed to investigate the diagnostic potential of PLR in the prediction of HCC at a cut-off with high accuracy (area under the curve [AUC]) > 0.80. Hemoglobin (HB) concentration, red blood cell (RBC) count, neutrophil (NEU) count, platelet count, platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) were significantly higher in the HCC patients than in the liver cirrhosis patients (p < 0.05). ROC curve analysis showed that the AUC, optimal cut-off value, sensitivity, and specificity of PLR to predict HCC patients were 0.912, 98.7, 81.2%, and 80.6% respectively. The results suggest that PLR is a potential biomarker that can be used to predict early HCC.
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Affiliation(s)
- Xu Chen
- Department of Laboratory Medicine, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, China
| | - Abdul Fatawu Mohammed
- Department of Laboratory Medicine, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, China
| | - Chengbin Li
- Department of Laboratory Medicine, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, China
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Okamura K, Sato M, Suzuki T, Nohara K. Arsenite exposure induces premature senescence and senescence-associated secretory phenotype (SASP) in human hepatocyte-derived cell line Huh-7. Environ Health Prev Med 2024; 29:74. [PMID: 39756915 DOI: 10.1265/ehpm.24-00139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2025] Open
Abstract
BACKGROUND Chronic arsenite exposure has been known to induce cancer in various organs; however, the underlying mechanisms remain elusive. The characteristic feature of carcinogenesis due to arsenic exposure is that the disease develops after a prolonged latent period, even after cessation of exposure. Our previous study revealed that arsenite exposure induces premature senescence in hepatic stellate cells and suggests that the senescence-associated secretory phenotype (SASP) factors from the senescent cells promote hepatic carcinogenesis. However, arsenite exposure in the liver occurs not only in hepatic stellate cells, but also in hepatocytes. Therefore, we examined whether arsenite exposure in hepatocytes also causes premature senescence and the enhancement of SASP factors. We also assessed whether those effects remained after cessation of arsenite exposure. METHODS Human hepatocyte-derived cell line Huh-7 was exposed to sodium arsenite for 72 hours to determine the concentration at which cell proliferation was inhibited. In the 5 µM of exposure, various cellular senescence markers and SASP factors were analyzed and compared with unexposed cells. We also examined whether those senescence markers and SASP factors were maintained after cessation of arsenite exposure. Finally, we explored whether the increased expression of SASP factor, which was upregulated in hepatocytes by arsenic exposure in this study, is related to the prognosis of human hepatocellular carcinoma. RESULTS After exposure to 5 µM of sodium arsenite for 72 hours, various senescent features, such as the induction of P21 mRNA, the reduction of LAMINB1 mRNA, morphological changes, phosphorylation of P53, and the presence of SA-β-gal positive cells were observed. Those changes were maintained after cessation of arsenite exposure. In addition, mRNA levels of SASP factors (MMP1, MMP3, MMP10, GDF15, PAI-1, and IL-6) were increased after arsenite exposure, and their high expression levels were maintained after cessation of arsenite exposure. Furthermore, by analyzing the TCGA database, we found that the increased expression levels of many SASP factors negatively correlated with prognosis. CONCLUSIONS Arsenite exposure induces premature senescence in hepatocyte-derived cells and increases SASP factors that are related to hepatic tumorigenesis. Once arsenite exposure induces premature senescence, the senescent cells remain even after cessation of exposure.
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Affiliation(s)
- Kazuyuki Okamura
- Health and Environmental Risk Division, National Institute for Environmental Studies
| | - Miyuki Sato
- Health and Environmental Risk Division, National Institute for Environmental Studies
| | - Takehiro Suzuki
- Health and Environmental Risk Division, National Institute for Environmental Studies
| | - Keiko Nohara
- Health and Environmental Risk Division, National Institute for Environmental Studies
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da Silva Soares E, Rocha CC, Valente FL, Dos Anjos LRA, de Oliveira FLD, de Oliveira Loures C, Rocha PT, Castro VR, Sarandy TB, Borges APB. Platelet count and MCHC as independent prognostic markers for feline mammary carcinomas. Res Vet Sci 2023; 164:105024. [PMID: 37827061 DOI: 10.1016/j.rvsc.2023.105024] [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: 12/13/2022] [Revised: 08/16/2023] [Accepted: 09/18/2023] [Indexed: 10/14/2023]
Abstract
Mammary neoplasms are common in felines species and represent a significant disease for its unfavorable prognosis. Changes in the blood count and serum biochemical profile of these patients have potential as non-invasive prognostic markers prior to mastectomy, however, they are poorly described in literature. In this study univariate and multivariate analyses were performed using these factors to determine the effect of each parameter on the one-year survival time after the surgical procedure in these animals. The median overall survival (OS) and the disease-free survival (DFS) were 365 and 242 days, respectively. In univariate analysis, values within the reference range of monocyte, platelet and creatinine counts were identified as significant prognostic factors for OS and only creatinine was significant for DFS (P < 0.05). In the multivariate analysis, platelets and mean corpuscular hemoglobin concentration (MCHC) remained independent prognostic factors for OS. The results presented suggest that monocytes, platelets and creatinine may be important non-invasive pre-surgical prognostic markers, and that platelet count and MCHC are independent prognostic markers for feline mammary carcinomas (FMC). The correlation between such alterations is of important relevance for veterinary oncology, and prospective studies are needed to validate their clinical use and that platelet count and MCHC are independent prognostic markers for FMC. The results found in this study can also be studied in human medicine, regarding blood markers in human breast cancer (HBC).
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Affiliation(s)
| | | | | | | | | | | | - Pâmela Thalita Rocha
- Department of Veterinary, Federal University of Viçosa (UFV), Viçosa, MG, Brazil
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Wang Z, Cui Y, Zhang Y, Wang X, Li J, Li J, Jiang N. Twelve-week treadmill endurance training in mice is associated with upregulation of interleukin-15 and natural killer cell activation and increases apoptosis rate in Hepa1-6 cell-derived mouse hepatomas. Braz J Med Biol Res 2023; 56:e12296. [PMID: 37585912 PMCID: PMC10427160 DOI: 10.1590/1414-431x2023e12296] [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: 03/05/2023] [Accepted: 06/23/2023] [Indexed: 08/18/2023] Open
Abstract
Regular exercise reduces the risk of malignancy and decreases the recurrence of cancer. However, the mechanisms behind this protection remain to be elucidated. Natural killer (NK) cells are lymphocytes of the innate immune system, which play essential roles in immune defense and effectively prevent cancer metastasis. Physical exercise can increase the activity of NK cells. Interleukin-15 (IL-15) is the best-studied cytokine activator of NK cells, and it was shown to have many positive functional effects on NK cells to improve antitumor responses. The aim of this study was to clarify the possible important mechanisms behind endurance exercise-induced changes in NK cell function, which may be highly correlated with IL-15. An animal model was used to study IL-15 expression level, tumor volume, cancer cell apoptosis, and NK cell infiltration after treadmill exercise. Although IL-15 was highly expressed in skeletal muscle, treadmill exercise further elevated IL-15 levels in plasma and muscle (P<0.05). In addition, tumor weight and volume of tumor-bearing mice were decreased (P<0.05), and liver tumor cell apoptosis was increased after 12 weeks of treadmill exercise (P<0.05). NK cell infiltration was upregulated in tumors from treadmill exercise mice, and the level of interferon-gamma (IFN-γ) and IL-15 were higher than in sedentary mice (P<0.05). The study indicated that regular endurance training can reduce cancer risk, which was related to increased IL-15 expression, activation of the immune killing effect of NK cells, and promotion of tumor cell apoptosis, which can ultimately control tumor growth.
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Affiliation(s)
- Zhe Wang
- Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Institute of Sport, Exercise & Health, Tianjin University of Sport, Tianjin, China
- Department of Common Subject, College of Basic Sciences, Logistics College of Chinese People’s Armed Police Force, Tianjin, China
| | - Yunlong Cui
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Hospital, Tianjin, China
| | - Yong Zhang
- Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Institute of Sport, Exercise & Health, Tianjin University of Sport, Tianjin, China
| | - Xinghao Wang
- Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Institute of Sport, Exercise & Health, Tianjin University of Sport, Tianjin, China
| | - Jing Li
- Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Institute of Sport, Exercise & Health, Tianjin University of Sport, Tianjin, China
| | - Jialin Li
- Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Institute of Sport, Exercise & Health, Tianjin University of Sport, Tianjin, China
| | - Ning Jiang
- Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Institute of Sport, Exercise & Health, Tianjin University of Sport, Tianjin, China
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Pinato DJ, Kaneko T, D’Alessio A, Forner A, Fessas P, Minguez B, Giannini EG, Grillo F, Díaz A, Mauri FA, Fulgenzi CA, Dalla Pria A, Goldin RD, Pieri G, Toniutto P, Avellini C, Plaz Torres MC, Akarca AU, Marafioti T, Bhoori S, Miró JM, Bower M, Bräu N, Mazzaferro V. Integrated phenotyping of the anti-cancer immune response in HIV-associated hepatocellular carcinoma. JHEP Rep 2023; 5:100741. [PMID: 37274775 PMCID: PMC10238838 DOI: 10.1016/j.jhepr.2023.100741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 03/03/2023] [Accepted: 03/07/2023] [Indexed: 06/07/2023] Open
Abstract
Background & Aims HIV-seropositivity shortens survival in patients with hepatocellular carcinoma (HCC). Although risk factors for HCC including HCV infection can influence T cell phenotype, it is unknown whether HIV can influence functional characteristics of the T cell infiltrate. Methods From the Liver Cancer in HIV biorepository, we derived 129 samples of transplanted (76%) or resected (20%) HCC in eight European and North American centres. We profiled intra- and peritumoural tissue to evaluate regulatory CD4+/FOXP3+ and immune-exhausted CD8+/PD1+ T cells in HIV+ (n = 66) and HIV- (n = 63) samples. We performed targeted transcriptomics and T-cell receptor sequencing in a restricted subset of samples evaluated in relationship with HIV status. We correlated immunopathologic features with patients' characteristics including markers of HIV infection. Results Of the 66 HIV+ patients, 83% were HCV coinfected with an undetectable HIV viral load (51%) and a median blood CD4+ cell count of 430 cells/mm3 (range 15-908). Patients who were HIV+ were compared with HIV- controls with similar staging characteristics including Barcelona Clinic Liver Cancer (BCLC) stage A-B (86% vs. 83%, p = 0.16), <3 nodules (90% vs. 83%, p = 0.3) and median alpha-foetoprotein values (10.9 vs. 12.8 ng/ml, p = 0.72). HIV+ samples had higher PD-L1 expression rates in tumour tissue (51% vs. 8% p <0.0001) and displayed denser intratumoural CD4+/FOXP3+ (p <0.0001), CD8+/PD1+ (p <0.0001), with lower total peritumoural CD4+ (p <0.0001) and higher peritumoural CD8+/PD1+ (p <0.0001). Gene set analysis revealed HIV+ cases to have evidence of dysregulated adaptive and innate immunity. Tumour-infiltrating lymphocyte clonality was not influenced by HIV status. Conclusions HIV-associated HCC harbours a profoundly immune-exhausted tumour microenvironment, warranting prospective testing of immunotherapy in this treatment-deprived patient population. Impact and Implications Hepatocellular carcinoma is a non-AIDS defining malignancy characterised by poor survival. The programmed cell death (PD-1) pathway governs antiviral and anticancer immune exhaustion and is a therapeutic target in HCC. This study highlights how HIV infection is associated with significantly higher PD-L1 expression in HCC cells and in the surrounding microenvironment, leading to changes in cytotoxic and regulatory T cell function and dysregulation of proinflammatory pathways. Taken together, our results suggest dysfunctional T cell immunity as a mechanism of worse outcome in these patients and suggest clinical testing of checkpoint inhibitors in HIV-associated HCC.
