|
1
|
Miao Y, Ge J, Zheng L, Liu G. Bioinspired Membrane-Based Cancer Vaccines for Immunotherapy: Progress and Perspectives. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2025:e2412679. [PMID: 40255117 DOI: 10.1002/smll.202412679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 03/25/2025] [Indexed: 04/22/2025]
Abstract
Cancer vaccines hold promise for tumor immunotherapy, with their success hinging on effective systems to boost anti-tumor immunity. Biological membranes are not only a delivery vehicle but also a source of antigens and adjuvants, garnering growing interest in vaccine research. This review starts with an introduction to the composition and mechanisms of cancer vaccines and describes the sources, advantages/disadvantages, engineering strategies, and applications of these membrane-based platforms for cancer vaccine development. This review also offers a critical analysis and discusses the further direction of the vaccine platform in view of clinical translation for tumor immunotherapy.
Collapse
Affiliation(s)
- Yanyu Miao
- State Key Laboratory of Vaccines for Infectious Diseases, Center for Molecular Imaging and Translational Medicine, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, Fujian Engineering Research Center of Molecular Theranostic Technology, School of Public Health, Xiamen University, Xiamen, 361102, China
| | - Jianlin Ge
- State Key Laboratory of Vaccines for Infectious Diseases, Center for Molecular Imaging and Translational Medicine, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, Fujian Engineering Research Center of Molecular Theranostic Technology, School of Public Health, Xiamen University, Xiamen, 361102, China
| | - Longyi Zheng
- School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Gang Liu
- State Key Laboratory of Vaccines for Infectious Diseases, Center for Molecular Imaging and Translational Medicine, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, Fujian Engineering Research Center of Molecular Theranostic Technology, School of Public Health, Xiamen University, Xiamen, 361102, China
| |
Collapse
|
|
2
|
Galasso L, Cerrito L, Maccauro V, Termite F, Ainora ME, Gasbarrini A, Zocco MA. Hepatocellular Carcinoma and the Multifaceted Relationship with Its Microenvironment: Attacking the Hepatocellular Carcinoma Defensive Fortress. Cancers (Basel) 2024; 16:1837. [PMID: 38791916 PMCID: PMC11119751 DOI: 10.3390/cancers16101837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 04/30/2024] [Accepted: 05/07/2024] [Indexed: 05/26/2024] Open
Abstract
Hepatocellular carcinoma is a malignant tumor that originates from hepatocytes in an inflammatory substrate due to different degrees of liver fibrosis up to cirrhosis. In recent years, there has been growing interest in the role played by the complex interrelationship between hepatocellular carcinoma and its microenvironment, capable of influencing tumourigenesis, neoplastic growth, and its progression or even inhibition. The microenvironment is made up of an intricate network of mesenchymal cells, immune system cells, extracellular matrix, and growth factors, as well as proinflammatory cytokines and translocated bacterial products coming from the intestinal microenvironment via the enterohepatic circulation. The aim of this paper is to review the role of the HCC microenvironment and describe the possible implications in the choice of the most appropriate therapeutic scheme in the prediction of tumor response or resistance to currently applied treatments and in the possible development of future therapeutic perspectives, in order to circumvent resistance and break down the tumor's defensive fort.
Collapse
Affiliation(s)
- Linda Galasso
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy (L.C.); (V.M.); (A.G.)
| | - Lucia Cerrito
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy (L.C.); (V.M.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Valeria Maccauro
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy (L.C.); (V.M.); (A.G.)
| | - Fabrizio Termite
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy (L.C.); (V.M.); (A.G.)
| | - Maria Elena Ainora
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy (L.C.); (V.M.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy (L.C.); (V.M.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Maria Assunta Zocco
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy (L.C.); (V.M.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| |
Collapse
|
|
3
|
Monaci S, Coppola F, Filippi I, Falsini A, Carraro F, Naldini A. Targeting hypoxia signaling pathways in angiogenesis. Front Physiol 2024; 15:1408750. [PMID: 38725568 PMCID: PMC11079266 DOI: 10.3389/fphys.2024.1408750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 04/10/2024] [Indexed: 05/12/2024] Open
Abstract
Oxygen (O2) supply is constantly maintained by the vascular network for a proper tissue oxygenation. Hypoxia is the result of an increased O2 demand and/or decreased supply and is common in both physiological conditions and human diseases. Angiogenesis is one of the adaptive responses to hypoxia and is mainly regulated by the hypoxia-inducible factors, HIFs. These heterodimeric transcription factors are composed of one of three O2-dependent α subunits (HIF-1, HIF-2, and HIF-3) and a constitutively expressed O2-insensitive subunit (HIF-1β). Among them HIF-1α is the most characterized and its activity is tightly controlled. Under hypoxia, its intracellular accumulation triggers the transcription of several genes, involved in cell survival/proliferation, autophagy, apoptosis, cell metabolism, and angiogenesis. HIF pathway is also modulated by specific microRNAs (miRNAs), thus resulting in the variation of several cellular responses, including alteration of the angiogenic process. The pro-angiogenic activity of HIF-1α is not restricted to endothelial cells, as it also affects the behavior of other cell types, including tumor and inflammatory/immune cells. In this context, exosomes play a crucial role in cell-cell communication by transferring bio-active cargos such as mRNAs, miRNAs, and proteins (e.g., VEGFA mRNA, miR210, HIF-1α). This minireview will provide a synopsis of the multiple factors able to modulate hypoxia-induced angiogenesis especially in the tumor microenvironment context. Targeting hypoxia signaling pathways by up-to-date approaches may be relevant in the design of therapeutic strategies in those pathologies where angiogenesis is dysregulated.
Collapse
Affiliation(s)
- Sara Monaci
- Cellular and Molecular Physiology Unit, Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
| | - Federica Coppola
- Cellular and Molecular Physiology Unit, Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
| | - Irene Filippi
- Cellular and Molecular Physiology Unit, Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
| | - Alessandro Falsini
- Cellular and Molecular Physiology Unit, Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
| | - Fabio Carraro
- Department of Medical Biotechnologies, University of Siena, Siena, Italy
| | - Antonella Naldini
- Cellular and Molecular Physiology Unit, Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
| |
Collapse
|
|
4
|
Kim E. Tumor Immune Microenvironment as a New Therapeutic Target for Hepatocellular Carcinoma Development. Dev Reprod 2023; 27:167-174. [PMID: 38292233 PMCID: PMC10824567 DOI: 10.12717/dr.2023.27.4.167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 10/15/2023] [Accepted: 11/18/2023] [Indexed: 02/01/2024]
Abstract
Development of hepatocellular carcinoma (HCC) is driven by a multistep and long-term process. Because current therapeutic strategies are limited for HCC patients, there are increasing demands for understanding of immunotherapy, which has made technological and conceptual innovations in the treatment of cancer. Here, I discuss HCC immunotherapy in the view of interaction between liver resident cells and immune cells.
Collapse
Affiliation(s)
- Eunjeong Kim
- BK21 FOUR KNU Creative BioResearch Group, School of Life
Sciences, Kyungpook National University, Daegu
41566, Korea
| |
Collapse
|
|
5
|
Identification of Anoikis-Related Subgroups and Prognosis Model in Liver Hepatocellular Carcinoma. Int J Mol Sci 2023; 24:ijms24032862. [PMID: 36769187 PMCID: PMC9918018 DOI: 10.3390/ijms24032862] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 12/10/2022] [Accepted: 12/17/2022] [Indexed: 02/05/2023] Open
Abstract
Resistance to anoikis is a key characteristic of many cancer cells, promoting cell survival. However, the mechanism of anoikis in hepatocellular carcinoma (HCC) remains unknown. In this study, we applied differentially expressed overlapping anoikis-related genes to classify The Cancer Genome Atlas (TCGA) samples using an unsupervised cluster algorithm. Then, we employed weighted gene coexpression network analysis (WGCNA) to identify highly correlated genes and constructed a prognostic risk model based on univariate Cox proportional hazards regression. This model was validated using external datasets from the International Cancer Genome Consortium (ICGC) and Gene Expression Omnibus (GEO). Finally, we used a CIBERSORT algorithm to investigate the correlation between risk score and immune infiltration. Our results showed that the TCGA cohorts could be divided into two subgroups, with subgroup A having a lower survival probability. Five genes (BAK1, SPP1, BSG, PBK and DAP3) were identified as anoikis-related prognostic genes. Moreover, the prognostic risk model effectively predicted overall survival, which was validated using ICGC and GEO datasets. In addition, there was a strong correlation between infiltrating immune cells and prognostic genes and risk score. In conclusion, we identified anoikis-related subgroups and prognostic genes in HCC, which could be significant for understanding the molecular mechanisms and treatment of HCC.
Collapse
|
|
6
|
Khanam A, Kottilil S. New Therapeutics for HCC: Does Tumor Immune Microenvironment Matter? Int J Mol Sci 2022; 24:ijms24010437. [PMID: 36613878 PMCID: PMC9820509 DOI: 10.3390/ijms24010437] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 12/21/2022] [Accepted: 12/22/2022] [Indexed: 12/28/2022] Open
Abstract
The incidence of liver cancer is continuously rising where hepatocellular carcinoma (HCC) remains the most common form of liver cancer accounting for approximately 80-90% of the cases. HCC is strongly prejudiced by the tumor microenvironment and being an inflammation-associated condition, the contribution of various immune mechanisms is critical in its development, progression, and metastasis. The tumor immune microenvironment is initially inflammatory which is subsequently replenished by the immunosuppressive cells contributing to tumor immune escape. Regardless of substantial advancement in systemic therapy, HCC has poor prognosis and outcomes attributed to the drug resistance, recurrence, and its metastatic behavior. Therefore, currently, new immunotherapeutic strategies are extensively targeted in preclinical and clinical settings in order to elicit robust HCC-specific immune responses and appear to be quite effective, extending current treatment alternatives. Understanding the complex interplay between the tumor and the immune cells and its microenvironment will provide new insights into designing novel immunotherapeutics to overcome existing treatment hurdles. In this review, we have provided a recent update on immunological mechanisms associated with HCC and discussed potential advancement in immunotherapies for HCC treatment.
Collapse
|
|
7
|
Liu T, Yuan Z, Wang H, Wang J, Xue L. Peroxisome-related genes in hepatocellular carcinoma correlated with tumor metabolism and overall survival. Clin Res Hepatol Gastroenterol 2022; 46:101835. [PMID: 34798303 DOI: 10.1016/j.clinre.2021.101835] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 10/30/2021] [Accepted: 11/10/2021] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIM A prominent hallmark of tumors is aberrant lipid metabolism, and various peroxisome-related genes (PRGs) are associated with aberrant tumoral metabolic signaling. However, the influence of PRGs on the prognosis of hepatocellular carcinoma (HCC) patients remains debatable. Thus, the current study was designed to evaluate the effect of PRGs on HCC and construct a prognostic model for predicting survival. METHODS We initially acquired HCC-related gene expression profiles from the Cancer Genome Atlas and International Cancer Genome Consortium databases. We then utilized Cox analysis and Lasso regression to identify suitable PRGs for the risk model. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted to clarify the functional roles of PRGs. Single-sample gene set enrichment analysis (ssGSEA) was conducted to confirm the relationship between PRGs and immunity. RESULTS Four PRGs were correlated with HCC patient survival: 2 risk genes (MPV17, and ABCD1) and 2 protective genes (ACSL1 and ACSL6). We derived risk scores based on PRGs to construct a predictive model that could accurately predict overall survival (OS) among HCC patients. Furthermore, GO and KEGG analyses revealed that these PRGs were potentially involved in lipid metabolism and ferroptosis in HCC. Moreover, ssGSEA results demonstrated that high PRG scores were associated with immune suppressor activation, which caused the suppression of immune effectors (CD8+ T-cells, B cells, and NK cells) and the attenuation of the immune-mediated antitumor effect. CONCLUSION PRGs act as key regulators in tumorigenesis and tumor progression by affecting lipid synthesis and utilization, which we used to predict the outcome of HCC patients. Moreover, PRGs have been shown to promote tumoral immune resistance by serving as a vital bridge between metabolism and immunity. Thus, a personalized treatment approach targeting PRGs would clinically benefit patients by blocking the interaction between tumor metabolism and immunity.