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Affiliation(s)
- David J. Pinato
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, UK
- Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Takahiro Kaneko
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, UK
- Tokyo Medical and Dental University, Tokyo, Japan
| | - Antonio D’Alessio
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, UK
- Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Alejandro Forner
- Liver Unit, Barcelona Clinic Liver Cancer (BCLC) Group, ICMDM, Hospital Clinic Barcelona, IDIBAPS. University of Barcelona, Barcelona, Spain
- National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
| | - Petros Fessas
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, UK
| | - Beatriz Minguez
- Liver Unit, Department of Internal Medicine Hospital Universitari Vall d’Hebron, Universitat Autonoma de Barcelona, Barcelona, Spain
- Vall d’Hebron Institute of Research (VHIR), CIBERehd Vall d’Hebron, Barcelona Hospital Campus, Barcelona, Spain
| | - Edoardo G. Giannini
- Gastroenterology Unit, Department of Internal Medicine, University of Genoa, IRCCS-Ospedale Policlinico San Martino, Genoa, Italy
| | - Federica Grillo
- Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, IRCCS-Ospedale Policlinico San Martino, Genoa, Italy
| | - Alba Díaz
- National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
- Pathology Department, Hospital Clínic, University of Barcelona, Barcelona, Catalonia, Spain
| | - Francesco A. Mauri
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, UK
| | - Claudia A.M. Fulgenzi
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, UK
- Medical Oncology Department, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
| | - Alessia Dalla Pria
- National Centre for HIV Malignancy, Department of Oncology, Chelsea & Westminster Hospital, London, UK
| | | | - Giulia Pieri
- Gastroenterology Unit, Department of Internal Medicine, University of Genoa, IRCCS-Ospedale Policlinico San Martino, Genoa, Italy
| | - Pierluigi Toniutto
- Hepatology and Liver Transplantation Unit, Department of Medical Area (DAME), University of Udine, Udine, Italy
| | - Claudio Avellini
- Azienda Ospedaliero-Universitaria “Santa Maria della Misericordia”, Institute of Histopathology, Udine, Italy
| | - Maria Corina Plaz Torres
- Gastroenterology Unit, Department of Internal Medicine, University of Genoa, IRCCS-Ospedale Policlinico San Martino, Genoa, Italy
| | - Ayse U. Akarca
- Department of Histopathology, University College London Hospital, London, UK
| | - Teresa Marafioti
- Department of Histopathology, University College London Hospital, London, UK
| | - Sherrie Bhoori
- Hepato-Pancreatic-Biliary Surgery and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Jose María Miró
- Department of Infectious Disease, Hospital Clinic-IDIBAPS, University of Barcelona, Barcelona, Spain
- CIBERINFEC, Instituto de Salud Carlos III, Madrid, Spain
| | - Mark Bower
- National Centre for HIV Malignancy, Department of Oncology, Chelsea & Westminster Hospital, London, UK
| | - Norbert Bräu
- James J. Peters VA Medical Center, Bronx, New York, NY, USA
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Vincenzo Mazzaferro
- Hepato-Pancreatic-Biliary Surgery and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
- Department of Oncology, University of Milan, Milan, Italy
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11
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Hu Y, Setayesh T, Vaziri F, Wu X, Hwang ST, Chen X, Yvonne Wan YJ. miR-22 gene therapy treats HCC by promoting anti-tumor immunity and enhancing metabolism. Mol Ther 2023; 31:1829-1845. [PMID: 37143325 PMCID: PMC10277895 DOI: 10.1016/j.ymthe.2023.04.019] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 03/29/2023] [Accepted: 04/28/2023] [Indexed: 05/06/2023] Open
Abstract
MicroRNA-22 (miR-22) can be induced by beneficial metabolites that have metabolic and immune effects, including retinoic acids, bile acids, vitamin D3, and short-chain fatty acids. The tumor suppressor effects of miR-22 have been suggested, but whether miR-22 treats orthotopic hepatocellular carcinoma (HCC) is not established. The role of miR-22 in regulating tumor immunity is also poorly understood. Our data showed that miR-22 delivered by adeno-associated virus serotype 8 effectively treated HCC. Compared with FDA-approved lenvatinib, miR-22 produced better survival outcomes without noticeable toxicity. miR-22 silenced hypoxia-inducible factor 1 (HIF1α) and enhanced retinoic acid signaling in both hepatocytes and T cells. Moreover, miR-22 treatment improved metabolism and reduced inflammation. In the liver, miR-22 reduced the abundance of IL17-producing T cells and inhibited IL17 signaling by reducing the occupancy of HIF1α in the Rorc and Il17a genes. Conversely, increasing IL17 signaling ameliorated the anti-HCC effect of miR-22. Additionally, miR-22 expanded cytotoxic T cells and reduced regulatory T cells (Treg). Moreover, depleting cytotoxic T cells also abolished the anti-HCC effects of miR-22. In patients, miR-22 high HCC had upregulated metabolic pathways and reduced IL17 pro-inflammatory signaling compared with miR-22 low HCC. Together, miR-22 gene therapy can be a novel option for HCC treatment.
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Affiliation(s)
- Ying Hu
- Department of Pathology and Laboratory Medicine, University of California Davis Health, Sacramento, CA 95817, USA
| | - Tahereh Setayesh
- Department of Pathology and Laboratory Medicine, University of California Davis Health, Sacramento, CA 95817, USA
| | - Farzam Vaziri
- Department of Pathology and Laboratory Medicine, University of California Davis Health, Sacramento, CA 95817, USA
| | - Xuesong Wu
- Department of Dermatology, University of California Davis Health, Sacramento, CA 95817, USA
| | - Samuel T Hwang
- Department of Dermatology, University of California Davis Health, Sacramento, CA 95817, USA
| | - Xin Chen
- Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA
| | - Yu-Jui Yvonne Wan
- Department of Pathology and Laboratory Medicine, University of California Davis Health, Sacramento, CA 95817, USA.
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12
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Xiong X, Song Q, Jing M, Yan W. Identification of PANoptosis-Based Prognostic Signature for Predicting Efficacy of Immunotherapy and Chemotherapy in Hepatocellular Carcinoma. Genet Res (Camb) 2023; 2023:6879022. [PMID: 37313428 PMCID: PMC10260314 DOI: 10.1155/2023/6879022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 05/16/2023] [Accepted: 05/24/2023] [Indexed: 06/15/2023] Open
Abstract
Background PANoptosis has been a research hotspot, but the role of PANoptosis in hepatocellular carcinoma (HCC) remains widely unknown. Drug resistance and low response rate are the main limitations of chemotherapy and immunotherapy in HCC. Thus, construction of a prognostic signature to predict prognosis and recognize ideal patients for corresponding chemotherapy and immunotherapy is necessary. Method The mRNA expression data of HCC patients was collected from TCGA database. Through LASSO and Cox regression, we developed a prognostic signature based on PANoptosis-related genes. KM analysis and ROC curve were implemented to evaluate the prognostic efficacy of this signature, and ICGC and GEO database were used as external validation cohorts. The immune cell infiltration, immune status, and IC50 of chemotherapeutic drugs were compared among different risk subgroups. The relationships between the signature and the efficacy of ICI therapy, sorafenib treatment, and transcatheter arterial chemoembolization (TACE) therapy were investigated. Result A 3-gene prognostic signature was constructed which divided the patients into low- and high-risk subgroups. Low-risk patients had better prognosis, and the risk score was proved to be an independent predictor of overall survival (OS), which had a well predictive effect. Patients in high-risk population had more immunosuppressive cells (Tregs, M0 macrophages, and MDSCs), higher TIDE score and TP53 mutation rate, and elevated activity of base excision repair (BER) pathways. Patients with low risk benefited more from ICI, TACE, and sorafenib therapy. The predictive value of the risk score was comparable with TIDE and MSI for OS under ICI therapy. The risk score could be a biomarker to predict the response to ICI, TACE, and sorafenib therapy. Conclusion The novel signature based on PANoptosis is a promising biomarker to distinguish the prognosis predict the benefit of ICI, TACE, and sorafenib therapy, and forecast the response to them.
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Affiliation(s)
- Xiaofeng Xiong
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qianben Song
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mengjia Jing
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Yan
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Ni Z, Wu B, Liu Z, Wang Q, Han X, Cheng W, Guo C. Clinical value of combined preoperative-postoperative neutrophil-to-lymphocyte ratio in predicting hepatocellular carcinoma prognosis after radiofrequency ablation. Br J Radiol 2023; 96:20220887. [PMID: 36715151 PMCID: PMC10161921 DOI: 10.1259/bjr.20220887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 12/24/2022] [Accepted: 01/09/2023] [Indexed: 01/31/2023] Open
Abstract
OBJECTIVE Previous studies focused on the prognostic significance of the pre- or post-operative neutrophil-lymphocyte ratio (NLR); the significance of combined pre- and post-operative NLR (PP-NLR) remains unknown. Therefore, we investigated the value of PP-NLR for predicting prognosis after radiofrequency ablation (RFA) in patients with hepatocellular carcinoma (HCC) to improve treatment and prolong survival. METHODS We investigated pre- and post-operative NLR and PP-NLR in predicting prognosis after RFA in patients with HCC. Optimal thresholds for leukocytes, lymphocytes, neutrophils, and NLR before and after RFA were retrospectively assessed in patients with HCC who had undergone RFA between January 2018 and June 2019 in Harbin Medical University Cancer Hospital. Risk factors for early HCC recurrence and those affecting recurrence-free survival (RFS) were analyzed. RESULTS The respective pre- and post-operative optimal thresholds were as follows: neutrophils, 3.431 and 4.975; leukocytes, 5.575 and 6.61; lymphocytes, 1.455 and 1.025; and NLR, 1.53 and 4.36. Univariate analysis revealed tumor number; alpha-fetoprotein level; post-operative leukocytes, lymphocytes, NLR, and neutrophils; pre-operative neutrophils and NLR; and PP-NLR as factors influencing early recurrence and RFS. Multivariate analysis indicated PP-NLR as an independent risk factor for poor RFS and early recurrence. CONCLUSION PP-NLR was more effective for predicting prognosis than pre- or post-operative NLR alone for patients with HCC. ADVANCES IN KNOWLEDGE The novelty of this study lies in the combination of pre- and post-operative NLR, namely PP-NLR, to study its prognostic value for HCC patients after RFA, which has not been found in previous studies. The contribution of our study is that PP-NLR can provide clinicians with a new reference index to judge the prognosis of patients and make timely treatment to help patients improve their prognosis.
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Affiliation(s)
- ZiHao Ni
- Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin, China
| | - BoLin Wu
- Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin, China
| | - Zhao Liu
- Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin, China
| | - QiuCheng Wang
- Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xue Han
- Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin, China
| | - Wen Cheng
- Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin, China
| | - CunLi Guo
- Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin, China
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Ait-Ahmed Y, Lafdil F. Novel insights into the impact of liver inflammatory responses on primary liver cancer development. LIVER RESEARCH 2023; 7:26-34. [PMID: 39959704 PMCID: PMC11791919 DOI: 10.1016/j.livres.2023.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 10/05/2022] [Accepted: 01/27/2023] [Indexed: 03/10/2023]
Abstract
Primary liver cancers rank among the deadliest cancers worldwide and often develop in patients with chronic liver diseases in an inflammatory context. This review highlights recent reports on the mechanisms of inflammatory-mediated hepatic cell transformation that trigger the tumorigenic process (initiation steps) and the impact of the immune response favoring tumor cell expansion (progression steps). Several cytokines, namely interleukin (IL)-6, IL-17, IL-1beta, and tumor necrosis factor-alpha, have been described to play a prominent role in the initiation of liver cancers. Additionally, inflammation contributes to cancer progression by favoring tumor escape from anti-tumor immune response, angiogenesis, and metastasis through tumor growth factor-beta and matrix metalloprotease upregulation. These recent studies allowed the development of novel therapeutic strategies aiming at regulating liver inflammation. These strategies are based on the use of anti-inflammatory agents, antibodies targeting immune checkpoint molecules such as programmed death ligand 1 and molecules targeting angiogenic factors, metastasis key factors, and microRNAs involved in tumor development. This review aims at summarizing the recent studies reporting different mechanisms by which the liver inflammatory responses could contribute to liver cancer development.
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Affiliation(s)
- Yeni Ait-Ahmed
- Université Paris-Est, UMR-S955, UPEC, Créteil, France
- Institut National de la Sante et de la Recherche Medicale (INSERM), U955, Créteil, France
| | - Fouad Lafdil
- Université Paris-Est, UMR-S955, UPEC, Créteil, France
- Institut National de la Sante et de la Recherche Medicale (INSERM), U955, Créteil, France
- Institut Universitaire de France (IUF), Paris, France
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Ali S, Rehman MU, Yatoo AM, Arafah A, Khan A, Rashid S, Majid S, Ali A, Ali MN. TGF-β signaling pathway: Therapeutic targeting and potential for anti-cancer immunity. Eur J Pharmacol 2023; 947:175678. [PMID: 36990262 DOI: 10.1016/j.ejphar.2023.175678] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 03/07/2023] [Accepted: 03/22/2023] [Indexed: 03/29/2023]
Abstract
Transforming growth factor-β (TGFβ) is a pleiotropic secretory cytokine exhibiting both cancer-inhibitory and promoting properties. It transmits its signals via Suppressor of Mother against Decapentaplegic (SMAD) and non-SMAD pathways and regulates cell proliferation, differentiation, invasion, migration, and apoptosis. In non-cancer and early-stage cancer cells, TGFβ signaling suppresses cancer progression via inducing apoptosis, cell cycle arrest, or anti-proliferation, and promoting cell differentiation. On the other hand, TGFβ may also act as an oncogene in advanced stages of tumors, wherein it develops immune-suppressive tumor microenvironments and induces the proliferation of cancer cells, invasion, angiogenesis, tumorigenesis, and metastasis. Higher TGFβ expression leads to the instigation and development of cancer. Therefore, suppressing TGFβ signals may present a potential treatment option for inhibiting tumorigenesis and metastasis. Different inhibitory molecules, including ligand traps, anti-sense oligo-nucleotides, small molecule receptor-kinase inhibitors, small molecule inhibitors, and vaccines, have been developed and clinically trialed for blocking the TGFβ signaling pathway. These molecules are not pro-oncogenic response-specific but block all signaling effects induced by TGFβ. Nonetheless, targeting the activation of TGFβ signaling with maximized specificity and minimized toxicity can enhance the efficacy of therapeutic approaches against this signaling pathway. The molecules that are used to target TGFβ are non-cytotoxic to cancer cells but designed to curtail the over-activation of invasion and metastasis driving TGFβ signaling in stromal and cancer cells. Here, we discussed the critical role of TGFβ in tumorigenesis, and metastasis, as well as the outcome and the promising achievement of TGFβ inhibitory molecules in the treatment of cancer.
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Devan AR, Pavithran K, Nair B, Murali M, Nath LR. Deciphering the role of transforming growth factor-beta 1 as a diagnostic-prognostic-therapeutic candidate against hepatocellular carcinoma. World J Gastroenterol 2022; 28:5250-5264. [PMID: 36185626 PMCID: PMC9521521 DOI: 10.3748/wjg.v28.i36.5250] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 04/30/2022] [Accepted: 08/16/2022] [Indexed: 02/06/2023] Open
Abstract
Transforming growth factor-beta (TGF-β) is a multifunctional cytokine that performs a dual role as a tumor suppressor and tumor promoter during cancer progression. Among different ligands of the TGF-β family, TGF-β1 modulates most of its biological outcomes. Despite the abundant expression of TGF-β1 in the liver, steatosis to hepatocellular carcinoma (HCC) progression triggers elevated TGF-β1 levels, contributing to poor prognosis and survival. Additionally, elevated TGF-β1 levels in the tumor microenvironment create an immunosuppressive stage via various mechanisms. TGF-β1 has a prime role as a diagnostic and prognostic biomarker in HCC. Moreover, TGF-β1 is widely studied as a therapeutic target either as monotherapy or combined with immune checkpoint inhibitors. This review provides clinical relevance and up-to-date information regarding the potential of TGF-β1 in diagnosis, prognosis, and therapy against HCC.
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Affiliation(s)
- Aswathy R Devan
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi 682041, Kerala, India
| | - Keechilat Pavithran
- Department of Medical Oncology and Hematology, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi 682041, Kerala, India
| | - Bhagyalakshmi Nair
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi 682041, Kerala, India
| | - Maneesha Murali
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi 682041, Kerala, India
| | - Lekshmi R Nath
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi 682041, Kerala, India
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17
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Li J, Li Q, Yuan Y, Xie Y, Zhang Y, Zhang R. High CENPA expression in papillary renal cell carcinoma tissues is associated with poor prognosis. BMC Urol 2022; 22:157. [PMID: 36163007 PMCID: PMC9511783 DOI: 10.1186/s12894-022-01106-4] [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: 03/10/2022] [Accepted: 09/19/2022] [Indexed: 11/10/2022] Open
Abstract
OBJECTIVE This work focused on investigating the relation of centromeric protein A (CENPA) gene expression with prognosis of papillary renal cell carcinoma (PRCC). METHODS We obtained data from PRCC cases in TCGA. Thereafter, CENPA levels between the paired PRCC and matched non-carcinoma samples were analyzed by Wilcoxon rank-sum test, while the relations of clinicopathological characteristics with CENPA level were examined by logistic regression and Wilcoxon rank-sum test. The prognostic value of CENPA was assessed by plotting the receiver operating feature curve (ROC) and calculating the value of area under curve (AUC). In addition, relations between clinicopathological characteristics and PRCC survival were analyzed through Kaplan-Meier (KM) and Cox regression analyses. After dividing the total number of patients into the trial cohort and the validation cohort in a ratio of 7:3, we constructed a nomogram in trial cohort according to multivariate Cox regression results for predicting how CENPA affected patient survival and used the calibration curve to verify its accuracy in both cohorts. We also determined CENPA levels within cancer and matched non-carcinoma samples through immunohistochemistry (IHC). Finally, we utilized functional enrichment for identifying key pathways related to differentially expressed genes (DEGs) between PRCC cases with CENPA up-regulation and down-regulation. RESULTS CENPA expression enhanced in PRCC tissues compared with healthy counterparts (P < 0.001). CENPA up-regulation was related to pathological TNM stage and clinical stage (P < 0.05). Meanwhile, the ROC curves indicated that CENPA had a remarkable diagnostic capacity for PRCC, and the expression of CENPA can significantly improve the predictive accuracy of pathological TNM stage and clinical stage for PRCC. As revealed by KM curves, PRCC cases with CENPA up-regulation were associated with poor survival compared with those with CENPA down-regulation (Risk ratio, RR = 3.07, 95% CI: 1.58-5.97, P = 0.001). In the meantime, univariate as well as multivariate analysis showed an independent association of CENPA with overall survival (OS, P < 0.05) and the nomogram demonstrated superior predictive ability in both cohorts. IHC analysis indicated that PRCC cases showed an increased CENPA positive rate compared with controls. As revealed by functional annotations, CENPA was enriched into pathways associated with neuroactive ligand receptor interactions, cytokine receptor interactions, extracellular matrix regulators, extracellular matrix glycoproteins and nuclear matrisome. CONCLUSION CENPA expression increases within PRCC samples, which predicts dismal PRCC survival. CENPA may become a molecular prognostic marker and therapeutic target for PRCC patients.
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Affiliation(s)
- Junwu Li
- Department of Urology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400000, China
| | - Qinke Li
- Department of Urology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400000, China
| | - Yang Yuan
- Department of Urology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400000, China
| | - Yiteng Xie
- Department of Urology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400000, China
| | - Yuanfeng Zhang
- Department of Urology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400000, China.
| | - Ronggui Zhang
- Department of Urology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400000, China.
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18
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Shi X, Li H, Xu Y, Nyalali AMK, Li F. The prognostic value of the preoperative inflammatory index on the survival of glioblastoma patients. Neurol Sci 2022; 43:5523-5531. [PMID: 35606674 PMCID: PMC9126244 DOI: 10.1007/s10072-022-06158-w] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 05/17/2022] [Indexed: 02/07/2023]
Abstract
OBJECTIVES The growth and development of tumors are closely related to the initiation and amplification of the inflammatory response. Various inflammatory biomarkers had attained growing attention for nearly two decades and were discovered strongly associated with cancer patients' prognosis, indicating that systemic inflammatory response is possibly essential to cancer progression. However, little was known about the sensitive biomarkers associated with the detection, persistence, treatment, and prognosis of GBM. Hence, the retrospective research endeavored to evaluate the prognostic value of preoperative inflammatory biomarkers in patients with GBM who initially received standardized treatment. METHODS The 232 glioblastoma patients eligible who were admitted to Qilu Hospitals in Shandong Province from January 2014 to January 2018 were collected for this analysis. Inflammatory markers, including the systemic immune-inflammation index (SII), systemic immune response index (SIRI), neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), monocyte-lymphocyte ratio (MLR), and albumin/globulin ratio (AGR), were designed. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and we calculated the area under the ROC curve to determine the AUC value. Besides, we used the Cox proportional hazard model to estimate the relationship between variables and PFS and OS. The statistical differences between variables and PFS and OS were tested through the log-rank test. What is more, the LR method was used to perform Cox multiple regression analysis. The results were represented by hazard ratio (HR), 95% CI, any 2-tailed P < 0.01 was accepted as statistically different. RESULTS The multivariate Cox proportional hazard model presented that SII ≥ 659.1 was an independent risk factor affecting OS (HR = 2.238, 95% CI = 1.471-3.406, P < 0.001) and postoperative PFS (HR = 2.000, 95% CI = 1.472-2.716, P < 0.001) in GBM patients. The 1-, 3-, and 5-year OS of the SII < 659.1 group was 70.8%, 26.9%, and 14.1%, respectively, while the 1- and 3-year OS of the SII ≥ 659.1 group was 37.5% and 11.5% (P < 0.001). The 1-, 3-, and 5-year PFS of the SII < 659.1 group was 36.3%, 19.6%, and 13%, respectively, while the 1-year PFS of the SII ≥ 659.1 group was 11.3% (P < 0.001). Results of patients' clinical and pathological characteristics paraded that in comparison to the lower SII group, the higher SII group had significantly inferior Karnofsky Performance Scale (KPS) scores (P < 0.001) and more frequent cystic changes of the tumors (P < 0.001), whereas the values of SIRI, NLR, PLR, MLR, and AGR were low. CONCLUSIONS SII is an independent inflammatory indicator for predicting the prognosis of GBM patients after receiving initially standardized treatments.
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Affiliation(s)
- Xiaohan Shi
- School of Nursing and Rehabilitation, Shandong University, No. 44 Wenhua Xi Road, Jinan, 250012, Shandong Province, China
| | - Huayu Li
- School of Nursing and Rehabilitation, Shandong University, No. 44 Wenhua Xi Road, Jinan, 250012, Shandong Province, China
| | - Yongxiang Xu
- Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Cheeloo College of Medicine, Shandong University, Wenhua Xi Road, Jinan, 250012, China.,Key Laboratory of Brain Functional Remodeling, Shandong, 250012, Jinan, China
| | - Alphonce M K Nyalali
- Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Cheeloo College of Medicine, Shandong University, Wenhua Xi Road, Jinan, 250012, China.,Department of Surgery, Songwe Regional Referral Hospital, Songwe Box 23, Mbeya, Tanzania.,Department of Orthopedics and Neurosurgery, Mbeya Zonal Referral Hospital and Mbeya College of Health and Allied Sciences, University of Dar Es Salaam, PO Box 419, Mbeya, Tanzania
| | - Feng Li
- Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Cheeloo College of Medicine, Shandong University, Wenhua Xi Road, Jinan, 250012, China. .,Key Laboratory of Brain Functional Remodeling, Shandong, 250012, Jinan, China. .,Department of Neurosurgery, Shandong First Medical University Affiliated Cancer Hospital, Jiyan Road, Jinan, 250117, Shandong Province, China. .,Qilu Medical College of Shandong University, Wenhua Xi Road, Jinan, 250012, Shandong Province, China.
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19
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Metformin modulate immune fitness in hepatocellular carcinoma: Molecular and cellular approach. Int Immunopharmacol 2022; 109:108889. [DOI: 10.1016/j.intimp.2022.108889] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Revised: 05/18/2022] [Accepted: 05/19/2022] [Indexed: 12/16/2022]
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Riaz F, Wei P, Pan F. Fine-tuning of regulatory T cells is indispensable for the metabolic steatosis-related hepatocellular carcinoma: A review. Front Cell Dev Biol 2022; 10:949603. [PMID: 35912096 PMCID: PMC9337771 DOI: 10.3389/fcell.2022.949603] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Accepted: 06/28/2022] [Indexed: 12/12/2022] Open
Abstract
The majority of chronic hepatic diseases are caused by nutritional imbalance. These nutritional inequities include excessive intake of alcohol and fat, which causes alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD), respectively. The pathogenesis of hepatic diseases is mainly dependent on oxidative stress, autophagy, DNA damage, and gut microbiota and their metabolites. These factors influence the normal physiology of the liver and impact the hepatic microenvironment. The hepatic microenvironment contains several immune cells and inflammatory cytokines which interact with each other and contribute to the progression of chronic hepatic diseases. Among these immune cells, Foxp3+ CD4+ regulatory T cells (Tregs) are the crucial subset of CD4+ T cells that create an immunosuppressive environment. This review emphasizes the function of Tregs in the pathogenesis of ALD and NAFLD and their role in the progression of NAFLD-associated hepatocellular carcinoma (HCC). Briefly, Tregs establish an immunosuppressive landscape in the liver by interacting with the innate immune cells and gut microbiota and their metabolites. Meanwhile, with the advancement of steatosis, these Tregs inhibit the proliferation, activation and functions of other cytotoxic T cells and support the progression of simple steatosis to HCC. Briefly, it can be suggested that targeting Tregs can act as a favourable prognostic indicator by modulating steatosis and insulin resistance during the pathogenesis of hepatic steatosis and NAFLD-associated HCC.
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Affiliation(s)
- Farooq Riaz
- Center for Cancer Immunology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Ping Wei
- Center for Cancer Immunology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Chongqing Key Laboratory of Pediatrics, Department of otolaryngology, Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China
| | - Fan Pan
- Center for Cancer Immunology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- *Correspondence: Fan Pan,
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Pham L, Kyritsi K, Zhou T, Ceci L, Baiocchi L, Kennedy L, Chakraborty S, Glaser S, Francis H, Alpini G, Sato K. The Functional Roles of Immune Cells in Primary Liver Cancer. THE AMERICAN JOURNAL OF PATHOLOGY 2022; 192:826-836. [PMID: 35337836 PMCID: PMC9194651 DOI: 10.1016/j.ajpath.2022.02.004] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 02/05/2022] [Accepted: 02/18/2022] [Indexed: 12/12/2022]
Abstract
Primary liver cancer includes hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). Incidence of liver cancer has been increasing in recent years, and the 5-year survival is <20%. HCC and CCA are often accompanied with a dense stroma coupled with infiltrated immune cells, which is referred to as the tumor microenvironment. Populations of specific immune cells, such as high density of CD163+ macrophages and low density of CD8+ T cells, are associated with prognosis and survival rates in both HCC and CCA. Immune cells in the tumor microenvironment can be a therapeutic target for liver cancer treatments. Previous studies have introduced immunotherapy using immune checkpoint inhibitors, pulsed dendritic cells, or transduced T cells, to enhance cytotoxicity of immune cells and inhibit tumor growth. This review summarizes current understanding of the roles of immune cells in primary liver cancer covering HCC and CCA.