Collapse
Affiliation(s)
- Tong Liu
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Haidian District, 49 Huayuan North Road, Beijing 100191, China
| | - Zhuhui Yuan
- Department of Radiation Oncology, Peking University Third Hospital, Haidian District, 49 Huayuan North Road, Beijing, China
| | - Hao Wang
- Department of Radiation Oncology, Peking University Third Hospital, Haidian District, 49 Huayuan North Road, Beijing, China
| | - Junjie Wang
- Department of Radiation Oncology, Peking University Third Hospital, Haidian District, 49 Huayuan North Road, Beijing, China.
| | - Lixiang Xue
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Haidian District, 49 Huayuan North Road, Beijing 100191, China; Biobank, Peking University Third Hospital, Haidian District, 49 Huayuan North Road, Beijing 100191, China.
| |
Collapse
|
|
8
|
Costante F, Airola C, Santopaolo F, Gasbarrini A, Pompili M, Ponziani FR. Immunotherapy for nonalcoholic fatty liver disease-related hepatocellular carcinoma: Lights and shadows. World J Gastrointest Oncol 2022; 14:1622-1636. [PMID: 36187401 PMCID: PMC9516656 DOI: 10.4251/wjgo.v14.i9.1622] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 05/05/2022] [Accepted: 07/05/2022] [Indexed: 02/05/2023] Open
Abstract
About one-fourth of adults globally suffer from nonalcoholic fatty liver disease (NAFLD), which is becoming a leading cause of chronic liver disease worldwide. Its prevalence has rapidly increased in recent years, and is projected to increase even more. NAFLD is a leading cause of hepatocellular carcinoma (HCC), the sixth-most prevalent cancer worldwide and the fourth most common cause of cancer-related death. Although the molecular basis of HCC onset in NAFLD is not completely known, inflammation is a key player. The tumor microenvironment (TME) is heterogeneous in patients with HCC, and is characterized by complex interactions between immune system cells, tumor cells and other stromal and resident liver cells. The etiology of liver disease plays a role in controlling the TME and modulating the immune response. Markers of immune suppression in the TME are associated with a poor prognosis in several solid tumors. Immunotherapy with immune checkpoint inhibitors (ICIs) has become the main option for treating cancers, including HCC. However, meta-analyses have shown that patients with NAFLD-related HCC are less likely to benefit from therapy based on ICIs alone. Conversely, the addition of an angiogenesis inhibitor showed better results regarding the objective response rate and progression-free survival. Adjunctive diagnostic and therapeutic strategies, such as the application of novel biomarkers and the modulation of gut microbiota, should be considered in the future to guide personalized medicine and improve the response to ICIs in patients with NAFLD-related HCC.
Collapse
Affiliation(s)
- Federico Costante
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma 00168, Italy
| | - Carlo Airola
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma 00168, Italy
| | - Francesco Santopaolo
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma 00168, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma 00168, Italy
- Catholic University, Largo Francesco Vito 1, 00168 Roma, Italy
| | - Maurizio Pompili
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma 00168, Italy
- Catholic University, Largo Francesco Vito 1, 00168 Roma, Italy
| | - Francesca Romana Ponziani
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma 00168, Italy
- Catholic University, Largo Francesco Vito 1, 00168 Roma, Italy
| |
Collapse
|
|
9
|
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.
Collapse
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
| |
Collapse
|
|
10
|
Subtil B, Cambi A, Tauriello DVF, de Vries IJM. The Therapeutic Potential of Tackling Tumor-Induced Dendritic Cell Dysfunction in Colorectal Cancer. Front Immunol 2021; 12:724883. [PMID: 34691029 PMCID: PMC8527179 DOI: 10.3389/fimmu.2021.724883] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 09/14/2021] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is the third most diagnosed malignancy and the second leading cause of cancer-related deaths worldwide. Locally advanced and metastatic disease exhibit resistance to therapy and are prone to recurrence. Despite significant advances in standard of care and targeted (immuno)therapies, the treatment effects in metastatic CRC patients have been modest. Untreatable cancer metastasis accounts for poor prognosis and most CRC deaths. The generation of a strong immunosuppressive tumor microenvironment (TME) by CRC constitutes a major hurdle for tumor clearance by the immune system. Dendritic cells (DCs), often impaired in the TME, play a critical role in the initiation and amplification of anti-tumor immune responses. Evidence suggests that tumor-mediated DC dysfunction is decisive for tumor growth and metastasis initiation, as well as for the success of immunotherapies. Unravelling and understanding the complex crosstalk between CRC and DCs holds promise for identifying key mechanisms involved in tumor progression and spread that can be exploited for therapy. The main goal of this review is to provide an overview of the current knowledge on the impact of CRC-driven immunosuppression on DCs phenotype and functionality, and its significance for disease progression, patient prognosis, and treatment response. Moreover, present knowledge gaps will be highlighted as promising opportunities to further understand and therapeutically target DC dysfunction in CRC. Given the complexity and heterogeneity of CRC, future research will benefit from the use of patient-derived material and the development of in vitro organoid-based co-culture systems to model and study DCs within the CRC TME.
Collapse
Affiliation(s)
- Beatriz Subtil
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - Alessandra Cambi
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - Daniele V. F. Tauriello
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - I. Jolanda M. de Vries
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| |
Collapse
|
|
11
|
Zheng X, Jin W, Wang S, Ding H. Progression on the Roles and Mechanisms of Tumor-Infiltrating T Lymphocytes in Patients With Hepatocellular Carcinoma. Front Immunol 2021; 12:729705. [PMID: 34566989 PMCID: PMC8462294 DOI: 10.3389/fimmu.2021.729705] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 08/17/2021] [Indexed: 12/20/2022] Open
Abstract
Primary liver cancer (PLC) is one of the most common malignancies in China, where it ranks second in mortality and fifth in morbidity. Currently, liver transplantation, hepatic tumor resection, radiofrequency ablation, and molecular-targeted agents are the major treatments for hepatocellular carcinoma (HCC). Overall, HCC has a poor survival rate and a high recurrence rate. Tumor-infiltrating lymphocytes (TILs) have been discovered to play essential roles in the development, prognosis, and immunotherapy treatment of HCC. As the major component cells of TILs, T cells are also proved to show antitumor and protumor effects in HCC. Foxp3+, CD8+, CD3+, and CD4+ T lymphocytes are the broadly studied subgroups of TILs. This article reviews the roles and mechanisms of different tumor-infiltrating T lymphocyte subtypes in HCC.
Collapse
Affiliation(s)
- Xiaoqin Zheng
- Department of Gastrointestinal and Hepatology, Beijing You’An Hospital, Capital Medical University, Beijing, China
| | - Wenjie Jin
- Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland
- Institute of Microbiology, Eidgenössische Technische Hochschule (ETH) Zürich, Zurich, Switzerland
| | - Shanshan Wang
- Beijing Institute of Hepatology, Beijing You’An Hospital, Capital Medical University, Beijing, China
| | - Huiguo Ding
- Department of Gastrointestinal and Hepatology, Beijing You’An Hospital, Capital Medical University, Beijing, China
| |
Collapse
|
|
12
|
Borgia M, Dal Bo M, Toffoli G. Role of Virus-Related Chronic Inflammation and Mechanisms of Cancer Immune-Suppression in Pathogenesis and Progression of Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:cancers13174387. [PMID: 34503196 PMCID: PMC8431318 DOI: 10.3390/cancers13174387] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 08/25/2021] [Accepted: 08/27/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Hepatocellular carcinoma pathogenesis is dependent on a chronic inflammation caused by several factors, including hepatotropic viruses, such as HCV and HBV. This chronic inflammation is established in the context of the immunotolerogenic environment peculiar of the liver, in which the immune system can be stimulated by HCV and HBV viral antigens. This complex interaction can be influenced by direct-acting antiviral drug treatments, capable of (almost totally) rapidly eradicating HCV infection. The influence of anti-viral treatments on HCC pathogenesis and progression remains to be fully clarified. Abstract Hepatocellular carcinoma (HCC) can be classified as a prototypical inflammation-driven cancer that generally arises from a background of liver cirrhosis, but that in the presence of nonalcoholic steatohepatitis (NASH), could develop in the absence of fibrosis or cirrhosis. Tumor-promoting inflammation characterizes HCC pathogenesis, with an epidemiology of the chronic liver disease frequently encompassing hepatitis virus B (HBV) or C (HCV). HCC tumor onset and progression is a serial and heterogeneous process in which intrinsic factors, such as genetic mutations and chromosomal instability, are closely associated with an immunosuppressive tumor microenvironment (TME), which may have features associated with the etiopathogenesis and expression of the viral antigens, which favor the evasion of tumor neoantigens to immune surveillance. With the introduction of direct-acting antiviral (DAA) therapies for HCV infection, sustained virological response (SVR) has become very high, although occurrence of HCC and reactivation of HBV in patients with co-infection, who achieved SVR in short term, have been observed in a significant proportion of treated cases. In this review, we discuss the main molecular and TME features that are responsible for HCC pathogenesis and progression. Peculiar functional aspects that could be related to the presence and treatment of HCV/HBV viral infections are also dealt with.
Collapse
|
|
13
|
Pardee AD, Butterfield LH. Immunotherapy of hepatocellular carcinoma: Unique challenges and clinical opportunities. Oncoimmunology 2021; 1:48-55. [PMID: 22720211 PMCID: PMC3376967 DOI: 10.4161/onci.1.1.18344] [Citation(s) in RCA: 122] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Current therapies for advanced hepatocellular carcinoma (HCC) are marginally effective and exacerbate underlying liver disease. The ability of immunotherapy to elicit nontoxic, systemic, long-lived anti-tumor activity makes it particularly well-suited for use in the setting of HCC. While therapeutic benefit has been achieved in early clinical trials, the efficacy of immune-based therapies is limited by several unique properties of HCC, most notably the inherently tolerogenic character of the liver in both healthy and diseased (chronically-infected or tumor-bearing) states. Therapeutic regimens that both counteract these immunosuppressive mechanisms and amplify tumor-specific immunity are expected to profoundly improve clinical outcomes for HCC patients.
Collapse
Affiliation(s)
- Angela D Pardee
- Department of Medicine; University of Pittsburgh School of Medicine; Pittsburgh, PA USA
| | | |
Collapse
|
|
14
|
Pardee AD, Butterfield LH. Immunotherapy of hepatocellular carcinoma: Unique challenges and clinical opportunities. Oncoimmunology 2021. [PMID: 22720211 DOI: 10.4161/onc-i.1.1.18344] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Current therapies for advanced hepatocellular carcinoma (HCC) are marginally effective and exacerbate underlying liver disease. The ability of immunotherapy to elicit nontoxic, systemic, long-lived anti-tumor activity makes it particularly well-suited for use in the setting of HCC. While therapeutic benefit has been achieved in early clinical trials, the efficacy of immune-based therapies is limited by several unique properties of HCC, most notably the inherently tolerogenic character of the liver in both healthy and diseased (chronically-infected or tumor-bearing) states. Therapeutic regimens that both counteract these immunosuppressive mechanisms and amplify tumor-specific immunity are expected to profoundly improve clinical outcomes for HCC patients.
Collapse
Affiliation(s)
- Angela D Pardee
- Department of Medicine; University of Pittsburgh School of Medicine; Pittsburgh, PA USA
| | | |
Collapse
|
|
15
|
Ruf B, Heinrich B, Greten TF. Immunobiology and immunotherapy of HCC: spotlight on innate and innate-like immune cells. Cell Mol Immunol 2021; 18:112-127. [PMID: 33235387 PMCID: PMC7852696 DOI: 10.1038/s41423-020-00572-w] [Citation(s) in RCA: 206] [Impact Index Per Article: 51.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 09/29/2020] [Indexed: 12/24/2022] Open
Abstract
Immune-based therapies such as immune checkpoint inhibitors have revolutionized the systemic treatment of various cancer types. The therapeutic application of monoclonal antibodies targeting inhibitory pathways such as programmed cell death-1(PD-1)/programmed cell death ligand 1 (PD-L1) and CTLA-4 to cells of the adaptive immune system has recently been shown to generate meaningful improvement in the clinical outcome of hepatocellular carcinoma (HCC). Nevertheless, current immunotherapeutic approaches induce durable responses in only a subset of HCC patients. Since immunologic mechanisms such as chronic inflammation due to chronic viral hepatitis or alcoholic and nonalcoholic fatty liver disease play a crucial role in the initiation, development, and progression of HCC, it is important to understand the underlying mechanisms shaping the unique tumor microenvironment of liver cancer. The liver is an immunologic organ with large populations of innate and innate-like immune cells and is exposed to bacterial, viral, and fungal antigens through the gut-liver axis. Here, we summarize and highlight the role of these cells in liver cancer and propose strategies to therapeutically target them. We also discuss current immunotherapeutic strategies in HCC and outline recent advances in our understanding of how the therapeutic potential of these agents might be enhanced.
Collapse
Affiliation(s)
- Benjamin Ruf
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Centre for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Bernd Heinrich
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Centre for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Tim F Greten
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Centre for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
- NCI CCR Liver Cancer Program, National Institutes of Health, Bethesda, MD, 20892, USA.
| |
Collapse
|
|
16
|
Immunological distinctions between nonalcoholic steatohepatitis and hepatocellular carcinoma. Exp Mol Med 2020; 52:1209-1219. [PMID: 32770081 PMCID: PMC8080649 DOI: 10.1038/s12276-020-0480-3] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 06/09/2020] [Accepted: 06/16/2020] [Indexed: 02/08/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), the most common cause of chronic liver disease, ranges from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH), which is a more aggressive form characterized by hepatocyte injury, inflammation, and fibrosis. Increasing evidence suggests that NASH is a risk factor for hepatocellular carcinoma (HCC), which is the fifth most common cancer worldwide and the second most common cause of cancer-related death. Recent studies support a strong mechanistic link between the NASH microenvironment and HCC development. The liver has a large capacity to remove circulating pathogens and gut-derived microbial compounds. Thus, the liver is a central player in immunoregulation. Altered immune responses are tightly associated with the development of NASH and HCC. The objective of this study was to differentiate the roles of specific immune cell subsets in NASH and HCC pathogenesis. Clarifying the role of specific cells in the immune system in the transition from non-alcoholic fatty liver disease (NAFLD) to liver cancer will help to understand disease progression and may open avenues towards new preventive and therapeutic strategies. NAFLD is the most common chronic liver disease. Growing evidence suggests that its most aggressive form, non-alcoholic steatohepatitis (NASH), can promote the development of liver cancer, the second most common cause of cancer deaths worldwide. Chang-Woo Lee and colleagues at Sungkyunkwan University, Suwon, South Korea review the immunological distinction between NASH and liver cancer, focusing on the levels and activities of six key types of immune system cells. Chronic inflammation mediated by the immune system can create conditions for NAFLD, NASH and liver cancer to develop and worsen.
Collapse
|
|
17
|
Harari A, Graciotti M, Bassani-Sternberg M, Kandalaft LE. Antitumour dendritic cell vaccination in a priming and boosting approach. Nat Rev Drug Discov 2020; 19:635-652. [PMID: 32764681 DOI: 10.1038/s41573-020-0074-8] [Citation(s) in RCA: 189] [Impact Index Per Article: 37.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/19/2020] [Indexed: 02/06/2023]
Abstract
Mobilizing antitumour immunity through vaccination potentially constitutes a powerful anticancer strategy but has not yet provided robust clinical benefits in large patient populations. Although major hurdles still exist, we believe that currently available strategies for vaccines that target dendritic cells or use them to present antitumour antigens could be integrated into existing clinical practice using prime-boost approaches. In the priming phase, these approaches capitalize on either standard treatment modalities to trigger in situ vaccination and release tumour antigens or vaccination with dendritic cells loaded with tumour lysates or patient-specific neoantigens. In a second boost phase, personalized synthetic vaccines specifically boost T cells that were triggered during the priming phase. This immunotherapy approach has been enabled by the substantial recent improvements in dendritic cell vaccines. In this Perspective, we discuss these improvements, highlight how the prime-boost approach can be translated into clinical practice and provide solutions for various anticipated hurdles.
Collapse
Affiliation(s)
- Alexandre Harari
- Center of Experimental Therapeutics, Department of Oncology, University Hospital of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland
| | - Michele Graciotti
- Center of Experimental Therapeutics, Department of Oncology, University Hospital of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland
| | - Michal Bassani-Sternberg
- Center of Experimental Therapeutics, Department of Oncology, University Hospital of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland
| | - Lana E Kandalaft
- Center of Experimental Therapeutics, Department of Oncology, University Hospital of Lausanne, Lausanne, Switzerland. .,Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland.
| |
Collapse
|
|
18
|
Mroweh M, Decaens T, Marche PN, Macek Jilkova Z, Clément F. Modulating the Crosstalk between the Tumor and Its Microenvironment Using RNA Interference: A Treatment Strategy for Hepatocellular Carcinoma. Int J Mol Sci 2020; 21:E5250. [PMID: 32722054 PMCID: PMC7432232 DOI: 10.3390/ijms21155250] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/20/2020] [Accepted: 07/22/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy with one of the highest mortality rates among solid cancers. It develops almost exclusively in the background of chronic liver inflammation, which can be caused by viral hepatitis, chronic alcohol consumption or an unhealthy diet. Chronic inflammation deregulates the innate and adaptive immune responses that contribute to the proliferation, survival and migration of tumor cells. The continuous communication between the tumor and its microenvironment components serves as the overriding force of the tumor against the body's defenses. The importance of this crosstalk between the tumor microenvironment and immune cells in the process of hepatocarcinogenesis has been shown, and therapeutic strategies modulating this communication have improved the outcomes of patients with liver cancer. To target this communication, an RNA interference (RNAi)-based approach can be used, an innovative and promising strategy that can disrupt the crosstalk at the transcriptomic level. Moreover, RNAi offers the advantage of specificity in comparison to the treatments currently used for HCC in clinics. In this review, we will provide the recent data pertaining to the modulation of a tumor and its microenvironment by using RNAi and its potential for therapeutic intervention in HCC.
Collapse
Affiliation(s)
- Mariam Mroweh
- Institute for Advanced Biosciences, Research Center Inserm U 1209/CNRS 5309, 38700 La Tronche, France; (M.M.); (T.D.); (P.N.M.)
- Université Grenoble Alpes, 38000 Grenoble, France
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences I, Lebanese University, Hadath Beirut 6573-14, Lebanon
| | - Thomas Decaens
- Institute for Advanced Biosciences, Research Center Inserm U 1209/CNRS 5309, 38700 La Tronche, France; (M.M.); (T.D.); (P.N.M.)
- Université Grenoble Alpes, 38000 Grenoble, France
- Service d’hépato-Gastroentérologie, Pôle Digidune, CHU Grenoble Alpes, 38700 La Tronche, France
| | - Patrice N Marche
- Institute for Advanced Biosciences, Research Center Inserm U 1209/CNRS 5309, 38700 La Tronche, France; (M.M.); (T.D.); (P.N.M.)
- Université Grenoble Alpes, 38000 Grenoble, France
| | - Zuzana Macek Jilkova
- Institute for Advanced Biosciences, Research Center Inserm U 1209/CNRS 5309, 38700 La Tronche, France; (M.M.); (T.D.); (P.N.M.)
- Université Grenoble Alpes, 38000 Grenoble, France
- Service d’hépato-Gastroentérologie, Pôle Digidune, CHU Grenoble Alpes, 38700 La Tronche, France
| | - Flora Clément
- Institute for Advanced Biosciences, Research Center Inserm U 1209/CNRS 5309, 38700 La Tronche, France; (M.M.); (T.D.); (P.N.M.)
- Université Grenoble Alpes, 38000 Grenoble, France
| |
Collapse
|
|
19
|
Huang H, Fang J, Fan X, Miyata T, Hu X, Zhang L, Zhang L, Cui Y, Liu Z, Wu X. Advances in Molecular Mechanisms for Traditional Chinese Medicine Actions in Regulating Tumor Immune Responses. Front Pharmacol 2020; 11:1009. [PMID: 32733246 PMCID: PMC7360845 DOI: 10.3389/fphar.2020.01009] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Accepted: 06/22/2020] [Indexed: 12/19/2022] Open
Abstract
Traditional Chinese medicine (TCM) has been developed for thousands of years with its various biological activities. The interest in TCM in tumor prevention and treatment is rising with its synergistic effect on tumor cells and tumor immunosuppressive microenvironment (TIM). Characteristic of TCM fits well within the whole system and multi-target cancer treatment. Herein we discuss the underlying mechanisms of TCM actions in TIM via regulating immunosuppressive cells, including restoring the antigen presentation function of dendritic cells, enhancing NK cells-mediated killing activity, restraining the functions of myeloid cell-derived suppressor cells, and inhibiting cancer-associated fibroblasts. TCM also regulates tumor progression through enhancing immune response, preventing immune escape and inducing cell death of tumor cells, which triggers immune response in nearby cells. In addition, we discuss TCM in clinical applications and the advantages and disadvantages of TCM in cancer prevention and treatment, as well as current therapeutic challenges and strategies. It might be helpful for understanding the therapeutic potential of TCM for cancer in clinic.
Collapse
Affiliation(s)
- Han Huang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Jiansong Fang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiude Fan
- Center for Liver Disease Research, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, United States
| | - Tatsunori Miyata
- Center for Liver Disease Research, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, United States
| | - Xiaoyue Hu
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Lihe Zhang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Liangren Zhang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Yimin Cui
- Department of Pharmacy, Peking University First Hospital, Beijing, China
| | - Zhenming Liu
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Xiaoqin Wu
- Center for Liver Disease Research, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, United States
| |
Collapse
|
|
20
|
Liu Y, Zhao JJ, Zhou ZQ, Pan QZ, Zhu Q, Tang Y, Xia JC, Weng DS. IL-37 induces anti-tumor immunity by indirectly promoting dendritic cell recruitment and activation in hepatocellular carcinoma. Cancer Manag Res 2019; 11:6691-6702. [PMID: 31410060 PMCID: PMC6646800 DOI: 10.2147/cmar.s200627] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Accepted: 06/11/2019] [Indexed: 12/15/2022] Open
Abstract
Introduction IL-37 is a cytokine of IL-1 family that plays an important role in innate immunity and inflammation, and has been studied as a tumor suppressor in many cancers. However, it remains unclear whether IL-37 plays a regulatory role in tumor-infiltrating dendritic cells (DCs) in hepatocellular carcinoma (HCC). Materials and methods We evaluated the relationship between IL-37 expression and tumor infiltration by DCs in 155 HCC samples through immunohistochemical analysis and Kaplan–Meier survival analysis. The effects of IL-37 on the anti-tumor activity of DCs were investigated by ELISA, flow cytometry, real-time quantitative PCR, cytotoxicity assays and tumorigenicity assays. Results The expression level of IL-37 in HCC samples was positively correlated with the degree of CD1a+ DCs infiltration. The survival rates of patients with both a high expression of IL-37 and a high infiltration by CD1a+ DCs were significantly higher than those of patients with a low expression of IL-37 and a low infiltration by CD1a+ DCs. In vitro chemotaxis analysis indicated that HCC cells overexpressing IL-37 recruited more DCs by secreting higher levels of specific chemokines (eg, CCL3 and CCL20). In addition, IL-37 indirectly up-regulated the expression of major histocompatibility class II molecules, CD86 and CD40 on DCs by acting on tumor cells; IL-37 also indirectly enhanced the anti-tumor effect of T lymphocytes by stimulating DCs to secrete cytokines such as IL-2, IL-12, IL-12p70, interferon-α (IFN-α) and IFN-γ. Finally, overexpression IL-37 in HCC cells significantly delayed tumor growth and increased recruitment of CD11c+ DCs to tumor tissues was also revealed in vivo mouse model. Conclusion DCs play an important role in IL-37 mediated anti-tumor immune responses in HCC, which may contribute to the development of novel cancer immunotherapeutic strategies.