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Affiliation(s)
- Linh Pham
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Science and Mathematics, Texas A&M University-Central Texas, Killeen, Texas
| | - Konstantina Kyritsi
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Tianhao Zhou
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Ludovica Ceci
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Leonardo Baiocchi
- Hepatology Unit, Department of Medicine, University of Tor Vergata, Rome, Italy
| | - Lindsey Kennedy
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana
| | - Sanjukta Chakraborty
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, Texas
| | - Shannon Glaser
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, Texas
| | - Heather Francis
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana
| | - Gianfranco Alpini
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana
| | - Keisaku Sato
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
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Jin X, Zhang S, Wang N, Guan L, Shao C, Lin Y, Liu J, Li Y. High Expression of TGF-β1 Contributes to Hepatocellular Carcinoma Prognosis via Regulating Tumor Immunity. Front Oncol 2022; 12:861601. [PMID: 35547872 PMCID: PMC9082360 DOI: 10.3389/fonc.2022.861601] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 03/23/2022] [Indexed: 12/16/2022] Open
Abstract
Background Transforming growth factor-beta (TGF-β) signaling is essential in initialization and progression of hepatocellular carcinoma (HCC). Therefore, a treatment targeting TGF-β pathway may be a promising option for HCC control. Methods First, publicly available RNA-seq datasets and clinical characteristics of 374 HCC patients in The Cancer Genome Atlas (TCGA) database were downloaded. Then, Cox regression analysis and LASSO analysis were used to construct a prognostic model for TGF-β family genes. The area under the curve (AUC) of the risk signature was calculated to evaluate the predictive power of the model. Cox regression analysis was applied to predict whether TGF-β1 can be an independent prognosis factor for HCC. Next, hazard ratio and survival analyses were performed to investigate the correlation between TGF-β1 expression and survival time. Furthermore, differential expression level of TGF-β1 in HCC tissues and cells was determined. In addition, Gene Set Enrichment Analysis (GSEA) identified the top significantly activated and inhibited signal pathways related to high expression of TGF-β1. Finally, the CIBERSORT tool was adopted to correlate the tumor-infiltrating immune cells (TICs) with TGF-β1 expression in HCC cohorts. Results Cox regression analysis and LASSO analysis revealed that seven TGF-β family members (including TGF-β1) could be used as prognostic factors for HCC. Interestingly, TGF-β1 was demonstrated to be an independent prognostic factor of HCC. RT-qPCR and immunofluorescence staining confirmed the high expression of TGF-β1 in HCC cell lines and tissues, which is significantly related to pathological classifications, poor prognosis, and short survival time. Finally, GSEA and CIBERSORT analyses suggested that TGF-β1 may interact with various immune cells and influence the prognosis of HCC patients through Tregs and γδ T cells. Conclusion We established a novel prognostic prediction method to predict the risk scores of TGF-β genes in HCC prognosis. TGF-β1 is highly expressed in HCC cell lines and tissues, correlates to poor prognosis, and thus can be used as a potential biomarker to predict HCC prognosis. We showed that TGF-β1 may play its roles in HCC prognosis by modulating the immune microenvironment of tumor cells. Our data may shed more light on better understanding the role of TGF-β1 in HCC prognosis.
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Affiliation(s)
- Xiuli Jin
- Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang, China
| | - Shuairan Zhang
- Department of Medical Oncology, First Affiliated Hospital of China Medical University, Shenyang, China
| | - Ningning Wang
- Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang, China
| | - Lin Guan
- Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang, China
| | - Chuanli Shao
- Emergency Department, Bengbu First People's Hospital, Bengbu, China
| | - Yingbo Lin
- Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden
| | - Jianping Liu
- Department of Gastroenterology, First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yiling Li
- Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang, China
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Qiu H, Wang N, Lin D, Yuan Y, Li J, Mao D, Meng Y. The positive feedback loop of furin and TGFβ1 enhances the immune responses of Tregs to hepatocellular carcinoma cells and hepatitis B virus in vitro. Cell Biol Int 2022; 46:1215-1226. [PMID: 35349767 DOI: 10.1002/cbin.11806] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 03/14/2022] [Accepted: 03/24/2022] [Indexed: 11/06/2022]
Abstract
Regulatory T cells (Tregs) can exert immunosuppressive activity. Furin can regulate Treg functions, hepatitis B virus (HBV) persistent infection, and hepatocellular carcinoma (HCC) development. However, it remains unknown whether furin can regulate the immune responses of Tregs to HBV and HCC cells. Here, coculture systems of HBV1.3P-HepG2.3P-HepG2 cells and Tregs transduced with or without lentiviral particles that could overexpress furin or knockdown furin/transforming growth factor β1 (TGFβ1) were established to investigate the regulatory relationship between furin and TGFβ1 and the effect of furin/TGFβ1 on Treg activity. Also, the effects of furin overexpression or furin/TGFβ1 knockdown in Tregs on the immunological activity of effector T cells (Teffs)/cytotoxic T lymphocytes (CTLs) and HBV replication/expression were explored in the coculture system of Teff/CTL, Treg, and HBV1.3P-HepG2 cells. Our results showed that furin expression and TGFβ1 secretion were notably increased in Tregs, and Furin and TGFβ1 formed a positive feedback loop to activate Tregs in the coculture system of Tregs and HBV1.3P-HepG2 cells. Furin or TGFβ1 knockdown in Tregs promoted Teff cell proliferation, stimulated interleukin-2 and interferon-γ secretion, and inhibited HBV replication/gene expression in the coculture system of Teff, Treg, and HBV1.3P-HepG2 cells. Moreover, furin or TGFβ1 depletion in Tregs enhanced the killing activity of CTLs against HBV1.3P-HepG2 cells and curbed HBV replication/gene expression in the coculture system of Tregs, CTLs, and HBV1.3P-HepG2 cells. In conclusion, the positive feedback loop of furin and TGFβ1 enhanced the immune responses of Tregs to HCC cells and HBV in vitro.
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Affiliation(s)
- Hua Qiu
- Department of Chinese Medicine (CM), Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Na Wang
- Department of Live Disease, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Dongyi Lin
- Department of Chinese Medicine (CM), Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Ying Yuan
- Department of Chinese Medicine (CM), Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Jinyuan Li
- Department of Chinese Medicine (CM), Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Dewen Mao
- Department of Live Disease, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Yinjie Meng
- Department of Live Disease, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, Guangxi, China
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Vitale C, Marzagalli M, Scaglione S, Dondero A, Bottino C, Castriconi R. Tumor Microenvironment and Hydrogel-Based 3D Cancer Models for In Vitro Testing Immunotherapies. Cancers (Basel) 2022; 14:1013. [PMID: 35205760 PMCID: PMC8870468 DOI: 10.3390/cancers14041013] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 02/12/2022] [Accepted: 02/14/2022] [Indexed: 02/05/2023] Open
Abstract
In recent years, immunotherapy has emerged as a promising novel therapeutic strategy for cancer treatment. In a relevant percentage of patients, however, clinical benefits are lower than expected, pushing researchers to deeply analyze the immune responses against tumors and find more reliable and efficient tools to predict the individual response to therapy. Novel tissue engineering strategies can be adopted to realize in vitro fully humanized matrix-based models, as a compromise between standard two-dimensional (2D) cell cultures and animal tests, which are costly and hardly usable in personalized medicine. In this review, we describe the main mechanisms allowing cancer cells to escape the immune surveillance, which may play a significant role in the failure of immunotherapies. In particular, we discuss the role of the tumor microenvironment (TME) in the establishment of a milieu that greatly favors cancer malignant progression and impact on the interactions with immune cells. Then, we present an overview of the recent in vitro engineered preclinical three-dimensional (3D) models that have been adopted to resemble the interplays between cancer and immune cells and for testing current therapies and immunotherapeutic approaches. Specifically, we focus on 3D hydrogel-based tools based on different types of polymers, discussing the suitability of each of them in reproducing the TME key features based on their intrinsic or tunable characteristics. Finally, we introduce the possibility to combine the 3D models with technological fluid dynamics platforms, reproducing the dynamic complex interactions between tumor cells and immune effectors migrated in situ via the systemic circulation, pointing out the challenges that still have to be overcome for setting more predictive preclinical assays.
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Affiliation(s)
- Chiara Vitale
- Department of Experimental Medicine (DIMES), University of Genova, 16132 Genova, Italy; (C.V.); (A.D.); (R.C.)
| | | | - Silvia Scaglione
- React4life SRL, 16121 Genova, Italy; (M.M.); (S.S.)
- National Research Council of Italy, Institute of Electronics, Information Engineering and Telecommunications (IEIIT), 16149 Genova, Italy
| | - Alessandra Dondero
- Department of Experimental Medicine (DIMES), University of Genova, 16132 Genova, Italy; (C.V.); (A.D.); (R.C.)
| | - Cristina Bottino
- Department of Experimental Medicine (DIMES), University of Genova, 16132 Genova, Italy; (C.V.); (A.D.); (R.C.)
- IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy
| | - Roberta Castriconi
- Department of Experimental Medicine (DIMES), University of Genova, 16132 Genova, Italy; (C.V.); (A.D.); (R.C.)
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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: 100] [Impact Index Per Article: 25.0] [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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Koyama Y, Kawai S, Uenaka N, Okazaki M, Asaoka M, Teraoka S, Ueda AI, Miyahara K, Kawate T, Kaise H, Yamada K, Ishikawa T. Absolute Lymphocyte Count, Platelet-to-Lymphocyte Ratio, and Overall Survival in Eribulin-treated HER2-negative Metastatic Breast Cancer Patients. CANCER DIAGNOSIS & PROGNOSIS 2021; 1:435-441. [PMID: 35403160 PMCID: PMC8962857 DOI: 10.21873/cdp.10058] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Accepted: 09/23/2021] [Indexed: 06/14/2023]
Abstract
BACKGROUND/AIM To investigate the utility of peripheral blood biomarkers - absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) - for predicting outcomes in eribulin-treated patients with metastatic human epidermal growth factor receptor type 2 (HER2)-negative breast cancer. PATIENTS AND METHODS ALC, NLR, and PLR were retrospectively obtained from pre-treatment blood sampling results of 120 patients and stratified according to means. Univariate and multivariate analyses were performed to investigate the association of clinicopathological factors, including these values, with overall survival (OS) and progression-free survival (PFS). RESULTS The ALC, NLR, and PLR cut-off points were 1,285/μl, 3.3, and 235, respectively. No biomarkers were associated with PFS. However, univariate analysis showed ALC (p=0.044) and PLR (p=0.044) to be significantly associated with OS. CONCLUSION ALC and PLR can predict eribulin efficacy in terms of OS, reflecting the antitumour immune response in the microenvironment and indicating eribulin's effectiveness.
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Affiliation(s)
- Yoichi Koyama
- Department of Breast Oncology and Surgery, Tokyo Medical University, Tokyo, Japan
| | - Saori Kawai
- Department of Breast Oncology and Surgery, Tokyo Medical University, Tokyo, Japan
| | - Natsuki Uenaka
- Department of Breast Oncology and Surgery, Tokyo Medical University, Tokyo, Japan
| | - Miki Okazaki
- Department of Breast Oncology and Surgery, Tokyo Medical University, Tokyo, Japan
| | - Mariko Asaoka
- Department of Breast Oncology and Surgery, Tokyo Medical University, Tokyo, Japan
| | - Saeko Teraoka
- Department of Breast Oncology and Surgery, Tokyo Medical University, Tokyo, Japan
| | - A I Ueda
- Department of Breast Oncology and Surgery, Tokyo Medical University, Tokyo, Japan
| | - Kana Miyahara
- Department of Breast Oncology and Surgery, Tokyo Medical University, Tokyo, Japan
| | - Takahiko Kawate
- Department of Breast Oncology and Surgery, Tokyo Medical University, Tokyo, Japan
| | - Hiroshi Kaise
- Department of Breast Oncology and Surgery, Tokyo Medical University, Tokyo, Japan
| | - Kimito Yamada
- Department of Breast Oncology and Surgery, Tokyo Medical University Hachioji Medical Centre, Tokyo, Japan
| | - Takashi Ishikawa
- Department of Breast Oncology and Surgery, Tokyo Medical University, Tokyo, Japan
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Does Neutrophil to Lymphocyte Ratio Have a Role in Identifying Cytokeratin 19-Expressing Hepatocellular Carcinoma? J Pers Med 2021; 11:jpm11111078. [PMID: 34834430 PMCID: PMC8621990 DOI: 10.3390/jpm11111078] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Revised: 10/21/2021] [Accepted: 10/22/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Cytokeratin 19-positive (CK19(+)) hepatocellular carcinomas (HCC) are generally associated with poor prognosis after hepatectomy. It is typically detected from postoperative immunochemistry. We have analyzed several clinically available biomarkers, in particular, neutrophil to lymphocyte ratio (NLR) and aim to develop a panel of biomarkers in identifying CK19 expression in (HCC) preoperatively. METHODS We retrospectively reviewed 36 HCC patients who underwent liver resections during January 2017 to March 2018 in Chang Gung Memorial Hospital. Patients were grouped based on the status of CK19 expression and their baseline characteristics, perioperative and oncologic outcomes were compared. Novel biomarkers including NLR, alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA) and uric acid were analyzed and correlated with CK19 expression. RESULTS NLR is highly associated with CK19 expression. NLR alone gave an AUROC of 0.728 (p-value = 0.043), higher than AFP, CEA or tumor size alone. NLR when combined with AFP, CEA and uric acid, gave an AUROC as high as 0.933 (p-value = 0.004). CONCLUSION The current study demonstrated the predictive capability of NLR in combination with AFP, CEA and uric acid for CK19 expression in HCC patients preoperatively. Further prospective, large-scale studies are warranted to validate our findings.