Collapse
Affiliation(s)
- Yuan Liu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.,Department of Biotherapy, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China
| | - Jing-Jing Zhao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.,Department of Biotherapy, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China
| | - Zi-Qi Zhou
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.,Department of Biotherapy, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China
| | - Qiu-Zhong Pan
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.,Department of Biotherapy, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China
| | - Qian Zhu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.,Department of Biotherapy, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China
| | - Yan Tang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.,Department of Biotherapy, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China
| | - Jian-Chuan Xia
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.,Department of Biotherapy, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China
| | - De-Sheng Weng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.,Department of Biotherapy, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China
| |
Collapse
|
|
21
|
Santos PM, Menk AV, Shi J, Tsung A, Delgoffe GM, Butterfield LH. Tumor-Derived α-Fetoprotein Suppresses Fatty Acid Metabolism and Oxidative Phosphorylation in Dendritic Cells. Cancer Immunol Res 2019; 7:1001-1012. [PMID: 30988028 DOI: 10.1158/2326-6066.cir-18-0513] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Revised: 01/14/2019] [Accepted: 04/09/2019] [Indexed: 11/16/2022]
Abstract
Cellular metabolism supports immune cell function. Here, we identify a reduction in fatty acid synthesis and mitochondrial metabolism in dendritic cells (DC) due to α-fetoprotein (AFP), a protein secreted by hepatocellular cancer (HCC). DCs cultured in the presence of AFP show reduced expression of the metabolic regulatory molecules SREBP-1 and PGC1-α. The negative effect of AFP on mitochondrial metabolism and ATP production was confirmed with observation of reduction in basal oxygen consumption rate (OCR) in DCs exposed to AFP derived from cord blood. More severe reduction in basal OCR was observed in tumor-derived DCs exposed to AFP due to downregulation of cytochrome c oxidase. We also showed reduced expression of PGC1-α in circulating myeloid DCs of patients with HCC and impaired capacity to stimulate antigen-specific effector functions. These data show the negative effects of AFP on DC metabolism. These findings elucidate a mechanism of immune suppression in HCC and may help generate therapeutic approaches to reverse such immunosuppression.
Collapse
Affiliation(s)
- Patricia M Santos
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania.,Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Ashley V Menk
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania.,Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Jian Shi
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania.,Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Allan Tsung
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Greg M Delgoffe
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania.,Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Lisa H Butterfield
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania. .,Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.,Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania.,Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
| |
Collapse
|
|
22
|
Nenu I, Breaban I, Pascalau S, Bora CN, Stefanescu H. The future is now: beyond first line systemic therapy in hepatocellular carcinoma. Transl Cancer Res 2019; 8:S261-S274. [PMID: 35117106 PMCID: PMC8797356 DOI: 10.21037/tcr.2018.11.23] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Accepted: 11/20/2018] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is becoming a worldwide concern due to its rising incidence. Although for the incipient stages there are curative therapies, the advanced disease represents a major provocation for the clinicians. 2008 marked as an important year for the hepatology community with the administration of sorafenib for late stages of HCC. Six years after this major discovery, the multikinase inhibitor still represents an important pillar, the first line treatment for the advanced liver cancer. Lenvatinib may represent a new promising first line strategy, but it is still unavailable in many countries. The last years represented an explosion in the research of HCC. Beyond the first line treatments there are a plethora of new emerging therapies. By far immunotherapy represents the major revolution in oncology. While adoptive immunotherapy is still at the beginning, immune check-point inhibitors bursted in many clinical trials with very encouraging results. This review summarises the major discoveries in the field of HCC with an emphasis on immunotherapy. It also briefly describes the important aspects of primary liver cancer immunology and the major ongoing clinical trials.
Collapse
Affiliation(s)
- Iuliana Nenu
- Regional Institute of Gastroenterology and Hepatology “Octavian Fodor”, Cluj-Napoca, Romania
- Liver Research Club, Cluj-Napoca, Romania
- “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Iulia Breaban
- Regional Institute of Gastroenterology and Hepatology “Octavian Fodor”, Cluj-Napoca, Romania
- Liver Research Club, Cluj-Napoca, Romania
| | - Sorana Pascalau
- Liver Research Club, Cluj-Napoca, Romania
- “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Cristina-Nelida Bora
- Liver Research Club, Cluj-Napoca, Romania
- “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Horia Stefanescu
- Regional Institute of Gastroenterology and Hepatology “Octavian Fodor”, Cluj-Napoca, Romania
- Liver Research Club, Cluj-Napoca, Romania
| |
Collapse
|
|
23
|
Cho Y, Han J, Kim W. Recent Advances and Future Directions in Immunotherapeutics for Hepatocellular Carcinoma. ACTA ACUST UNITED AC 2019. [DOI: 10.17998/jlc.19.1.1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
|
|
24
|
Mantovani S, Oliviero B, Lombardi A, Varchetta S, Mele D, Sangiovanni A, Rossi G, Donadon M, Torzilli G, Soldani C, Porta C, Pedrazzoli P, Chiellino S, Santambrogio R, Opocher E, Maestri M, Bernuzzi S, Rossello A, Clément S, De Vito C, Rubbia-Brandt L, Negro F, Mondelli MU. Deficient Natural Killer Cell NKp30-Mediated Function and Altered NCR3 Splice Variants in Hepatocellular Carcinoma. Hepatology 2019; 69:1165-1179. [PMID: 30153337 DOI: 10.1002/hep.30235] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Accepted: 08/21/2018] [Indexed: 12/13/2022]
Abstract
The activating natural cytotoxicity receptor NKp30 is critical for natural killer (NK) cell function and tumor immune surveillance. The natural cytotoxicity receptor-3 (NCR3) gene is transcribed into several splice variants whose physiological relevance is still incompletely understood. In this study, we investigated the role of NKp30 and its major ligand B7 homolog 6 (B7-H6) in patients with hepatocellular carcinoma (HCC). Peripheral blood NK cell phenotype was skewed toward a defective/exhausted immune profile with decreased frequencies of cells expressing NKp30 and natural killer group 2, member D and an increased proportion of cells expressing T-cell immunoglobulin and mucin-domain containing-3. Moreover, NKp30-positive NK cells had a reduced expression of NCR3 immunostimulatory splice variants and an increased expression of the inhibitory variant in patients with advanced tumor, resulting in deficient NKp30-mediated functionality. Tumor-infiltrating lymphocytes showed a prevalent inhibitory NKp30 isoform profile, consistent with decreased NKp30-mediated function. Of note, there were significant differences in the cytokine milieu between the neoplastic and the surrounding non-neoplastic tissue, which may have further influenced NKp30 function. Exposure of NK cells to B7-H6-expressing HCC cells significantly down-modulated NKp30, that was prevented by small interfering RNA-mediated knockdown, suggesting a role for this ligand in inhibiting NKp30-mediated responses. Interestingly, B7-H6 expression was reduced in HCC tissue and simultaneously augmented as a soluble form in HCC patients, particularly those with advanced staging or larger nodule size. Conclusion: These findings provide evidence in support of a role of NKp30 and its major ligand in HCC development and evolution.
Collapse
Affiliation(s)
- Stefania Mantovani
- Division of Infectious Diseases and Immunology, Department of Medical Sciences and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Barbara Oliviero
- Division of Infectious Diseases and Immunology, Department of Medical Sciences and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Andrea Lombardi
- Department of Internal Medicine and Therapeutics, University of Pavia, Italy.,Division of Clinical Pathology, University Hospitals, Geneva, Switzerland
| | - Stefania Varchetta
- Division of Infectious Diseases and Immunology, Department of Medical Sciences and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Dalila Mele
- Division of Infectious Diseases and Immunology, Department of Medical Sciences and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Angelo Sangiovanni
- CRC "A. M. and A. Migliavacca" Center for Liver Disease, Division of Gastroenterology and Hepatology
| | - Giorgio Rossi
- Liver Transplant Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Matteo Donadon
- Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center, Humanitas University, Milan, Italy
| | - Guido Torzilli
- Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center, Humanitas University, Milan, Italy
| | - Cristiana Soldani
- Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center, Humanitas University, Milan, Italy
| | - Camillo Porta
- Medical Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Paolo Pedrazzoli
- Medical Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Silvia Chiellino
- Medical Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Roberto Santambrogio
- Division of Gastrointestinal Surgery, San Paolo Hospital, University of Milan School of Medicine, Milan, Italy
| | - Enrico Opocher
- Division of Gastrointestinal Surgery, San Paolo Hospital, University of Milan School of Medicine, Milan, Italy
| | - Marcello Maestri
- Department of General Surgery, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Stefano Bernuzzi
- Immunohematological and Transfusional Service and Centre of Transplantation Immunology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | | | - Sophie Clément
- Division of Clinical Pathology, University Hospitals, Geneva, Switzerland
| | - Claudio De Vito
- Division of Clinical Pathology, University Hospitals, Geneva, Switzerland
| | | | - Francesco Negro
- Division of Clinical Pathology, University Hospitals, Geneva, Switzerland.,Division of Gastroenterology and Hepatology, University Hospitals, Geneva, Switzerland
| | - Mario U Mondelli
- Division of Infectious Diseases and Immunology, Department of Medical Sciences and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.,Department of Internal Medicine and Therapeutics, University of Pavia, Italy
| |
Collapse
|
|
25
|
|
|
26
|
Martin Lluesma S, Graciotti M, Chiang CLL, Kandalaft LE. Does the Immunocompetent Status of Cancer Patients Have an Impact on Therapeutic DC Vaccination Strategies? Vaccines (Basel) 2018; 6:E79. [PMID: 30477198 PMCID: PMC6313858 DOI: 10.3390/vaccines6040079] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Revised: 11/09/2018] [Accepted: 11/21/2018] [Indexed: 12/24/2022] Open
Abstract
Although different types of therapeutic vaccines against established cancerous lesions in various indications have been developed since the 1990s, their clinical benefit is still very limited. This observed lack of effectiveness in cancer eradication may be partially due to the often deficient immunocompetent status of cancer patients, which may facilitate tumor development by different mechanisms, including immune evasion. The most frequently used cellular vehicle in clinical trials are dendritic cells (DCs), thanks to their crucial role in initiating and directing immune responses. Viable vaccination options using DCs are available, with a positive toxicity profile. For these reasons, despite their limited therapeutic outcomes, DC vaccination is currently considered an additional immunotherapeutic option that still needs to be further explored. In this review, we propose potential actions aimed at improving DC vaccine efficacy by counteracting the detrimental mechanisms recognized to date and implicated in establishing a poor immunocompetent status in cancer patients.
Collapse
Affiliation(s)
- Silvia Martin Lluesma
- Center of Experimental Therapeutics, Ludwig Center for Cancer Research, Department of Oncology, University of Lausanne, Lausanne 1011, Switzerland.
| | - Michele Graciotti
- Vaccine development laboratory, Ludwig Center for Cancer Research, Lausanne 1011, Switzerland.
| | - Cheryl Lai-Lai Chiang
- Vaccine development laboratory, Ludwig Center for Cancer Research, Lausanne 1011, Switzerland.
| | - Lana E Kandalaft
- Center of Experimental Therapeutics, Ludwig Center for Cancer Research, Department of Oncology, University of Lausanne, Lausanne 1011, Switzerland.
- Vaccine development laboratory, Ludwig Center for Cancer Research, Lausanne 1011, Switzerland.
| |
Collapse
|
|
27
|
Bazhin AV, von Ahn K, Fritz J, Werner J, Karakhanova S. Interferon-α Up-Regulates the Expression of PD-L1 Molecules on Immune Cells Through STAT3 and p38 Signaling. Front Immunol 2018; 9:2129. [PMID: 30356906 PMCID: PMC6190899 DOI: 10.3389/fimmu.2018.02129] [Citation(s) in RCA: 77] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2018] [Accepted: 08/29/2018] [Indexed: 12/11/2022] Open
Abstract
Interferon-α (IFNα) has one of the longest histories of use amongst cytokines in clinical oncology and has been applied for the treatment of many types of cancers. Due to its immune-activating properties, IFNα is also an attractive candidate for combinatory anti-cancer therapies. Despite its extensive use in animal tumor models as well as in several clinical trials, the different mechanisms underlying patient responses and affecting desirable clinical benefits are still under investigation. Here we show that in addition to its immune-activating properties, IFNα induces the expression of a key negative regulator, immunosuppressive PD-L1 molecule, in the majority of the specific immune cell populations, particularly in the dendritic cells (DC). DC can modulate immune responses by a variety of mechanisms, including expression of T-cell regulatory molecules and cytokines. Our results showed that treatment of DC with IFNα-2b led to pronounced up-regulation of surface expression of PD-L1 molecules, increased IL-6 and decreased IL-12 production. Moreover, we present evidence that IFNα-treated DC exhibited a reduced capacity to stimulate interferon-γ production in T cells compared to control DC. This T-cell response after treatment of DC with IFNα was recovered by a pre-treatment with an anti-PD-L1 blocking antibody. Further analyses revealed that IFNα regulated PD-L1 expression through the STAT3 and p38 signaling pathways, since blocking of STAT3 and p38 activation with specific inhibitors prevented PD-L1 up-regulation. Our findings underline the important roles of p38 and STAT3 in the regulation of PD-L1 expression and prove that IFNα induces STAT3/p38-mediated expression of PD-L1 and thereby a reduced stimulatory ability of DC. The augmentation of PD-L1 expression in immune cells through IFNα treatment should be considered by use of IFNα in an anti-cancer therapy.
Collapse
Affiliation(s)
- Alexandr V. Bazhin
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
| | - Katharina von Ahn
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Jasmin Fritz
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Jens Werner
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
| | - Svetlana Karakhanova
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
- Section Surgical Research, University of Heidelberg, Heidelberg, Germany
| |
Collapse
|
|
28
|
Payne KK, Aqbi HF, Butler SE, Graham L, Keim RC, Wan W, Idowu MO, Bear HD, Wang XY, Manjili MH. Gr1 -/low CD11b -/low MHCII + myeloid cells boost T cell anti-tumor efficacy. J Leukoc Biol 2018; 104:1215-1228. [PMID: 29985529 PMCID: PMC6258302 DOI: 10.1002/jlb.5a0717-276rr] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Revised: 06/05/2018] [Accepted: 06/06/2018] [Indexed: 01/04/2023] Open
Abstract
Conventional APCs that express MHC class II (MHCII) and co-stimulatory molecules include dendritic cells (DCs) and macrophages. Beyond these conventional APCs, immune stimulatory cells have been more recently shown to extend to a class of atypical APCs, composed of mast cells, basophils, and eosinophils. Here, we describe a unique type of APC, Gr1-/low CD11b-/low cells with a granularity and size characteristic of myeloid cells and with the ability to present Ag for crosspresentation. These cells constitutively express MHCII and the costimulatory molecules, CD80, CD86, and CD40. They do not express pan markers of myeloid DCs (CD11c), plasmacytoid DCs (Ly6C), or macrophages (F4/80), and their frequency is inversely correlated with myeloid-derived suppressor cells (MDSCs) in tumor-bearing mice. Among splenocytes, they are more abundant than DCs and macrophages, and they exhibit antitumor immune stimulatory function at a steady state without further activation, ex vivo. They are also found within the tumor bed where they retain their immune stimulatory function. Our findings suggest the use of these novel APCs in additional preclinical studies to further investigate their utility in APC-based cancer immunotherapies.
Collapse
Affiliation(s)
- Kyle K Payne
- Department of Microbiology & Immunology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.,Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.,Department of Immunology, Moffitt Cancer Center, Tampa, Florida, USA
| | - Hussein F Aqbi
- Department of Microbiology & Immunology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.,Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Savannah E Butler
- Department of Microbiology & Immunology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.,Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Laura Graham
- Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.,Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Rebecca C Keim
- Department of Microbiology & Immunology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.,Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Wen Wan
- Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.,Department of Biostatistics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Michael O Idowu
- Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.,Department of Pathology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Harry D Bear
- Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.,Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Xiang-Yang Wang
- Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.,Department of Human & Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.,VCU Institute of Molecular Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Masoud H Manjili
- Department of Microbiology & Immunology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.,Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.,VCU Institute of Molecular Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| |
Collapse
|
|
29
|
Renuka, Agnihotri N, Bhatnagar A. Differential ratios of fish/corn oil ameliorated the colon carcinoma in rat by altering intestinal intraepithelial CD8+ T lymphocytes, dendritic cells population and modulating the intracellular cytokines. Biomed Pharmacother 2018; 98:600-608. [DOI: 10.1016/j.biopha.2017.12.041] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2017] [Revised: 12/06/2017] [Accepted: 12/13/2017] [Indexed: 12/30/2022] Open
|
|
30
|
Longo V, Gnoni A, Gardini AC, Pisconti S, Licchetta A, Scartozzi M, Memeo R, Palmieri VO, Aprile G, Santini D, Nardulli P, Silvestris N, Brunetti O. Immunotherapeutic approaches for hepatocellular carcinoma. Oncotarget 2017; 8:33897-33910. [PMID: 28420805 PMCID: PMC5464921 DOI: 10.18632/oncotarget.15406] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Accepted: 02/01/2017] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a cancer with a high mortality rate due to the fact that the diagnosis usually occurs at anadvanced stage. Even in case of curative surgical treatment, recurrence is common. Sorafenib and regorafenib are the only therapeutic agents that have been demonstrated to be effective in advanced HCC, thus novel curative approaches are urgently needed. Recent studies focus on the role of immune system in HCC. In fact, the unique immune response in the liver favors tolerance, which can represent a real challenge for conventional immunotherapy in these patients. Spontaneous immune responses against tumor antigens have been detected, and new immune therapies are under investigation: dendritic cell vaccination, immune-modulator strategy, and immune checkpoint inhibition. In recent years different clinical trials examining the use of immunotherapy to treat HCC have been conducted with initial promising results. This review article will summarize the literature data concerning the potential immunotherapeutic approaches in HCC patients.
Collapse
Affiliation(s)
- Vito Longo
- Medical Oncology Unit, Hospital of Taranto, Taranto, Italy
| | - Antonio Gnoni
- Medical Oncology Unit, Hospital of Gallipoli, Gallipoli, Italy
| | - Andrea Casadei Gardini
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRCCS, Meldola, FC, Italy
| | | | | | - Mario Scartozzi
- Department of Medical Oncology, University of Cagliari, Cagliari, Monserrato, CA, Italy
| | - Riccardo Memeo
- Department of Hepatobiliary Surgery, Ospedale Regionale “F.Miulli”, Strada Pr. Acquaviva - Santeramo, Bari, Italy
| | - Vincenzo Ostilio Palmieri
- Department of Biomedical Sciences and Human Oncology, Clinica Medica “A. Murri”, University of Bari Medical School, Bari, Italy
| | - Giuseppe Aprile
- Department of Oncology, San Bortolo Hospital ULSS 6, Vicenza, Italy
| | - Daniele Santini
- Medical Oncology Unit, University Campus Biomedico, Rome, Italy
| | - Patrizia Nardulli
- Pharmacy Unit, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Bari, Italy
| | - Nicola Silvestris
- Medical Oncology Unit, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Viale Orazio Flacco, Bari, Italy
| | - Oronzo Brunetti
- Medical Oncology Unit, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Viale Orazio Flacco, Bari, Italy
| |
Collapse
|
|
31
|
Fernández A, Pupo A, Mena-Ulecia K, Gonzalez C. Pharmacological Modulation of Proton Channel Hv1 in Cancer Therapy: Future Perspectives. Mol Pharmacol 2016; 90:385-402. [PMID: 27260771 DOI: 10.1124/mol.116.103804] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2016] [Accepted: 06/02/2016] [Indexed: 12/23/2022] Open
Abstract
The pharmacological modulation of the immunosuppressive tumor microenvironment has emerged as a relevant component for cancer therapy. Several approaches aiming to deplete innate and adaptive suppressive populations, to circumvent the impairment in antigen presentation, and to ultimately increase the frequency of activated tumor-specific T cells are currently being explored. In this review, we address the potentiality of targeting the voltage-gated proton channel, Hv1, as a novel strategy to modulate the tumor microenvironment. The function of Hv1 in immune cells such as macrophages, neutrophils, dendritic cells, and T cells has been associated with the maintenance of NADPH oxidase activity and the generation of reactive oxygen species, which are required for the host defense against pathogens. We discuss evidence suggesting that the Hv1 proton channel could also be important for the function of these cells within the tumor microenvironment. Furthermore, as summarized here, tumor cells express Hv1 as a primary mechanism to extrude the increased amount of protons generated metabolically, thus maintaining physiologic values for the intracellular pH. Therefore, because this channel might be relevant for both tumor cells and immune cells supporting tumor growth, the pharmacological inhibition of Hv1 could be an innovative approach for cancer therapy. With that focus, we analyzed the available compounds that inhibit Hv1, highlighted the need to develop better drugs suitable for patients, and commented on the future perspectives of targeting Hv1 in the context of cancer therapy.
Collapse
Affiliation(s)
- Audry Fernández
- Interdisciplinary Center for Neurosciences of Valparaíso, Faculty of Sciences, University of Valparaíso, Chile
| | - Amaury Pupo
- Interdisciplinary Center for Neurosciences of Valparaíso, Faculty of Sciences, University of Valparaíso, Chile
| | - Karel Mena-Ulecia
- Interdisciplinary Center for Neurosciences of Valparaíso, Faculty of Sciences, University of Valparaíso, Chile
| | - Carlos Gonzalez
- Interdisciplinary Center for Neurosciences of Valparaíso, Faculty of Sciences, University of Valparaíso, Chile
| |
Collapse
|
|
32
|
Jin J, Zhu P, Liao Y, Li J, Liao W, He S. Elevated preoperative aspartate aminotransferase to lymphocyte ratio index as an independent prognostic factor for patients with hepatocellular carcinoma after hepatic resection. Oncotarget 2016; 6:19217-27. [PMID: 26057470 PMCID: PMC4662486 DOI: 10.18632/oncotarget.4265] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Accepted: 05/13/2015] [Indexed: 12/15/2022] Open
Abstract
Few studies have elucidated the relationship between preoperative aspartate aminotransferase (AST) to lymphocyte ratio and high incidence of hepatocellular carcinoma (HCC). In search of a simple non-invasive prognostic marker, we investigated the prognostic significance of AST to lymphocyte ratio index (ALRI) in HCC. We reviewed retrospectively clinical parameters of 371 HCC patients who were treated with hepatectomy. Receiver operating characteristic (ROC) curve analysis was performed to determine the cut-off value of preoperative ALRI. The predictive value of preoperative ALRI in HCC was evaluated by univariate and multivariate analyses using Cox proportional hazards regression modeling, and the survival probability of HCC patients was acquired by the Kaplan-Meier plots. In addition, stratified analysis was used to investigate the impact of preoperative ALRI on survival in different HCC subgroups. The results showed that preoperative ALRI was closely correlated with age (p = 0.007), median size (p = 0.004), clinical tumor-node-metastasis (TNM) stage (p < 0.001), and portal vein tumor thrombosis (PVTT) (p < 0.001). Survival analysis indicated that HCC patients with preoperative ALRI > 25.2 have a poorer disease-free survival (DFS) and overall survival (OS) after tumor resection. Multivariate analysis further identified preoperative ALRI > 25.2 (p = 0.002), III-IV of TNM stage (p = 0.011), PVTT (p = 0.035), size of tumor > 5 cm (p < 0.001) as independent risk factors of DFS; and preoperative ALRI > 25.2 (p = 0.001), III-IV of TNM stage (p = 0.005), PVTT (p = 0.012), size of tumor > 5 cm (p < 0.001), recurrence (p < 0.001) as independent prognostic factors for OS in HCC patients. Additionally, preoperative ALRI also showed different prognostic value in various subgroups of HCC. Elevated preoperative ALRI as a noninvasive, simple, and easily assessable parameter is an independent effective predictor of prognosis for patients with HCC.