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28
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DEN-Induced Rat Model Reproduces Key Features of Human Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:cancers13194981. [PMID: 34638465 PMCID: PMC8508319 DOI: 10.3390/cancers13194981] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 09/28/2021] [Accepted: 09/30/2021] [Indexed: 01/15/2023] Open
Abstract
Simple Summary Hepatocellular carcinoma is the most frequent form of primary liver cancer, characterized by increasing incidence and high mortality. Animal models of hepatocellular carcinoma are widely used to study the biology of cancer and to test potential therapies. Herein, we describe how the rat model of DEN-induced hepatocellular carcinoma mimics the pathogenesis of hepatocellular carcinoma seen in humans, including liver damage, chronic inflammation, hepatocytes proliferation, liver fibrosis and cirrhosis, disorganized vasculature, and modulations of the liver’s immune microenvironment. Our results should help the hepatocellular carcinoma field to better tailor the use of the DEN-induced rat liver cancer model for testing specific experimental hypotheses or to perform preclinical testing. Abstract Hepatocellular carcinoma (HCC) is the most common type of liver cancer. The majority of HCC cases are associated with liver fibrosis or cirrhosis developing from chronic liver injuries. The immune system of the liver contributes to the severity of tissue damage, the establishment of fibrosis and the disease’s progression towards HCC. Herein, we provide a detailed characterization of the DEN-induced HCC rat model during fibrosis progression and HCC development with a special focus on the liver’s inflammatory microenvironment. Fischer 344 male rats were treated weekly for 14 weeks with intra-peritoneal injections of 50 mg/kg DEN. The rats were sacrificed before starting DEN-injections at 0 weeks, after 8 weeks, 14 weeks and 20 weeks after the start of DEN-injections. We performed histopathological, immunohistochemical, RT-qPCR, RNA-seq and flow cytometry analysis. Data were compared between tumor and non-tumor samples from the DEN-treated versus untreated rats, as well as versus human HCCs. Chronic DEN injections lead to liver damage, hepatocytes proliferation, liver fibrosis and cirrhosis, disorganized vasculature, and a modulated immune microenvironment that mimics the usual events observed during human HCC development. The RNA-seq results showed that DEN-induced liver tumors in the rat model shared remarkable molecular characteristics with human HCC, especially with HCC associated with high proliferation. In conclusion, our study provides detailed insight into hepatocarcinogenesis in a commonly used model of HCC, facilitating the future use of this model for preclinical testing.
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Bao S, Jiang X, Jin S, Tu P, Lu J. TGF-β1 Induces Immune Escape by Enhancing PD-1 and CTLA-4 Expression on T Lymphocytes in Hepatocellular Carcinoma. Front Oncol 2021; 11:694145. [PMID: 34249750 PMCID: PMC8270637 DOI: 10.3389/fonc.2021.694145] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 06/14/2021] [Indexed: 12/30/2022] Open
Abstract
Primary liver cancer (PLC) is one of the most common types of cancer worldwide. Hepatocellular carcinoma (HCC) accounts for approximately 90% of PLC cases. The HCC microenvironment plays an important role in the occurrence and development of HCC. Immunotherapy for the HCC microenvironment has become an effective treatment strategy. T lymphocytes are an important part of the HCC microenvironment, and programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) are the main immunosuppressive molecules of T lymphocytes. Transforming growth factor β1 (TGF-β1) can inhibit the immune function of T lymphocytes and promote the occurrence and development of tumors. However, few studies have explored whether TGF-β1 can upregulate the expression of PD-1 and CTLA-4 on T cells. In this study, we showed that TGF-β1 upregulated the expression of PD-1 and CTLA-4 on T lymphocytes and attenuated the cytotoxicity of T lymphocytes for HCC cells in vitro and in vivo. In addition, TGF-β1 increased the apoptosis of T lymphocytes induced by HCC cells. Finally, we found that the mechanism by which TGF-β1 upregulates the expression of PD-1 and CTLA-4 on T lymphocytes may be related to the calcineurin-nuclear factor of activated T cells 1 (CaN/NFATc1) pathway. This study will provide some experimental basis for liver cancer immunotherapy based on the tumor microenvironment.
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Affiliation(s)
- Shixiang Bao
- School of Life Sciences, Anhui Medical University, Hefei, China
| | - Xiaopei Jiang
- School of Life Sciences, Anhui Medical University, Hefei, China
| | - Shuai Jin
- School of Life Sciences, Anhui Medical University, Hefei, China
| | - Peipei Tu
- School of Life Sciences, Anhui Medical University, Hefei, China
| | - Jingtao Lu
- School of Life Sciences, Anhui Medical University, Hefei, China
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30
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Liang L, Huang Q, Gan M, Jiang L, Yan H, Lin Z, Zhu H, Wang R, Hu K. High SEC61G expression predicts poor prognosis in patients with Head and Neck Squamous Cell Carcinomas. J Cancer 2021; 12:3887-3899. [PMID: 34093796 PMCID: PMC8176234 DOI: 10.7150/jca.51467] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 04/23/2021] [Indexed: 01/11/2023] Open
Abstract
Background: Overexpression of the membrane protein SEC61 translocon gamma subunit (SEC61G) has been observed in a variety of cancers; however, its role in head and neck squamous cell carcinomas (HNSCC) is unknown. This study aimed to elucidate the relationship between SEC61G and HNSCC based on data from The Cancer Genome Atlas (TCGA) database. Methods: Data for HNSCC patients were collected from TCGA and the expression level of SEC61G was compared between paired HNSCC and normal tissues using the Wilcoxon rank-sum test. The relationship between clinicopathologic features and SEC61G expression was also analyzed using the Wilcoxon rank-sum test and logistic regression. Receiver operating characteristic (ROC) curves were generated to evaluate the value of SEC61G as a binary classifier using the area under the curve (AUC value). The association of clinicopathologic characteristics with prognosis in HNSCC patients was assessed using Cox regression and the Kaplan-Meier methods. A nomogram, based on Cox multivariate analysis, was used to predict the impact of SEC61G on prognosis. Functional enrichment analysis was performed to determine the hallmark pathways associated with differentially expressed genes in HNSCC patients exhibiting high and low SEC61G expression. Results: The expression of SEC61G was significantly elevated in HNSCC tissues compared to normal tissues (P < 0.001). The high expression of SEC61G was significantly correlated with the T stage, M stage, clinical stage, TP53 mutation status, PIK3CA mutation status, primary therapy outcome, and cervical lymph node dissection (all P < 0.05). Meanwhile, ROC curves suggested the significant diagnostic ability of SEC61G for HNSCC (AUC = 0.923). Kaplan-Meier survival analysis showed that patients with HNSCC characterized by high SEC61G expression had a poorer prognosis than patients with low SEC61G expression (hazard ratio = 1.95, 95% confidence interval 1.48-2.56, P < 0.001). Univariate and multivariate analyses revealed that SEC61G was independently associated with overall survival (P = 0.027). Functional annotations indicated that SEC61G is involved in pathways related to translation and regulation of SLITs/ROBOs expression, SRP-dependent co-translational protein targeting to the membrane, nonsense-mediated decay, oxidative phosphorylation, and Parkinson's disease. Conclusion: SEC61G plays a vital role in HNSCC progression and prognosis; it may, therefore, serve as an effective biomarker for the prediction of patient survival.
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Affiliation(s)
- Leifeng Liang
- Department of Oncology, The Sixth Affiliated Hospital of Guangxi Medical University, Yulin, Guangxi, China
| | - Qingwen Huang
- Department of Pathology, The Sixth Affiliated Hospital of Guangxi Medical University, Yulin, Guangxi, China
| | - Mei Gan
- Department of Oncology, The Sixth Affiliated Hospital of Guangxi Medical University, Yulin, Guangxi, China
| | - Liujun Jiang
- Department of Oncology, The Sixth Affiliated Hospital of Guangxi Medical University, Yulin, Guangxi, China
| | - Haolin Yan
- Department of Oncology, The Sixth Affiliated Hospital of Guangxi Medical University, Yulin, Guangxi, China
| | - Zhan Lin
- Department of Oncology, The Sixth Affiliated Hospital of Guangxi Medical University, Yulin, Guangxi, China
| | - Haisheng Zhu
- Department of Oncology, The Sixth Affiliated Hospital of Guangxi Medical University, Yulin, Guangxi, China
| | - Rensheng Wang
- Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Kai Hu
- Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
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Gallage S, García-Beccaria M, Szydlowska M, Rahbari M, Mohr R, Tacke F, Heikenwalder M. The therapeutic landscape of hepatocellular carcinoma. MED 2021; 2:505-552. [PMID: 35590232 DOI: 10.1016/j.medj.2021.03.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 02/23/2021] [Accepted: 03/11/2021] [Indexed: 02/07/2023]
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Profiles of immune cell infiltration in head and neck squamous carcinoma. Biosci Rep 2021; 40:222105. [PMID: 32095823 PMCID: PMC7042147 DOI: 10.1042/bsr20192724] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2019] [Revised: 01/20/2020] [Accepted: 02/12/2020] [Indexed: 12/15/2022] Open
Abstract
Tumor immune infiltration cells (TIICs) are highly heterogeneous, not only in different cancer subtypes but also within different cancer regions. We conducted the Cell-type Identification using Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) method. We assessed the relative proportions of 22 TIICs in HNSC using publicly available TCGA transcriptional datasets, analyzed the proportions of TIICs between HNSC tissues and normal tissues, along with accompanying clinicopathological data, and the impact of TIICs on clinical outcome. After the filter criteria, a total of 395 patients were included in the analysis. We found significant differences in naïve B cells, monocytes, resting mast cells, activated mast cells, CD8+ T cells, and M0 macrophages between HNSC tissues and adjacent non-cancer tissues. We also found that some TIIC subgroups were significantly associated with clinical parameters. Moreover, the patients with low Tregs fraction had worse OS and DFS than those with high Tregs fraction. However, low M0 macrophages fraction was associated with better OS and DFS in HNSC patients. Moreover, Tregs and M0 macrophages are likely to be important determinants of prognosis, which may serve as a potential immunotherapy target for HNSC. Then, we screened the immune-related differentially expressed genes (DEGs), performed the GO and KEGG enrichment analysis, constructed the protein–protein interaction network, and screened the prognosis-related hub genes in HNSC. However, further clinical investigation and basic experiments are needed to validate our results, and uncover the molecular mechanisms interlinking TIICs in HNSC and their roles in prognosis and therapy.
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Qi Z, Liu Y, Mints M, Mullins R, Sample R, Law T, Barrett T, Mazul AL, Jackson RS, Kang SY, Pipkorn P, Parikh AS, Tirosh I, Dougherty J, Puram SV. Single-Cell Deconvolution of Head and Neck Squamous Cell Carcinoma. Cancers (Basel) 2021; 13:1230. [PMID: 33799782 PMCID: PMC7999850 DOI: 10.3390/cancers13061230] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 02/26/2021] [Indexed: 12/24/2022] Open
Abstract
Complexities in cell-type composition have rightfully led to skepticism and caution in the interpretation of bulk transcriptomic analyses. Recent studies have shown that deconvolution algorithms can be utilized to computationally estimate cell-type proportions from the gene expression data of bulk blood samples, but their performance when applied to tumor tissues, including those from head and neck, remains poorly characterized. Here, we use single-cell data (~6000 single cells) collected from 21 head and neck squamous cell carcinoma (HNSCC) samples to generate cell-type-specific gene expression signatures. We leverage bulk RNA-seq data from >500 HNSCC samples profiled by The Cancer Genome Atlas (TCGA), and using single-cell data as a reference, apply two newly developed deconvolution algorithms (CIBERSORTx and MuSiC) to the bulk transcriptome data to quantitatively estimate cell-type proportions for each tumor in TCGA. We show that these two algorithms produce similar estimates of constituent/major cell-type proportions and that a high T-cell fraction correlates with improved survival. By further characterizing T-cell subpopulations, we identify that regulatory T-cells (Tregs) were the major contributor to this improved survival. Lastly, we assessed gene expression, specifically in the Treg population, and found that TNFRSF4 (Tumor Necrosis Factor Receptor Superfamily Member 4) was differentially expressed in the core Treg subpopulation. Moreover, higher TNFRSF4 expression was associated with greater survival, suggesting that TNFRSF4 could play a key role in mechanisms underlying the contribution of Treg in HNSCC outcomes.
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Affiliation(s)
- Zongtai Qi
- Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA; (Z.Q.); (R.M.); (R.S.); (T.L.); (T.B.); (A.L.M.); (R.S.J.); (P.P.)
| | - Yating Liu
- Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA;
| | - Michael Mints
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel; (M.M.); (I.T.)
| | - Riley Mullins
- Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA; (Z.Q.); (R.M.); (R.S.); (T.L.); (T.B.); (A.L.M.); (R.S.J.); (P.P.)
| | - Reilly Sample
- Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA; (Z.Q.); (R.M.); (R.S.); (T.L.); (T.B.); (A.L.M.); (R.S.J.); (P.P.)
- Clinical Research Training Center, Washington University School of Medicine, St Louis, MO 63110, USA
| | - Travis Law
- Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA; (Z.Q.); (R.M.); (R.S.); (T.L.); (T.B.); (A.L.M.); (R.S.J.); (P.P.)
| | - Thomas Barrett
- Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA; (Z.Q.); (R.M.); (R.S.); (T.L.); (T.B.); (A.L.M.); (R.S.J.); (P.P.)
| | - Angela L. Mazul
- Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA; (Z.Q.); (R.M.); (R.S.); (T.L.); (T.B.); (A.L.M.); (R.S.J.); (P.P.)
| | - Ryan S. Jackson
- Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA; (Z.Q.); (R.M.); (R.S.); (T.L.); (T.B.); (A.L.M.); (R.S.J.); (P.P.)
| | - Stephen Y. Kang
- Division of Head and Neck Oncology, Department of Otolaryngology—Head and Neck Surgery, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA; (S.Y.K.); (A.S.P.)
| | - Patrik Pipkorn
- Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA; (Z.Q.); (R.M.); (R.S.); (T.L.); (T.B.); (A.L.M.); (R.S.J.); (P.P.)
| | - Anuraag S. Parikh
- Division of Head and Neck Oncology, Department of Otolaryngology—Head and Neck Surgery, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA; (S.Y.K.); (A.S.P.)
- Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA
- Department of Otolaryngology, Massachusetts Eye and Ear, Boston, MA 02114, USA
| | - Itay Tirosh
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel; (M.M.); (I.T.)
| | - Joseph Dougherty
- Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA; (Z.Q.); (R.M.); (R.S.); (T.L.); (T.B.); (A.L.M.); (R.S.J.); (P.P.)
- Department of Otolaryngology, Harvard Medical School, Boston, MA 02114, USA
| | - Sidharth V. Puram
- Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA; (Z.Q.); (R.M.); (R.S.); (T.L.); (T.B.); (A.L.M.); (R.S.J.); (P.P.)
- Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA;
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Abdel Mouti M, Pauklin S. TGFB1/INHBA Homodimer/Nodal-SMAD2/3 Signaling Network: A Pivotal Molecular Target in PDAC Treatment. Mol Ther 2021; 29:920-936. [PMID: 33429081 PMCID: PMC7934636 DOI: 10.1016/j.ymthe.2021.01.002] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 10/17/2020] [Accepted: 01/02/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer remains a grueling disease that is projected to become the second-deadliest cancer in the next decade. Standard treatment of pancreatic cancer is chemotherapy, which mainly targets the differentiated population of tumor cells; however, it paradoxically sets the roots of tumor relapse by the selective enrichment of intrinsically chemoresistant pancreatic cancer stem cells that are equipped with an indefinite capacity for self-renewal and differentiation, resulting in tumor regeneration and an overall anemic response to chemotherapy. Crosstalk between pancreatic tumor cells and the surrounding stromal microenvironment is also involved in the development of chemoresistance by creating a supportive niche, which enhances the stemness features and tumorigenicity of pancreatic cancer cells. In addition, the desmoplastic nature of the tumor-associated stroma acts as a physical barrier, which limits the intratumoral delivery of chemotherapeutics. In this review, we mainly focus on the transforming growth factor beta 1 (TGFB1)/inhibin subunit beta A (INHBA) homodimer/Nodal-SMAD2/3 signaling network in pancreatic cancer as a pivotal central node that regulates multiple key mechanisms involved in the development of chemoresistance, including enhancement of the stem cell-like properties and tumorigenicity of pancreatic cancer cells, mediating cooperative interactions between pancreatic cancer cells and the surrounding stroma, as well as regulating the deposition of extracellular matrix proteins within the tumor microenvironment.
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Affiliation(s)
- Mai Abdel Mouti
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Headington, University of Oxford, Oxford OX3 7LD, UK
| | - Siim Pauklin
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Headington, University of Oxford, Oxford OX3 7LD, UK.
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Park JH, Kim HY, Lee A, Seo YK, Kim IH, Park ET, Kang MS, Park SJ, Park S. Enlightening the Immune Mechanism of the Abscopal Effect in a Murine HCC Model and Overcoming the Late Resistance With Anti-PD-L1. Int J Radiat Oncol Biol Phys 2020; 110:510-520. [PMID: 33383126 DOI: 10.1016/j.ijrobp.2020.12.031] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 11/27/2020] [Accepted: 12/20/2020] [Indexed: 12/22/2022]
Abstract
PURPOSE The establishment of a preclinical model of the abscopal effect on hepatocellular carcinoma (HCC) and evaluation of whether the hypofractionated radiation therapy (RT) multitumor Hepa1-6 mouse HCC model could be used to suppress nonradiated tumor mass was performed in this study. METHODS AND MATERIALS Hepa1-6 mouse liver cancer cell lines were used to form tumors. Immunogenicity was analyzed using ELISpot and immune cell labeled antibody. Interferon (IFN) β expression was confirmed through polymerase chain reaction. RESULTS After investigation, the intratumoral transcription of type Ⅰ IFN increased by 2-fold. The antitumor immune response to Hepa 1-6 cells induced by radiation was increased. Moreover, the influx of activated CD8+ T cells was increased in nonirradiated tumors. The number of dendritic cells and activation status were evaluated by flow cytometry on the second day after irradiation. Flow cytometry revealed a significantly increased dendritic cell population expressing the CD11c molecule in tumor-draining lymph nodes. Furthermore, because irradiation leads to adaptation of immune resistance of tumor cells against RT, we sought to elucidate a potent tool to overcome the resistance and confirm the ability of PD-L1 antibody to survive late RT resistance. CONCLUSIONS The immunologic mechanism of the abscopal effect was revealed and the application of PD-L1 inhibitor successfully performed as a breakthrough in late RT resistance in the Hepa1-6 tumor model.
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Affiliation(s)
- Jin Hee Park
- Department of Microbiology, College of Medicine, Inje University, Busan, Republic of Korea
| | - Hee Yeon Kim
- Department of Surgery, Busan Paik Hospital, College of Medicine, Inje University, Busan, Republic of Korea
| | - Anbok Lee
- Department of Surgery, Busan Paik Hospital, College of Medicine, Inje University, Busan, Republic of Korea
| | - Young Kyeong Seo
- Department of Internal Medicine, Busan Paik Hospital, College of Medicine, Inje University, Busan, Republic of Korea
| | - Il-Hwan Kim
- Department of Internal Medicine, Haeundae Paik Hospital, College of Medicine, Inje University, Busan, Republic of Korea
| | - Eun-Tae Park
- Department of Radiation Oncology, Busan Paik Hospital, College of Medicine, Inje University, Busan, Republic of Korea
| | - Mi Seon Kang
- Department of Pathology, Busan Paik Hospital, College of Medicine, Inje University, Busan, Republic of Korea
| | - Sung Jae Park
- Department of Internal Medicine, Busan Paik Hospital, College of Medicine, Inje University, Busan, Republic of Korea
| | - SaeGwang Park
- Department of Microbiology, College of Medicine, Inje University, Busan, Republic of Korea.
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Mesaros O, Jimbu L, Neaga A, Popescu C, Berceanu I, Tomuleasa C, Fetica B, Zdrenghea M. Macrophage Polarization in Chronic Lymphocytic Leukemia: Nurse-Like Cells Are the Caretakers of Leukemic Cells. Biomedicines 2020; 8:E516. [PMID: 33228048 PMCID: PMC7699370 DOI: 10.3390/biomedicines8110516] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 11/09/2020] [Accepted: 11/17/2020] [Indexed: 02/07/2023] Open
Abstract
Macrophages are terminally differentiated innate immune cells. Through their activation, they can be polarized towards the pro-inflammatory M1 type or the wound healing-associated, anti-inflammatory M2 type macrophages. In the tumor microenvironment (TME), M2 is the dominant phenotype and these cells are referred to as tumor-associated macrophages (TAMs). TAMs secrete cytokines and chemokines, exerting an antiapoptotic, proliferative and pro-metastatic effect on the tumor cells. TAMs can be found in many cancers, including chronic lymphocytic leukemia (CLL), where they are called nurse-like cells (NLCs). Despite the generally indolent behavior of CLL, the proportion of treatment-refractory patients is significant. As with the majority of cancers, despite significant recent progress, CLL pathogenesis is poorly understood. The emerging role of the TME in nurturing the neoplastic process warrants the investigation of macrophages as a significant pathogenetic element of tumors. In this paper, we review the current knowledge on the role of stromal macrophages in CLL.
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Affiliation(s)
- Oana Mesaros
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 8 Babes str., 400012 Cluj-Napoca, Romania; (L.J.); (A.N.); (C.P.); (C.T.); (M.Z.)
- Department of Hematology, Ion Chiricuta Oncology Institute, 34-36 Republicii Street, 400015 Cluj-Napoca, Romania; (I.B.); (B.F.)
| | - Laura Jimbu
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 8 Babes str., 400012 Cluj-Napoca, Romania; (L.J.); (A.N.); (C.P.); (C.T.); (M.Z.)
- Department of Hematology, Ion Chiricuta Oncology Institute, 34-36 Republicii Street, 400015 Cluj-Napoca, Romania; (I.B.); (B.F.)
| | - Alexandra Neaga
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 8 Babes str., 400012 Cluj-Napoca, Romania; (L.J.); (A.N.); (C.P.); (C.T.); (M.Z.)
| | - Cristian Popescu
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 8 Babes str., 400012 Cluj-Napoca, Romania; (L.J.); (A.N.); (C.P.); (C.T.); (M.Z.)
- Department of Infectious Diseases, County Emergency Hospital Alba Iulia, 20 Decebal str., 510093 Alba-Iulia, Romania
| | - Iulia Berceanu
- Department of Hematology, Ion Chiricuta Oncology Institute, 34-36 Republicii Street, 400015 Cluj-Napoca, Romania; (I.B.); (B.F.)
| | - Ciprian Tomuleasa
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 8 Babes str., 400012 Cluj-Napoca, Romania; (L.J.); (A.N.); (C.P.); (C.T.); (M.Z.)
- Department of Hematology, Ion Chiricuta Oncology Institute, 34-36 Republicii Street, 400015 Cluj-Napoca, Romania; (I.B.); (B.F.)
| | - Bogdan Fetica
- Department of Hematology, Ion Chiricuta Oncology Institute, 34-36 Republicii Street, 400015 Cluj-Napoca, Romania; (I.B.); (B.F.)
| | - Mihnea Zdrenghea
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 8 Babes str., 400012 Cluj-Napoca, Romania; (L.J.); (A.N.); (C.P.); (C.T.); (M.Z.)
- Department of Hematology, Ion Chiricuta Oncology Institute, 34-36 Republicii Street, 400015 Cluj-Napoca, Romania; (I.B.); (B.F.)
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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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Morris AH, Orbach SM, Bushnell GG, Oakes RS, Jeruss JS, Shea LD. Engineered Niches to Analyze Mechanisms of Metastasis and Guide Precision Medicine. Cancer Res 2020; 80:3786-3794. [PMID: 32409307 PMCID: PMC7501202 DOI: 10.1158/0008-5472.can-20-0079] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Revised: 03/04/2020] [Accepted: 05/11/2020] [Indexed: 12/20/2022]
Abstract
Cancer metastasis poses a challenging problem both clinically and scientifically, as the stochastic nature of metastatic lesion formation introduces complexity for both early detection and the study of metastasis in preclinical models. Engineered metastatic niches represent an emerging approach to address this stochasticity by creating bioengineered sites where cancer can preferentially metastasize. As the engineered niche captures the earliest metastatic cells at a nonvital location, both noninvasive and biopsy-based monitoring of these sites can be performed routinely to detect metastasis early and monitor alterations in the forming metastatic niche. The engineered metastatic niche also provides a new platform technology that serves as a tunable site to molecularly dissect metastatic disease mechanisms. Ultimately, linking the engineered niches with advances in sensor development and synthetic biology can provide enabling tools for preclinical cancer models and fosters the potential to impact the future of clinical cancer care.
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Affiliation(s)
- Aaron H Morris
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan
| | - Sophia M Orbach
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan
| | - Grace G Bushnell
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan
- Department of Internal Medicine, Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan
| | - Robert S Oakes
- Fischell Department of Bioengineering, University of Maryland, College Park, Maryland
| | - Jacqueline S Jeruss
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan.
- Department of Surgery, University of Michigan, Ann Arbor, Michigan
| | - Lonnie D Shea
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan.
- Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan
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Can Hematological Inflammatory Parameters Predict Mortality in Hepatocellular Carcinoma? J Gastrointest Cancer 2020; 52:666-675. [PMID: 32617832 DOI: 10.1007/s12029-020-00448-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
PURPOSE Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. Inflammatory and hematological parameters such as neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) provided useful information especially in the diagnosis, treatment, and follow-up of malignancies. In this study, we planned to demonstrate the efficacy of NLR and PLR levels in the evaluation of the prognosis of patients with HCC in our clinic. MATERIAL AND METHODS This study was planned as a prospective observational cohort study. The study included 105 patients with HCC on the base of cirrhosis. Our study group was classified according to Barcelona Clinic Liver Cancer (BCLC), Okuda staging system, and Milan criteria at the time of admission. RESULTS The mean age of all cases was 60.6 ± 12.4 years, and 77 (73.3%) of the patients were male. The mean life expectancy of all patients was 7.7 ± 4.3 months. During 1-year follow-up, 61 (58.1%) HCC patients died. The mean survival of the patients who died was 4.6 ± 3.0 months. In our study, patients with NLR > 2.7, patients with PLR > 100.29, BCLC advanced stage, and Okuda advanced stage, and patients who did not meet the Milan criteria had shorter survival duration. NLR > 2.7, BCLC advanced stage, and Child C were determined as independent risk factors affecting mortality. CONCLUSION There was a strong correlation between NLR-PLR levels and mortality. PLR and NLR levels can be used in conjunction with other staging systems to regulate, monitor, and predict the survival of HCC patients.