Collapse
Affiliation(s)
- Junfei Jin
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, People's Republic of China.,Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Pengpeng Zhu
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Yan Liao
- Disease Prevention and Control Center of Guilin, Guilin, Guangxi, People's Republic of China
| | - Jun Li
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Weijia Liao
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, People's Republic of China.,Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Songqing He
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, People's Republic of China.,Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, Guilin Medical University, Guilin, Guangxi, People's Republic of China
| |
Collapse
|
|
33
|
Tagliamonte M, Petrizzo A, Tornesello ML, Ciliberto G, Buonaguro FM, Buonaguro L. Combinatorial immunotherapy strategies for hepatocellular carcinoma. Curr Opin Immunol 2016; 39:103-113. [PMID: 26851637 DOI: 10.1016/j.coi.2016.01.005] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Revised: 01/12/2016] [Accepted: 01/12/2016] [Indexed: 12/18/2022]
Abstract
Hepatocellular carcinoma (HCC) is the most common liver malignancy. The prognosis for HCC patients greatly varies according to the stage at diagnosis. Overall it is poor, with a 5-year survival rate of approximately 5-6%. Immunotherapeutic interventions represent a novel and effective therapeutic tool. However, only few immunotherapy trials for HCC have been conducted so far with contrasting results, suggesting that significant improvements are needed. Indeed, the liver is characterized by a strong intrinsic immune suppressive microenvironment which needs to be counterbalanced with immune stimulatory approaches. Therefore, the implementation of combinatorial protocols combining immune stimulatory strategies with specific immunotherapy approaches could result in a dramatic improvement of efficacy and clinical outcome in HCC patients. The present review aims at describing the state of the art in immunotherapy strategies for HCC and future perspectives.
Collapse
Affiliation(s)
- Maria Tagliamonte
- Lab of Molecular Biology & Viral Oncology, Dept Experimental Oncology
| | | | | | - Gennaro Ciliberto
- Scientific Direction, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Pascale" - IRCCS, Naples, Italy
| | | | - Luigi Buonaguro
- Lab of Molecular Biology & Viral Oncology, Dept Experimental Oncology.
| |
Collapse
|
|
34
|
Synergistic Effect and Molecular Mechanisms of Traditional Chinese Medicine on Regulating Tumor Microenvironment and Cancer Cells. BIOMED RESEARCH INTERNATIONAL 2016; 2016:1490738. [PMID: 27042656 PMCID: PMC4793102 DOI: 10.1155/2016/1490738] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/25/2015] [Accepted: 01/26/2016] [Indexed: 12/23/2022]
Abstract
The interaction of tumor cells with the microenvironment is like a relationship between the “seeds” and “soil,” which is a hotspot in recent cancer research. Targeting at tumor microenvironment as well as tumor cells has become a new strategy for cancer treatment. Conventional cancer treatments mostly focused on single targets or single mechanism (the seeds or part of the soil); few researches intervened in the whole tumor microenvironment and achieved ideal therapeutic effect as expected. Traditional Chinese medicine displays a broad range of biological effects, and increasing evidence has shown that it may relate with synergistic effect on regulating tumor microenvironment and cancer cells. Based on literature review and our previous studies, we summarize the synergistic effect and the molecular mechanisms of traditional Chinese medicine on regulating tumor microenvironment and cancer cells.
Collapse
|
|
35
|
Legitimo A, Consolini R, Failli A, Orsini G, Spisni R. Dendritic cell defects in the colorectal cancer. Hum Vaccin Immunother 2015; 10:3224-35. [PMID: 25483675 PMCID: PMC4514061 DOI: 10.4161/hv.29857] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) results from the accumulation of both genetic and epigenetic alterations of the genome. However, also the formation of an inflammatory milieu plays a pivotal role in tumor development and progression. Dendritic cells (DCs) play a relevant role in tumor by exerting differential pro-tumorigenic and anti-tumorigenic functions, depending on the local milieu. Quantitative and functional impairments of DCs have been widely observed in several types of cancer, including CRC, representing a tumor-escape mechanism employed by cancer cells to elude host immunosurveillance. Understanding the interactions between DCs and tumors is important for comprehending the mechanisms of tumor immune surveillance and escape, and provides novel approaches to therapy of cancer. This review summarizes updated information on the role of the DCs in colon cancer development and/or progression.
Collapse
Key Words
- APC, antigen presenting cells
- CRC, Colorectal cancer
- CTLA-4, anticytotoxic T-lymphocyte antigen 4
- DCregs, regulatory DCs
- DCs, dendritic cells
- GM-CSF, granulocyte macrophage colony stimulating factor
- HMGB, high mobility group box
- HNSCC, head and neck squamous cell carcinoma
- IFN, interferon
- IL, interleukin
- MDSCs, myeloid-derived suppressor cells
- MHC, major histocompatibility complex
- NK,natural killer
- PAMP, pathogen-associated molecular pattern
- PD-1, programmed death 1
- PRRs, pattern recognition receptors
- TDLNs, draining lymph nodes
- TGF, transforming growth factor
- TIDCs, tumor-infiltrating DCs
- TLR, toll-like receptor
- TNF, tumor necrosis factor
- Th, T helper
- VEGF, vascular endothelial growth factor
- colorectal cancer
- dendritic cells
- immune response
- immunoescape
- mDCs, myeloid dendritic cells
- pDCs, plasmacytoid dendritic cells
- tumor microenvironment
Collapse
Affiliation(s)
- Annalisa Legitimo
- a Department of Clinical and Experimental Medicine ; University of Pisa ; Pisa , Italy
| | | | | | | | | |
Collapse
|
|
36
|
Hong YP, Li ZD, Prasoon P, Zhang Q. Immunotherapy for hepatocellular carcinoma: From basic research to clinical use. World J Hepatol 2015; 7:980-992. [PMID: 25954480 PMCID: PMC4419101 DOI: 10.4254/wjh.v7.i7.980] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 11/10/2014] [Accepted: 02/09/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a common cancer worldwide with a poor prognosis. Few strategies have been proven efficient in HCC treatment, particularly for those patients not indicated for curative resection or transplantation. Immunotherapy has been developed for decades for cancer control and is attaining more attention as a result of encouraging outcomes of new strategies such as chimeric antigen receptor T cells and immune checkpoint blockade. Right at the front of the new era of immunotherapy, we review the immunotherapy in HCC treatment, from basic research to clinical trials, covering anything from immunomodulators, tumor vaccines and adoptive immunotherapy. The mechanisms, efficacy and safety as well as the approach particulars are unveiled to assist readers to gain a concise but extensive understanding of immunotherapy of HCC.
Collapse
|
|
37
|
Momiyama K, Nagai H, Ogino Y, Mukouzu T, Matsui D, Kogame M, Matsui T, Wakui N, Shinohara M, Igarashi Y, Sumino Y. The Importance of Lamivudine Therapy in Liver Cirrhosis Patients Related HBV with Advanced Hepatocellular Carcinoma Receiving Hepatic Arterial Infusion Chemotherapy. ACTA ACUST UNITED AC 2015; 2:112-118. [PMID: 27595062 PMCID: PMC4997933 DOI: 10.2174/2212697x02666150602220735] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2014] [Revised: 04/08/2015] [Accepted: 06/02/2015] [Indexed: 01/11/2023]
Abstract
Purpose: We have previously reported that continuous hepatic arterial infusion chemotherapy (HAIC) might be more effective for advanced hepatocellular carcinoma (aHCC) in patients with liver cirrhosis (LC) related to HCV infection (C-LC) or alcohol abuse (A-LC) than in patients who had LC related to HBV infection (B-LC). The aim of the present study was to retrospectively assess the efficacy of lamivudine therapy for B-LC patients with aHCC undergoing HAIC. Methods: Seventeen adult Japanese B-LC patients with aHCC were treated by HAIC with or without lamivudine (100 mg/day) between 2002 and 2008 at our hospital. Their tumors were inoperable according to computed tomography findings. HAIC (LV at 12 mg/hr, CDDP at 10 mg/hr, and 5-FU at 250 mg/22 hr) was given via the proper hepatic artery every 5 days for 4 weeks using a catheter connected to a subcutaneously implanted drug delivery system. Results: Nine of the 17 patients received lamivudine at a dose of 100 mg/day together with HAIC (LAM group), while 8 patients did not receive lamivudine and only had HAIC (non-LAM group). The response rate was 12.5 in the non-LAM group and 0.0% in the LAM group. However, the survival of the LAM group was better than that of the non-LAM group, although there was no significant difference between them. The median survival time of the LAM and non-LAM groups was 310 and 157 days, respectively. HBV-DNA levels were significantly lower after chemotherapy compared with that before chemotherapy in the LAM group. In the non-LAM group, the percentage of Th2 cells before HAIC and after HAIC was significantly higher than in the control group. However, the percentage of Th2 cells in the LAM group after HAIC was not different from that in the control group, although it was significantly higher in the LAM group than in the control group before chemotherapy. Conclusions: These results indicate that lamivudine therapy may prolong the survival of B-LC patients receiving HAIC for aHCC by reducing HBV-DNA level and inhibiting the increase of Th2 cells in host immunity.
Collapse
Affiliation(s)
- Koichi Momiyama
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, 6-11-1, Omorinishi, Ota-ku, Tokyo, 143-8541, Japan
| | - Hidenari Nagai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, 6-11-1, Omorinishi, Ota-ku, Tokyo, 143-8541, Japan
| | - Yu Ogino
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, 6-11-1, Omorinishi, Ota-ku, Tokyo, 143-8541, Japan
| | - Takanori Mukouzu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, 6-11-1, Omorinishi, Ota-ku, Tokyo, 143-8541, Japan
| | - Daigo Matsui
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, 6-11-1, Omorinishi, Ota-ku, Tokyo, 143-8541, Japan
| | - Michio Kogame
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, 6-11-1, Omorinishi, Ota-ku, Tokyo, 143-8541, Japan
| | - Teppei Matsui
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, 6-11-1, Omorinishi, Ota-ku, Tokyo, 143-8541, Japan
| | - Noritaka Wakui
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, 6-11-1, Omorinishi, Ota-ku, Tokyo, 143-8541, Japan
| | - Mie Shinohara
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, 6-11-1, Omorinishi, Ota-ku, Tokyo, 143-8541, Japan
| | - Yoshinori Igarashi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, 6-11-1, Omorinishi, Ota-ku, Tokyo, 143-8541, Japan
| | - Yasukiyo Sumino
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, 6-11-1, Omorinishi, Ota-ku, Tokyo, 143-8541, Japan
| |
Collapse
|
|
38
|
Pardee AD, Shi J, Butterfield LH. Tumor-derived α-fetoprotein impairs the differentiation and T cell stimulatory activity of human dendritic cells. THE JOURNAL OF IMMUNOLOGY 2014; 193:5723-32. [PMID: 25355916 DOI: 10.4049/jimmunol.1400725] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Several tumor-derived factors have been implicated in dendritic cell (DC) dysfunction in cancer patients. α-fetoprotein (AFP) is an oncofetal Ag that is highly expressed in abnormalities of prenatal development and several epithelial cancers, including hepatocellular carcinoma (HCC). In HCC patients exhibiting high levels of serum AFP, we observed a lower ratio of myeloid/plasmacytoid circulating DCs compared with patients with low serum AFP levels and healthy donors. To test the effect of AFP on DC differentiation in vitro, peripheral blood monocytes from healthy donors were cultured in the presence of cord blood-derived normal AFP (nAFP) or HCC tumor-derived AFP (tAFP), and DC phenotype and function were assessed. Although the nAFP and tAFP isoforms only differ at one carbohydrate group, low (physiological) levels of tAFP, but not nAFP, significantly inhibited DC differentiation. tAFP-conditioned DCs expressed diminished levels of DC maturation markers, retained a monocyte-like morphology, exhibited limited production of inflammatory mediators, and failed to induce robust T cell proliferative responses. Mechanistic studies revealed that the suppressive activity of tAFP is dependent on the presence of low molecular mass (LMM) species that copurify with tAFP and function equivalently to the LMM fractions of both tumor and nontumor cell lysates. These data reveal the unique ability of tAFP to serve as a chaperone protein for LMM molecules, both endogenous and ubiquitous in nature, which function cooperatively to impair DC differentiation and function. Therefore, novel therapeutic approaches that antagonize the regulatory properties of tAFP will be critical to enhance immunity and improve clinical outcomes.