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Sachdeva M, Arora SK. Prognostic role of immune cells in hepatocellular carcinoma. EXCLI JOURNAL 2020; 19:718-733. [PMID: 32636725 PMCID: PMC7332804 DOI: 10.17179/excli2020-1455] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 05/22/2020] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC), with rising incidence rates, is the most commonly occurring malignancy of the liver that exerts a heavy disease burden particularly in developing countries. A dynamic cross-talk between immune cells and malignant cells in tumor microenvironment governs the hepatocarcinogenesis. Monitoring immune contexture as prognostic markers is quite relevant and essential to evaluate clinical outcomes and to envisage response to therapy. In this review, we present an overview of the prognostic value of various tumor infiltrating immune cells and the continually evolving immune checkpoints as novel biomarkers during HCC. Tumor infiltration by immune cells such as T cells, NK cells and dendritic cells is linked with improved prognosis and favorable outcome, while the intra-tumoral presence of regulatory T cells (Tregs) or myeloid derived suppressor cells (MDSCs) on the other hand is associated with poor clinical outcome. In addition to these, the overexpression of negative regulatory molecules on tumor cells also provides inhibitory signals to T cells and is associated with poor prognosis. The limitation of a single marker can be overcome by advanced prognostication models and algorithms that evaluate multiple prognostic factors and ultimately aid the clinician in improving the disease free and overall survival of HCC patients.
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Affiliation(s)
- Meenakshi Sachdeva
- Department of Translational & Regenerative Medicine, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Sunil K Arora
- Department of Immunopathology & Department of Translational & Regenerative Medicine, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
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Yu S, Wang Y, Hou J, Li W, Wang X, Xiang L, Tan D, Wang W, Jiang L, Claret FX, Jiao M, Guo H. Tumor-infiltrating immune cells in hepatocellular carcinoma: Tregs is correlated with poor overall survival. PLoS One 2020; 15:e0231003. [PMID: 32240238 PMCID: PMC7117689 DOI: 10.1371/journal.pone.0231003] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Accepted: 03/13/2020] [Indexed: 12/13/2022] Open
Abstract
Systematic interrogation of tumor-infiltrating immune cells (TIICs) is key to the prediction of clinical outcome and development of immunotherapies. However, little is known about the TIICs of hepatocellular carcinoma (HCC) and its impact on the prognosis of patients and potential for immunotherapy. We applied CIBERSORT of 1090 tumors to infer the infiltration of 22 subsets of TIICs using gene expression data. Unsupervised clustering analysis by 22 TIICs revealed 4 clusters of tumors, mainly defined by macrophages and T cells, with distinct prognosis and associations with immune checkpoint molecules, including PD-1, CD274, CTLA-4, LAG-3 and IFNG. We found tumors with decreased number of M1 macrophages or increased regulatory T cells were associated with poor prognosis. Based on the multivariate Cox analysis, a nomogram was also established for clinical application. In conclusion, composition of the TIICs in HCC was quite different, which is an important determinant of prognosis with great potential to identify candidates for immunotherapy.
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Affiliation(s)
- SiZhe Yu
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an, Shaanxi, PR China
| | - Yu Wang
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an, Shaanxi, PR China
- Department of Respirology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi’an, Shaanxi, PR China
| | - Jia Hou
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an, Shaanxi, PR China
| | - WenYuan Li
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an, Shaanxi, PR China
| | - Xiao Wang
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an, Shaanxi, PR China
| | - LuoChengLing Xiang
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an, Shaanxi, PR China
| | - DeLi Tan
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an, Shaanxi, PR China
| | - WenJuan Wang
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an, Shaanxi, PR China
| | - LiLi Jiang
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an, Shaanxi, PR China
| | - Francois X. Claret
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America
| | - Min Jiao
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an, Shaanxi, PR China
- * E-mail: (MJ); (HG)
| | - Hui Guo
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an, Shaanxi, PR China
- Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education of China, Xi’an, Shaanxi, PR China
- * E-mail: (MJ); (HG)
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Ueshima E, Nishiofuku H, Takaki H, Hirata Y, Kodama H, Tanaka T, Kichikawa K, Yamakado K, Okada T, Sofue K, Yamaguchi M, Sugimoto K, Murakami T. Hepatic Artery Embolization Induces the Local Overexpression of Transforming Growth Factor β1 in a Rat Hepatoma Model. Liver Cancer 2020; 9:63-72. [PMID: 32071910 PMCID: PMC7024851 DOI: 10.1159/000502774] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 08/17/2019] [Indexed: 02/04/2023] Open
Abstract
INTRODUCTION The underlying mechanism involved in the recurrence of hepatoma after hepatic arterial embolization (HAE) is not adequately examined. An immunosuppressive cytokine, transforming growth factor β1 (TGF-β1), can lead to tumor progression and is affected by hypoxia in various cancers. The study aimed to assess the effect of HAE on the expression of TGF-β1 in a rat hepatoma model. METHODS Sprague-Dawley rats bearing N1S1 hepatoma cells underwent HAE (HAE group, n = 5) or sham treatment (sham group, n = 4). The animals were euthanized at 48 h, and liver tissues were harvested. Immunohistochemistry (IHC) and quantitative polymerase chain reaction (qPCR) were performed to compare the expression of TGF-β1 and hypoxia-inducible factor 1α (HIF-1α) between the HAE and sham groups. In vitro experiments with the N1S1 cell line were also performed under normoxic (21% O2) or hypoxic (1% O2) conditions for 48 h, and the expression of TGF-β1 and HIF-1α was assessed with western blotting and enzyme-linked immunosorbent assay. Statistical data comparisons were performed by Student t test. RESULTS IHC showed that both the TGF-β1-positive and HIF-1α-positive tumor peripheral areas were larger in the HAE group (6.59 ± 2.49 and 10.26 ± 4.14%; p < 0.001, respectively) than in the sham group (0.34 ± 0.41 and 0.40 ± 0.84% respectively). Similarly, qPCR showed that the mRNA expression levels of TGF-β1 and HIF-1α were higher (1.95 ± 0.38-fold and 1.62 ± 0.37-fold; p < 0.001 and p = 0.002, respectively) in the HAE group than those in the sham group. TGF-β1 expression was suppressed when HIF-1α inhibitors were added (p = 0.001), and HIF-1α expression was upregulated when exogenous TGF-β1 was added (p = 0.033) in N1S1 cells. CONCLUSION HAE enhanced local TGF-β1 expression in a rat hepatoma model. In vitro experiments suggest that HAE-induced hypoxic stress may trigger the interdependent expression of TGF-β1 and HIF-1α.
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Affiliation(s)
- Eisuke Ueshima
- aDepartment of Diagnostic and Interventional Radiology, Kobe University, Kobe, Japan,*Eisuke Ueshima, MD, PhD, Department of Diagnostic and Interventional Radiology, Kobe University Hospital, 7-5-2, Kusunoki-cho, Chuou-ku, Kobe, Hyogo (Japan), E-Mail
| | | | - Haruyuki Takaki
- cDepartment of Radiology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Yutaka Hirata
- dDepartment of Physiology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Hiroshi Kodama
- cDepartment of Radiology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Toshihiro Tanaka
- bDepartment of Radiology, Nara Medical University, Kashihara, Japan
| | | | - Koichiro Yamakado
- cDepartment of Radiology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Takuya Okada
- aDepartment of Diagnostic and Interventional Radiology, Kobe University, Kobe, Japan
| | - Keitaro Sofue
- aDepartment of Diagnostic and Interventional Radiology, Kobe University, Kobe, Japan
| | - Masato Yamaguchi
- aDepartment of Diagnostic and Interventional Radiology, Kobe University, Kobe, Japan
| | - Koji Sugimoto
- aDepartment of Diagnostic and Interventional Radiology, Kobe University, Kobe, Japan
| | - Takamichi Murakami
- aDepartment of Diagnostic and Interventional Radiology, Kobe University, Kobe, Japan
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Guo W, Lu X, Liu Q, Zhang T, Li P, Qiao W, Deng M. Prognostic value of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio for breast cancer patients: An updated meta-analysis of 17079 individuals. Cancer Med 2019; 8:4135-4148. [PMID: 31197958 PMCID: PMC6675722 DOI: 10.1002/cam4.2281] [Citation(s) in RCA: 111] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2019] [Revised: 04/25/2019] [Accepted: 05/10/2019] [Indexed: 12/11/2022] Open
Abstract
Aims This study aimed to evaluate the prognostic effect of neutrophil‐to‐lymphocyte ratio (NLR) and platelet‐to‐lymphocyte ratio (PLR) for patients with breast cancer (BC). Methods A literature search was performed by searching medical databases. Basic characteristics and prognostic data were extracted from included studies. Primary outcomes, such as overall survival (OS) and disease‐free survival (DFS), were synthesized and compared. Subgroup analyses were performed according to pathology, geographical region, cut‐off value, and tumor progression. Results A total of 39 studies comprising 17079 BC patients were included in this meta‐analysis. Among them, 28 studies with 142 64 BC patients investigated predicting role of NLR for OS, showing elevated NLR were associated poor prognosis (hazard ratio [HR]: 1.78, 95% confidence interval [CI]: 1.49‐2.13, P < 0.001). Twenty‐seven studies containing 115 04 patients explored the role of NLR in predicting DFS, showing elevated NLR was associated with poor DFS with HR of 1.60 (95% CI: 1.42‐1.96, P < 0.001). Twelve studies explored the role of PLR in predicting OS, showing patients with higher PLR were associated with a significantly worse prognosis with a pooled HR of 1.32 (95% CI: 1.11‐1.57, P = 0.002). Eleven studies with 5013 patients shown patients with elevated PLR were associated shorter DFS (HR: 1.43, 95% CI: 1.09‐1.86, P = 0.009). Subgroup analyses shown a greater magnitude of association between NLR and OS in triple‐negative BC patients than in HER2‐positive ones. Conclusions Our study suggested that elevated NLR and PLR were associated with poor OS as well as high risk of recurrence for BC patients. Subgroup analyses confirmed the prognostic effect of NLR and PLR in HER2‐positive BC patients. As easily accessible parameters, NLR and PLR should be identified as useful biomarkers in the management of BC.
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Affiliation(s)
- Wanying Guo
- Department of Breast Surgery, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Xin Lu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Qipeng Liu
- Department of Breast Surgery, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Ting Zhang
- Department of Breast Surgery, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Peng Li
- Department of Breast Surgery, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Weiqiang Qiao
- Department of Breast Surgery, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Miao Deng
- Department of Breast Surgery, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
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Recent Insight into the Role of Fibrosis in Nonalcoholic Steatohepatitis-Related Hepatocellular Carcinoma. Int J Mol Sci 2019; 20:ijms20071745. [PMID: 30970564 PMCID: PMC6480228 DOI: 10.3390/ijms20071745] [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: 02/01/2019] [Revised: 03/20/2019] [Accepted: 03/23/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most widespread tumors in the world and its prognosis is poor because of lack of effective treatments. Epidemiological studies show that non-alcoholic steatohepatitis (NASH) and advanced fibrosis represent a relevant risk factors to the HCC development. However little is known of pathophysiological mechanisms linking liver fibrogenesis to HCC in NASH. Recent advances in scientific research allowed to discover some mechanisms that may represent potential therapeutic targets. These include the integrin signaling, hepatic stellate cells (HSCs) activation, Hedgehog signaling and alteration of immune system. In the near future, knowledge of fibrosis-dependent carcinogenic mechanisms, will help optimize antifibrotic therapies as an approach to prevent and treat HCC in patients with NASH and advanced fibrosis.
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Zhang H, Jiang Z, Zhang L. Dual effect of T helper cell 17 (Th17) and regulatory T cell (Treg) in liver pathological process: From occurrence to end stage of disease. Int Immunopharmacol 2019; 69:50-59. [PMID: 30669025 DOI: 10.1016/j.intimp.2019.01.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2018] [Revised: 01/02/2019] [Accepted: 01/04/2019] [Indexed: 02/06/2023]
Abstract
Liver disease is a complicated pathological status with acute or chronic progressions, causing a series of damages to liver and massive burden to public health and society. Th17 and Treg, two subsets of CD4+ T helper cells, seem to keep a subtle balance in the maintenance of organic immune homeostasis including liver. The dysfunction of Th17/Treg balance in liver has been proved associated with hepatic injury and disease. Herein, we summarized the research advance of Th17 and Treg cells in different phenotypes of liver diseases in the past decade. It is known to all that hepatic diseases start from stimulations or infections like virus, autoimmune, alcohol and so on in the early stage, which would cause inflammation. With the disease consistently existed, severe outcomes like cirrhosis and hepatocellular carcinoma appear finally. In conclusion, it is found that Th17 and Treg cells serve as an important role in the immune response imbalance of liver diseases from the beginning to the end stage. However, the effect of these two subsets of CD4+ T helper cells is not a stereotype. Pathological role which exacerbates the disease and protective character which inhibits damage to liver are co-existed in the effect of Th17 and Treg cells. Still, more studies should be carried out to enrich the understandings of liver disease and Th17/Treg immune balance in the future.
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Affiliation(s)
- Haoran Zhang
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China
| | - Zhenzhou Jiang
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China.
| | - Luyong Zhang
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China; Center for Drug Screening and Pharmacodynamics Evaluation, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China.
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Ding W, Xu X, Qian Y, Xue W, Wang Y, Du J, Jin L, Tan Y. Prognostic value of tumor-infiltrating lymphocytes in hepatocellular carcinoma: A meta-analysis. Medicine (Baltimore) 2018; 97:e13301. [PMID: 30557978 PMCID: PMC6320107 DOI: 10.1097/md.0000000000013301] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Accepted: 10/25/2018] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND In patients with hepatocellular carcinoma (HCC), the prognostic role of tumor-infiltrating lymphocytes (TILs) for survival is still controversial. A meta-analysis was performed to investigate the prognostic effect of TILs in HCC. METHODS We identify studies from PubMed, Embase, and the Cochrane Library to evaluate the prognostic value of TILs in patients with HCC. A meta-analysis was conducted to estimate overall survival and disease-free survival. The hazard ratio (HR) and 95% confidence interval (CI) were calculated employing fixed-effect or random-effect models depending on the heterogeneity of the included trials. RESULTS A total of 7905 patients from 46 observational studies were enrolled. For TILs subsets, the density of CD8+, FOXP3+, CD3+, and Granzyme B+ lymphocytes was significantly associated with improved survival (P < .05). The density of FOXP3+ TILs in intratumor (IT) was the most significant prognostic marker (pooled HR = 1.894; 95% CI = 1.659-2.164; P < .001). Patients with high infiltration of CD8+ TILs in IT (pooled HR = 0.676; 95% CI = 0.540-0.845; P = .001) or in margin of tumor (MT) (pooled HR = 0.577; 95% CI = 0.437-0.760; P < .001) had better OS. The pooled analysis revealed that high density of Granzyme B+ T-lymphocytes in IT was statistically significant associated with better OS (pooled HR = 0.621; 95% CI = 0.516-0.748; P < .001) and DFS (pooled HR = 0.678; 95% CI = 0.563-0.815; P < .001). It was interesting that high density of CD3+ in IT foreboded worse OS (pooled HR = 1.008; 95% CI = 1.000-1.015; P = .037), but better DFS (pooled HR = 0.596; 95% CI = 0.374-0.948; P = .029). CONCLUSION Our findings suggested that some TIL subsets could serve as prognostic biomarkers in HCC. High-quality randomized controlled trials are needed to determine if these TILs could serve as targets for immunotherapy in HCC.
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Affiliation(s)
- Wei Ding
- Department of General Surgery, Wujin Hospital Affiliated to Jiangsu University, Changzhou, Jiangsu Province
| | - Xuezhong Xu
- Department of General Surgery, Wujin Hospital Affiliated to Jiangsu University, Changzhou, Jiangsu Province
| | - Yan Qian
- Department of respiration, Changzhou Second People's Hospital Affiliated to Nanjing Medical University, Changzhou, China
| | - Wenbo Xue
- Department of General Surgery, Wujin Hospital Affiliated to Jiangsu University, Changzhou, Jiangsu Province
| | - Yibo Wang
- Department of General Surgery, Wujin Hospital Affiliated to Jiangsu University, Changzhou, Jiangsu Province
| | - Jianguo Du
- Department of General Surgery, Wujin Hospital Affiliated to Jiangsu University, Changzhou, Jiangsu Province
| | - Lei Jin
- Department of General Surgery, Wujin Hospital Affiliated to Jiangsu University, Changzhou, Jiangsu Province
| | - Yulin Tan
- Department of General Surgery, Wujin Hospital Affiliated to Jiangsu University, Changzhou, Jiangsu Province
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Li K, Huang SH, Lao XM, Yang L, Liao GQ, Liang YJ. Interaction of cancer cell-derived Foxp3 and tumor microenvironment in human tongue squamous cell carcinoma. Exp Cell Res 2018; 370:643-652. [PMID: 30040923 DOI: 10.1016/j.yexcr.2018.07.029] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 07/17/2018] [Accepted: 07/18/2018] [Indexed: 02/07/2023]
Abstract
The forkhead transcription factor, Foxp3, has been proved essential for differentiation and activation of regulatory T cells (Tregs). Recently, Foxp3 expression in tumor cells (cancer cell-derived Foxp3) has gained increasing interest, but the function has yet to be confirmed. In the current investigation, we identified the interaction of cancer cell-derived Foxp3 and tumor microenvironment in human tongue squamous cell carcinoma(TSCC) by various in vitro methods. We detected cancer cell-derived Foxp3 was closely associated with the infiltration of Foxp3 + lymphocytes in TSCC lesions using immunohistochemical staining. The cytokines secretion (IFN-γ, TGFβ, IL-2, IL-6, IL-1β, IL-10, IL-8, IL-17, IL-23) of PBMC and differentiation of CD4 +T cells were modulated by the expression of Foxp3 in TSCC, shown by ELISA and flow cytometry. As feedback, increasing TGFβ and decreasing IL-17 further up-regulated cancer cell-derived Foxp3. Furthermore, CHIP on chip assay showed that both TGFβ and IL-17 decreased the number of Foxp3-binding genes in TSCC. GO and pathway analysis suggested that, treated with TGFβ or Th17, Foxp3-binding genes were inclined to the negative regulation of TGFβ signal pathway. Taken together, this study showed cancer cell-derived Foxp3 contributed to Tregs expansion in TSCC microenvironment with positive and negative feedbacks.
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Affiliation(s)
- Kan Li
- Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University，56th Lingyuanxi Road, Guangzhou, Guangdong 510055, China; Guangdong Province Key Laboratory of Stomatology, No. 74, 2nd Zhongshan Road, Guangzhou 510080, Guangdong, China
| | - Si-Hui Huang
- Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University，56th Lingyuanxi Road, Guangzhou, Guangdong 510055, China; Guangdong Province Key Laboratory of Stomatology, No. 74, 2nd Zhongshan Road, Guangzhou 510080, Guangdong, China
| | - Xiao-Mei Lao
- Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University，56th Lingyuanxi Road, Guangzhou, Guangdong 510055, China; Guangdong Province Key Laboratory of Stomatology, No. 74, 2nd Zhongshan Road, Guangzhou 510080, Guangdong, China
| | - Le Yang
- Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University，56th Lingyuanxi Road, Guangzhou, Guangdong 510055, China; Guangdong Province Key Laboratory of Stomatology, No. 74, 2nd Zhongshan Road, Guangzhou 510080, Guangdong, China
| | - Gui-Qing Liao
- Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University，56th Lingyuanxi Road, Guangzhou, Guangdong 510055, China; Guangdong Province Key Laboratory of Stomatology, No. 74, 2nd Zhongshan Road, Guangzhou 510080, Guangdong, China.
| | - Yu-Jie Liang
- Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University，56th Lingyuanxi Road, Guangzhou, Guangdong 510055, China; Guangdong Province Key Laboratory of Stomatology, No. 74, 2nd Zhongshan Road, Guangzhou 510080, Guangdong, China.
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Deng X, Luo S, Luo X, Hu M, Ma F, Wang Y, Lai X, Zhou L. Polysaccharides from Chinese Herbal Lycium barbarum Induced Systemic and Local Immune Responses in H22 Tumor-Bearing Mice. J Immunol Res 2018; 2018:3431782. [PMID: 29967800 PMCID: PMC6008830 DOI: 10.1155/2018/3431782] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Revised: 03/18/2018] [Accepted: 03/29/2018] [Indexed: 12/12/2022] Open
Abstract
Lycium barbarum polysaccharide (LBP) is isolated from the fruit of Chinese herbal Lycium barbarum. Previous studies had demonstrated that LBP could inhibit tumor growth and enhance the immunity in mice. However, the effect of LBP on systemic and local immune responses in vivo, especially on phenotypic and functional changes of T cells, is still largely unknown. In the present study, we investigated the effects of LBP on systemic and local T cell-dependent antitumor immune responses in H22 tumor-bearing mice. The results showed that LBP could inhibit the solid tumor growth in mice, but showed little effect on the body weight or spleen index. Furthermore, LBP could maintain high levels of T cells in peripheral blood (PB), tumor draining lymph node (TDLN), and tumor tissue, prevent the increase of Tregs while promote infiltration of CD8+ T cells in tumor tissue, inhibit the production of TGF-β1 and IL-10 in serum, decrease the exhaustion phenotype of T cells, and maintain cytotoxicity of lymphocytes. Taken together, our results demonstrated that LBP simultaneously induced systemic and local immune responses in H22 tumor-bearing mice by alleviating immunosuppression and maintaining antitumor immune responses in mice.
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Affiliation(s)
- Xiangliang Deng
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
- Infinitus Chinese Herbal Immunity Research Centre, Guangzhou 510600, China
- Dongguan Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Dongguan 523000, China
| | - Shuang Luo
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Xia Luo
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Minghua Hu
- Infinitus Chinese Herbal Immunity Research Centre, Guangzhou 510600, China
| | - Fangli Ma
- Infinitus Chinese Herbal Immunity Research Centre, Guangzhou 510600, China
| | - Yuanyuan Wang
- Infinitus Chinese Herbal Immunity Research Centre, Guangzhou 510600, China
| | - Xiaoping Lai
- Dongguan Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Dongguan 523000, China
| | - Lian Zhou
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
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Amicone L, Marchetti A. Microenvironment and tumor cells: two targets for new molecular therapies of hepatocellular carcinoma. Transl Gastroenterol Hepatol 2018; 3:24. [PMID: 29971255 DOI: 10.21037/tgh.2018.04.05] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Accepted: 04/11/2018] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC), is one of the most frequent human cancer and is characterized by a high mortality rate. The aggressiveness appears strictly related to the liver pathological background on which cancer develops. Inflammation and the consequent fibro/cirrhosis, derived from chronic injuries of several origins (viral, toxic and metabolic) and observable in almost all oncological patients, represents the most powerful risk factor for HCC and, at the same time, an important obstacle to the efficacy of systemic therapy. Multiple microenvironmental cues, indeed, play a pivotal role in the pathogenesis, evolution and recurrence of HCC as well as in the resistance to standard therapies observed in most of patients. The identification of altered pathways in cancer cells and of microenvironmental changes, strictly connected in pathogenic feedback loop, may permit to plan new therapeutic approaches targeting tumor cells and their permissive microenvironment, simultaneously.
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Affiliation(s)
- Laura Amicone
- Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy
| | - Alessandra Marchetti
- Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy
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50
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Peng L, Yuan XQ, Zhang CY, Ye F, Zhou HF, Li WL, Liu ZY, Zhang YQ, Pan X, Li GC. High TGF-β1 expression predicts poor disease prognosis in hepatocellular carcinoma patients. Oncotarget 2018; 8:34387-34397. [PMID: 28415739 PMCID: PMC5470976 DOI: 10.18632/oncotarget.16166] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Accepted: 03/04/2017] [Indexed: 12/16/2022] Open
Abstract
Transforming growth factor beta (TGF-β) promotes the pathogenesis of hepatocellular carcinoma (HCC). We evaluated the associations between TGF-β1 expression and clinicopathological parameters in HCC patients from The Cancer Genome Atlas (TCGA), as well as the prognostic power of TGF-β1 expression. Eligible studies were retrieved from several databases, and effects (hazard ratios (HRs) with 95% confidence intervals (CIs)) for overall survival (OS), disease-free survival (DFS), recurrence-free survival (RFS), metastasis-free survival (MFS), and progression-free survival (PFS) were pooled to assess the prognostic ability of TGF-β1 expression in HCC patients. Twelve qualified articles and our TCGA data comprising 2,021 HCC patients were incorporated. In the TCGA analysis, HCC patients with higher TGF-β1 expression presented a shorter OS than those with lower TGF-β1 expression (HR = 1.42, p < 0.05). In the meta-analysis, univariate analyses showed that HCC patients with higher TGF-β1 expression had a shorter OS (pooling HR = 1.71, p < 0.01) and DFS/RFS/MFS/PFS (pooling HR = 1.60, p < 0.01) than those with lower TGF-β1 expression. In conclusion, our results suggested that high TGF-β1 expression promotes a poor prognosis in HCC patients.
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Affiliation(s)
- Li Peng
- Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and the Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Xiangya Hospital, Central South University, Changsha 410078, P.R. China.,Cancer Research Institute, Central South University, Changsha 410078, P.R. China
| | - Xiao-Qing Yuan
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, P.R. China.,Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, P.R. China
| | - Chao-Yang Zhang
- Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and the Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Xiangya Hospital, Central South University, Changsha 410078, P.R. China.,Cancer Research Institute, Central South University, Changsha 410078, P.R. China
| | - Fei Ye
- Department of Cardiology, the Third Xiangya Hospital, Central South University, Changsha 410100, P.R. China
| | - Hui-Fang Zhou
- Department of Physiology, Changsha Health Vocational College, Changsha 410100, P.R. China
| | - Wen-Ling Li
- Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and the Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Xiangya Hospital, Central South University, Changsha 410078, P.R. China.,Cancer Research Institute, Central South University, Changsha 410078, P.R. China
| | - Zhao-Yang Liu
- Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and the Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Xiangya Hospital, Central South University, Changsha 410078, P.R. China.,Cancer Research Institute, Central South University, Changsha 410078, P.R. China
| | - Ya-Qin Zhang
- Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and the Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Xiangya Hospital, Central South University, Changsha 410078, P.R. China.,Cancer Research Institute, Central South University, Changsha 410078, P.R. China
| | - Xi Pan
- Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and the Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Xiangya Hospital, Central South University, Changsha 410078, P.R. China.,Cancer Research Institute, Central South University, Changsha 410078, P.R. China.,Department of Oncology, the third Xiangya Hospital, Central South University, Changsha 410013, P.R. China
| | - Guan-Cheng Li
- Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and the Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Xiangya Hospital, Central South University, Changsha 410078, P.R. China.,Cancer Research Institute, Central South University, Changsha 410078, P.R. China
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