Collapse
Affiliation(s)
- Angela D Pardee
- Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213
| | - Jian Shi
- Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213
| | - Lisa H Butterfield
- Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213
| |
Collapse
|
|
39
|
Huang X, Qin J, Lu S. Kanglaite stimulates anticancer immune responses and inhibits HepG2 cell transplantation‑induced tumor growth. Mol Med Rep 2014; 10:2153-9. [PMID: 25119060 DOI: 10.3892/mmr.2014.2479] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2013] [Accepted: 04/25/2014] [Indexed: 11/05/2022] Open
Abstract
Previous studies revealed that Kanglaite (KLT) exhibits antitumor and immunomodulatory activities. In the present study, we show that KLT treatment stimulated the immune response by increasing the number of T cells and natural killer (NK) cells in the blood of hepatocellular carcinoma (HCC) patients. Experiments in tumor-bearing mice were further designed in order to explore the effects of KLT on the immune system and the underlying molecular mechanisms. The results showed that KLT improves the tumor cell transplantation-induced reduction in the serum level of the cytokines IFN‑γ and IL‑2, and rescues the levels of CD4+ T cells in host mice. These events enhanced the cytotoxic activities of natural killer and CD8+ T cells against the hepatic HepG2 cancer cells. KLT administration further increased the mRNA level of certain nuclear factor κB (NF‑κB)‑responsive genes in CD4+ cells. The chromatin immunoprecipitation assay showed that KLT increases the association of the NF-κB p65 subunit to the promoter regions of interleukin (IL)-2- and B-cell lymphoma (Bcl)-2-encoding genes in CD4+ T cells. Our study demonstrated that KLT is the main active ingredient of coix seed exhibiting anticancer and immunomodulatory properties. Induction of NF-κB‑mediated gene transcription in CD4+ T cells is involved in the immunomodulatory activity of KLT.
Collapse
Affiliation(s)
- Xinli Huang
- Center of Liver Transplantation, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Liver Transplantation, Ministry of Health, Nanjing 210029, P.R. China
| | - Jianjie Qin
- Center of Liver Transplantation, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Liver Transplantation, Ministry of Health, Nanjing 210029, P.R. China
| | - Sen Lu
- Center of Liver Transplantation, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Liver Transplantation, Ministry of Health, Nanjing 210029, P.R. China
| |
Collapse
|
|
40
|
Bruno A, Pagani A, Pulze L, Albini A, Dallaglio K, Noonan DM, Mortara L. Orchestration of angiogenesis by immune cells. Front Oncol 2014; 4:131. [PMID: 25072019 PMCID: PMC4078768 DOI: 10.3389/fonc.2014.00131] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2014] [Accepted: 05/16/2014] [Indexed: 12/20/2022] Open
Abstract
It is widely accepted that the tumor microenvironment (TUMIC) plays a major role in cancer and is indispensable for tumor progression. The TUMIC involves many "players" going well beyond the malignant-transformed cells, including stromal, immune, and endothelial cells (ECs). The non-malignant cells can acquire tumor-promoting functions during carcinogenesis. In particular, these cells can "orchestrate" the "symphony" of the angiogenic switch, permitting the creation of new blood vessels that allows rapid expansion and progression toward malignancy. Considerable attention within the context of tumor angiogenesis should focus not only on the ECs, representing a fundamental unit, but also on immune cells and on the inflammatory tumor infiltrate. Immune cells infiltrating tumors typically show a tumor-induced polarization associated with attenuation of anti-tumor functions and generation of pro-tumor activities, among these angiogenesis. Here, we propose a scenario suggesting that the angiogenic switch is an immune switch arising from the pro-angiogenic polarization of immune cells. This view links immunity, inflammation, and angiogenesis to tumor progression. Here, we review the data in the literature and seek to identify the "conductors" of this "orchestra." We also suggest that interrupting the immune → inflammation → angiogenesis → tumor progression process can delay or prevent tumor insurgence and malignant disease.
Collapse
Affiliation(s)
- Antonino Bruno
- Scientific and Technology Pole, IRCCS MultiMedica , Milan , Italy
| | - Arianna Pagani
- Department of Biotechnology and Life Sciences, University of Insubria , Varese , Italy
| | - Laura Pulze
- Department of Biotechnology and Life Sciences, University of Insubria , Varese , Italy
| | - Adriana Albini
- Department of Research and Statistics, IRCCS Arcispedale Santa Maria Nuova , Reggio Emilia , Italy
| | - Katiuscia Dallaglio
- Department of Research and Statistics, IRCCS Arcispedale Santa Maria Nuova , Reggio Emilia , Italy
| | - Douglas M Noonan
- Scientific and Technology Pole, IRCCS MultiMedica , Milan , Italy ; Department of Biotechnology and Life Sciences, University of Insubria , Varese , Italy
| | - Lorenzo Mortara
- Department of Biotechnology and Life Sciences, University of Insubria , Varese , Italy
| |
Collapse
|
|
41
|
Vogt A, Sievers E, Lukacs-Kornek V, Decker G, Raskopf E, Meumann N, Büning H, Sauerbruch T, Strassburg CP, Schmidt-Wolf IGH, Gonzalez-Carmona MA. Improving immunotherapy of hepatocellular carcinoma (HCC) using dendritic cells (DC) engineered to express IL-12 in vivo. Liver Int 2014; 34:447-61. [PMID: 23998316 DOI: 10.1111/liv.12284] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2013] [Accepted: 07/24/2013] [Indexed: 12/18/2022]
Abstract
BACKGROUND Interleukin 12 (IL-12), one of the most potent Th1-cytokines, has been used to improve dendritic cells (DC)-based immunotherapy of cancer. However, it failed to achieve clinical response in patients with hepatocellular carcinoma (HCC). In this study, improved conditions of immunotherapy with DC engineered to express IL-12 were studied in murine subcutaneous HCC. METHODS Tumour-lysate pulsed DC were transduced with IL-12-encoding adenoviruses or cultivated with recombinant (r)IL-12. DC were injected intratumourally, subcutaneously or intravenously at different stages of tumour-development. RESULTS Dendritic cell overexpressing IL-12 by adenoviruses showed enhanced expression of costimulatory molecules and stronger priming of HCC-specific effector cells than DC cultured with rIL-12. Intratumoural but not systemic injections of IL-12-DC induced the strongest antitumoural effects reaching complete regressions in 75% of early-staged tumours and in 33% of advanced tumours. Importantly, antitumoural effects could be further enhanced through combination with sorafenib. Analysing the tumour-environment, IL-12-DC increased the levels of Th1-cytokines/chemokines and of CD4(+) -, CD8(+) -T- and NK-cells. Induced immunity was tumour-specific and sustained since all tumour-free animals were protected towards hepatic tumour-cell rechallenge. However, IL-12-DC also enhanced immunosuppressive cytokines, regulatory T cells and even myeloid-derived suppressor cells within the tumours. CONCLUSIONS Induced IL-12-overexpression by adenoviral vectors can effectively immunostimulate DC. Intratumoural but not systemic injection of activated IL-12-DC was crucial for effective tumour regression. The mechanism of this approach seems to be the induction of a sufficient Th1 tumour-environment allowing the recruitment of effector cells rather than the inhibition of tumour immunosuppression. Thus, improved immunotherapy with IL-12-DC represents a promising approach towards HCC.
Collapse
Affiliation(s)
- Annabelle Vogt
- Department of Medicine I, University of Bonn, Bonn, Germany
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
42
|
Palombo F, Focaccetti C, Barnaba V. Therapeutic implications of immunogenic cell death in human cancer. Front Immunol 2014; 4:503. [PMID: 24432020 PMCID: PMC3880935 DOI: 10.3389/fimmu.2013.00503] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Accepted: 12/20/2013] [Indexed: 11/15/2022] Open
Abstract
Dendritic cells (DCs) are central to the adoptive immune response, and their function is regulated by diverse signals in a context-specific manner. Different DCs have been described in physiologic conditions, inflammation, and cancer, prompting a series of questions on how adoptive immune responses, or tolerance, develop against tumors. Increasing evidence suggests that tumor treatments induce a dramatic change on tumor-infiltrating lymphocytes and, in particular, on some DC subtypes. In this review, we summarize the latest evidence on the role of DCs in cancer and preliminary evidence on chemotherapy-associated antigens identified in human cancers.
Collapse
Affiliation(s)
- Fabio Palombo
- Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma , Rome , Italy
| | - Chiara Focaccetti
- Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma , Rome , Italy
| | - Vincenzo Barnaba
- Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma , Rome , Italy ; Istituto Pasteur - Fondazione Cenci Bolognetti , Rome , Italy
| |
Collapse
|
|
43
|
Tesone AJ, Svoronos N, Allegrezza MJ, Conejo-Garcia JR. Pathological mobilization and activities of dendritic cells in tumor-bearing hosts: challenges and opportunities for immunotherapy of cancer. Front Immunol 2013; 4:435. [PMID: 24339824 PMCID: PMC3857526 DOI: 10.3389/fimmu.2013.00435] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2013] [Accepted: 11/22/2013] [Indexed: 12/22/2022] Open
Abstract
A common characteristic of solid tumors is the pathological recruitment of immunosuppressive myeloid cells, which in certain tumors includes dendritic cells (DCs). DCs are of particular interest in the field of cancer immunotherapy because they induce potent and highly specific anti-tumor immune responses, particularly in the early phase of tumorigenesis. However, as tumors progress, these cells can be transformed into regulatory cells that contribute to an immunosuppressive microenvironment favoring tumor growth. Therefore, controlling DC phenotype has the potential to elicit effective anti-tumor responses while simultaneously weakening the tumor’s ability to protect itself from immune attack. This review focuses on the dual nature of DCs in the tumor microenvironment, the regulation of DC phenotype, and the prospect of modifying DCs in situ as a novel immunotherapeutic approach.
Collapse
Affiliation(s)
- Amelia J Tesone
- Tumor Microenvironment and Metastasis Program, Wistar Institute , Philadelphia, PA , USA
| | | | | | | |
Collapse
|
|
44
|
Orsini G, Legitimo A, Failli A, Ferrari P, Nicolini A, Spisni R, Miccoli P, Consolini R. Defective generation and maturation of dendritic cells from monocytes in colorectal cancer patients during the course of disease. Int J Mol Sci 2013; 14:22022-41. [PMID: 24213603 PMCID: PMC3856049 DOI: 10.3390/ijms141122022] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2013] [Revised: 10/09/2013] [Accepted: 10/17/2013] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is the second-leading cause of cancer-related deaths in Western countries. Today, the role of the host’s immune system in controlling the progression and spread of solid tumors is broadly established. Tumor immunosurveillance escape mechanisms, such as those involving dendritic cells (DCs), the most important antigen-presenting cells, are likewise recognized processes involved in cancer. The present study evaluates the ability of CRC patients to generate DCs in vitro from circulating monocytes at both pre- and post-operative timepoints; the results are correlated with the stage of disease to shed light on the systemic immune statuses of CRC patients. Our data showed that patients’ DCs had lower co-stimulatory molecule expression and were less able to present antigens to allogeneic T cells compared to healthy controls’ (HC) DCs. Furthermore altered cytokine secretion, such as increased IL-10 and reduced IL-12 and TNF-α, was observed. At the post-operative timepoints we observed a recovery of the patients’ ability to generate immature DCs, compared to HCs, but the maturational capacity remained affected. Our study conclusively highlights the persistently impaired in vitro generation of fully mature and functional DCs, which appears to be more altered during advanced stages. This work sheds light on a dendritic cell-based tumor immune escape mechanism that could be useful for the development of more effective immunotherapeutic strategies.
Collapse
Affiliation(s)
- Giulia Orsini
- Laboratory of Immunology, Department of Clinical and Experimental Medicine, University of Pisa, via Roma, 67, Pisa 56126, Italy; E-Mails: (A.L.); (A.F.); (R.C.)
- Author to whom correspondence should be addressed; E-Mail: or ; Tel.: +39-050-992-222
| | - Annalisa Legitimo
- Laboratory of Immunology, Department of Clinical and Experimental Medicine, University of Pisa, via Roma, 67, Pisa 56126, Italy; E-Mails: (A.L.); (A.F.); (R.C.)
| | - Alessandra Failli
- Laboratory of Immunology, Department of Clinical and Experimental Medicine, University of Pisa, via Roma, 67, Pisa 56126, Italy; E-Mails: (A.L.); (A.F.); (R.C.)
| | - Paola Ferrari
- Department of Clinical and Experimental Medicine, Azienda Ospedaliero-Universitaria Pisana (AOUP), via Roma, 67, Pisa 56126, Italy; E-Mail:
| | - Andrea Nicolini
- Department of Clinical and Experimental Medicine, Section Medical Oncology, University of Pisa, via Roma, 67, Pisa 56126, Italy; E-Mail:
| | - Roberto Spisni
- Department of Surgery, Molecular, Medical and Critical Area Pathology, University of Pisa, via Paradisa, 2, Pisa 56126, Italy; E-Mails: (R.S.) (P.M.)
| | - Paolo Miccoli
- Department of Surgery, Molecular, Medical and Critical Area Pathology, University of Pisa, via Paradisa, 2, Pisa 56126, Italy; E-Mails: (R.S.) (P.M.)
| | - Rita Consolini
- Laboratory of Immunology, Department of Clinical and Experimental Medicine, University of Pisa, via Roma, 67, Pisa 56126, Italy; E-Mails: (A.L.); (A.F.); (R.C.)
| |
Collapse
|
|
45
|
Mossanen JC, Tacke F. Role of lymphocytes in liver cancer. Oncoimmunology 2013; 2:e26468. [PMID: 24498546 PMCID: PMC3906418 DOI: 10.4161/onci.26468] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2013] [Revised: 09/10/2013] [Accepted: 09/11/2013] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) typically occurs in patients with chronic inflammatory liver diseases, such as viral hepatitis or (non-)alcoholic steatohepatitis. Inflammation appears indeed as a crucial factor in hepatocarcinogenesis. Nevertheless, sophisticated animal models and studies of human samples revealed that the HCC also elicits antitumor immune responses. Patrolling and infiltrating lymphocytes (e.g., NKT and T cells, respectively) can exert decisive functions in the transition from chronic hepatic inflammation to cancer as well as in antitumor immune responses. An improved understanding of the cellular and molecular mechanisms whereby inflammation promotes or restricts hepatocarcinogenesis will open new avenues for therapeutic approaches to liver cancer.
Collapse
Affiliation(s)
- Jana C Mossanen
- Department of Medicine III; RWTH-University Hospital Aachen; Aachen, Germany
| | - Frank Tacke
- Department of Medicine III; RWTH-University Hospital Aachen; Aachen, Germany
| |
Collapse
|
|
46
|
Quantification of blood dendritic cells in colorectal cancer patients during the course of disease. Pathol Oncol Res 2013; 20:267-76. [PMID: 24022399 DOI: 10.1007/s12253-013-9691-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2012] [Accepted: 08/30/2013] [Indexed: 01/07/2023]
Abstract
Colorectal cancer is a malignancy with poor prognosis that might be associated with defective immune function. The aim of the present study was to investigate circulating dendritic cells in colorectal cancer patients, in order to contribute to elucidate tumor-escape mechanisms and to point out a possible correlation with the clinical condition of the disease. Therefore, we enumerated ex vivo myeloid and plasmacytoid dendritic cells, through multicolor flow cytometry, in 26 colorectal patients and 33 healthy controls. Furthermore we performed several analyses at determined time points in order to define the immunological trend of cancer patients after surgery and other conventional treatments. At the pre-operative time point the absolute number of plasmacytoid dendritic cells in cancer patients was significantly reduced in comparison to controls, this result being mainly referred to stage III-IV patients. The number of myeloid dendritic cells did not show any significant difference compared to healthy controls; interestingly the expression of the tolerogenic antigen CD85k was significantly higher on cancer patients' myeloid dendritic cells than controls'. At the following samplings, circulating dendritic cell absolute number did not show any difference compared to controls. Conclusively the impairment of the number of circulating dendritic cells may represent one of the tumor escape mechanisms occurring in colorectal cancer. These alterations seem to be correlated to cancer progression. Our work sheds light on one of dendritic cell-based tumor immune escape mechanisms. This knowledge may be useful to the development of more effective immunotherapeutic strategies.
Collapse
|
|
47
|
Wörmann SM, Diakopoulos KN, Lesina M, Algül H. The immune network in pancreatic cancer development and progression. Oncogene 2013; 33:2956-67. [PMID: 23851493 DOI: 10.1038/onc.2013.257] [Citation(s) in RCA: 144] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2012] [Revised: 04/22/2013] [Accepted: 04/22/2013] [Indexed: 02/07/2023]
Abstract
The presence of stromal desmoplasia is a hallmark of spontaneous pancreatic ductal adenocarcinoma, forming a unique microenvironment that comprises many cell types. Only recently, the immune system has entered the pathophysiology of pancreatic ductal adenocarcinoma development. Tumor cells in the pancreas seem to dysbalance the immune system, thus facilitating spontaneous cancer development. This review will try to assemble all relevant data to demonstrate the implications of the immune network on spontaneous cancer development.
Collapse
Affiliation(s)
- S M Wörmann
- Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - K N Diakopoulos
- Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - M Lesina
- Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - H Algül
- Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| |
Collapse
|
|
48
|
Long J, Zhou B, Li H, Dai Q, Zhang B, Xing S, Zeng Z, Chen W, Yang J. Improvement of HBsAg gene-modified dendritic cell-based vaccine efficacy by optimizing immunization method or the application of β-glucosylceramide. Immunol Invest 2013; 42:137-55. [PMID: 23323523 DOI: 10.3109/08820139.2012.744418] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Hepatocellular carcinoma (HCC) in China is mostly Hepatitis B virus infection related. The antitumor efficacy of HBsAg gene-modified dendritic cells (DC) has been widely tested both in vitro and in vivo. In this study, we analyzed whether adenoviral vector mediated HBsAg expression would alter cell surface phenotype or autologous T cell stimulating function of mature DCs. Further, the anti-tumor efficacy of pAd-HBsAg-DC-based vaccine was evaluated in mice bearing HBsAg expressing HCC. We also tested whether β-glucosylceramide (β-GC) would enhance the anti-tumor activity of pAd-HBsAg-DC. Results revealed that pAd-HBsAg-DC expressed and secreted HBsAg, while maintaining phenotypic characteristics of mature DCs. Vaccination with pAd-HBsAg-DC conferred specific therapeutic antitumor immunity to animal model bearing HBsAg expressing HCC. The application of β-GC activated mice hepatic NKT cells and enhanced the antitumor activity of pAd-HBsAg-DC. Most importantly, in vivo results showed that the inhibiting effect of pAd-HBsAg-DC vaccination on tumor growth was more significant when applied before tumor inoculation, suggesting that genetically modified DC based therapeutic cancer vaccine may achieve the most optimized antitumor effect when applied before tumor onset, and β-GC may serve as a potent innate immune enhancer for augmenting the antitumor effect of pAd-HBsAg-DC vaccine.
Collapse
Affiliation(s)
- Jianting Long
- Department of Medicinal Oncology, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, PR China
| | | | | | | | | | | | | | | | | |
Collapse
|
|
49
|
Shu G, Yang T, Wang C, Su H, Xiang M. Gastrodin stimulates anticancer immune response and represses transplanted H22 hepatic ascitic tumor cell growth: Involvement of NF-κB signaling activation in CD4+ T cells. Toxicol Appl Pharmacol 2013; 269:270-9. [PMID: 23578476 DOI: 10.1016/j.taap.2013.02.019] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2012] [Revised: 02/20/2013] [Accepted: 02/25/2013] [Indexed: 11/28/2022]
Abstract
Gastrodia elata Blume (G. elata) is a famous restorative food in East Asia. It can be used as an auxiliary reagent in hepatocellular carcinoma (HCC) treatment. Previous studies unveiled that G. elata exhibited immunomodulatory activities. To explore the active ingredients contributing to its immunomodulatory activities, gastrodin, vanillin, and parishin B were purified from G. elata and their anti-HCC effects were assessed in vivo. Among these compounds, only gastrodin was capable of repressing transplanted H22 ascitic hepatic tumor cell growth in vivo with low toxicity. Further investigations were designed to explore the effects of gastrodin on the immune system of tumor-bearing mice and potential molecular mechanisms underlying these effects. Our data showed that gastrodin ameliorated tumor cell transplantation-induced activation of endogenous pro-apoptotic pathway in CD4+ T cells and abnormalities in serum cytokine profiles in host animals. These events enhanced cytotoxic activities of natural killer and CD8+ T cells against H22 hepatic cancer cells. Gastrodin administration specifically upregulated mRNA levels of several nuclear factor κB (NF-κB) responsive genes in CD4+ T cells but not in CD8+ T cells. Chromatin immunoprecipitation assay showed that gastrodin increased the association of NF-κB p65 subunit to the promoter regions of IL-2 and Bcl-2 encoding genes in CD4+ T cells. Our investigations demonstrated that gastrodin is the main active ingredient contributing to the anticancer immunomodulatory properties of G. elata. Promoting NF-κB-mediated gene transcription in CD4+ T cells is implicated in its immunomodulatory activity.
Collapse
Affiliation(s)
- Guangwen Shu
- College of Pharmacy, South-Central University for Nationalities, Wuhan, PR China
| | | | | | | | | |
Collapse
|
|
50
|
Changes in peripheral blood immune cells: their prognostic significance in metastatic renal cell carcinoma patients treated with molecular targeted therapy. Med Oncol 2013; 30:556. [PMID: 23539200 DOI: 10.1007/s12032-013-0556-1] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2013] [Accepted: 03/21/2013] [Indexed: 01/06/2023]
Abstract
Recently, novel molecular targeted agents markedly changed the treatment of renal cell carcinoma (RCC), with promising results. However, there is little understanding of how these agents affect immune cell populations in RCC, an immunogenic tumor. Therefore, we investigated the changes in the peripheral blood immune cells in 58 RCC patients during the first 4 weeks of treatment with sorafenib, sunitinib, everolimus, or temsirolimus and evaluated whether these changes were associated with clinical outcomes. The immunological parameters were the proportion of type-1 (Th1) and type-2 (Th2) T cells, regulatory T cells (Treg), mature dendritic cells, and the neutrophil-to-lymphocyte ratio (NLR). The changes in these immune cells varied with the agents and the clinical response, dichotomized by the median progression-free survival (PFS) time (PFS-short or PFS-long). A significant decrease in the Th1/Th2 ratio was seen after sunitinib treatment only in the PFS-short group, suggesting a shift toward Th2 that down-regulates host immunity. The NLRs indicative of the balance between host immunity and cancer-related inflammation were consistently lower in the PFS-long group than in the PFS-short group, suggesting that lower NLR is associated with better clinical response. Only sunitinib decreased NLR remarkably regardless of PFS status, which may favor anti-tumor immunity. When patients were dichotomized by the cutoff values, Th1/Th2 ratio was not associated with PFS in any targeted therapy, while lower pre-treatment NLR was associated with longer PFS in each targeted therapy. In addition, in RCC patients given sequential targeted therapy, those with a lower baseline NLR survived significantly longer compared with the counterparts. Moreover, those whose baseline NLR was sustained low during the initial therapy survived the longest. Our results suggest the diverse changes in host immune cells in RCC patients during targeted therapy. The changes in NLR during the early phase of targeted therapy may be a powerful discriminator of who will benefit from the subsequent treatment.
Collapse
|