|
1
|
Pizurica M, Zheng Y, Carrillo-Perez F, Noor H, Yao W, Wohlfart C, Vladimirova A, Marchal K, Gevaert O. Digital profiling of gene expression from histology images with linearized attention. Nat Commun 2024; 15:9886. [PMID: 39543087 PMCID: PMC11564640 DOI: 10.1038/s41467-024-54182-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Accepted: 11/04/2024] [Indexed: 11/17/2024] Open
Abstract
Cancer is a heterogeneous disease requiring costly genetic profiling for better understanding and management. Recent advances in deep learning have enabled cost-effective predictions of genetic alterations from whole slide images (WSIs). While transformers have driven significant progress in non-medical domains, their application to WSIs lags behind due to high model complexity and limited dataset sizes. Here, we introduce SEQUOIA, a linearized transformer model that predicts cancer transcriptomic profiles from WSIs. SEQUOIA is developed using 7584 tumor samples across 16 cancer types, with its generalization capacity validated on two independent cohorts comprising 1368 tumors. Accurately predicted genes are associated with key cancer processes, including inflammatory response, cell cycles and metabolism. Further, we demonstrate the value of SEQUOIA in stratifying the risk of breast cancer recurrence and in resolving spatial gene expression at loco-regional levels. SEQUOIA hence deciphers clinically relevant information from WSIs, opening avenues for personalized cancer management.
Collapse
Affiliation(s)
- Marija Pizurica
- Department of Medicine, Stanford Center for Biomedical Informatics Research (BMIR), Stanford University, Stanford, CA, 94305, USA
- Internet Technology and Data Science Lab (IDLab), Ghent University, Ghent, 9052, Belgium
| | - Yuanning Zheng
- Department of Medicine, Stanford Center for Biomedical Informatics Research (BMIR), Stanford University, Stanford, CA, 94305, USA
| | - Francisco Carrillo-Perez
- Department of Medicine, Stanford Center for Biomedical Informatics Research (BMIR), Stanford University, Stanford, CA, 94305, USA
| | - Humaira Noor
- Department of Medicine, Stanford Center for Biomedical Informatics Research (BMIR), Stanford University, Stanford, CA, 94305, USA
| | - Wei Yao
- Roche Information Solutions, Roche Diagnostics Corporation, Santa Clara, CA, 95050, USA
| | | | - Antoaneta Vladimirova
- Roche Information Solutions, Roche Diagnostics Corporation, Santa Clara, CA, 95050, USA
| | - Kathleen Marchal
- Internet Technology and Data Science Lab (IDLab), Ghent University, Ghent, 9052, Belgium
| | - Olivier Gevaert
- Department of Medicine, Stanford Center for Biomedical Informatics Research (BMIR), Stanford University, Stanford, CA, 94305, USA.
- Department of Biomedical Data Science, Stanford University, Stanford, CA, 94305, USA.
| |
Collapse
|
|
2
|
Budginaite E, Kloft M, van Kuijk SMJ, Canao PA, Kooreman LFS, Pennings AJ, Magee DR, Woodruff HC, Grabsch HI. The clinical importance of the host anti-tumour reaction patterns in regional tumour draining lymph nodes in patients with locally advanced resectable gastric cancer: a systematic review and meta-analysis. Gastric Cancer 2023; 26:847-862. [PMID: 37776394 PMCID: PMC10640417 DOI: 10.1007/s10120-023-01426-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 08/16/2023] [Indexed: 10/02/2023]
Abstract
BACKGROUND The status of regional tumour draining lymph nodes (LN) is crucial for prognostic evaluation in gastric cancer (GaC) patients. Changes in lymph node microarchitecture, such as follicular hyperplasia (FH), sinus histiocytosis (SH), or paracortical hyperplasia (PH), may be triggered by the anti-tumour immune response. However, the prognostic value of these changes in GaC patients is unclear. METHODS A systematic search in multiple databases was conducted to identify studies on the prognostic value of microarchitecture changes in regional tumour-negative and tumour-positive LNs measured on histopathological slides. Since the number of GaC publications was very limited, the search was subsequently expanded to include junctional and oesophageal cancer (OeC). RESULTS A total of 28 articles (17 gastric cancer, 11 oesophageal cancer) met the inclusion criteria, analyzing 26,503 lymph nodes from 3711 GaC and 1912 OeC patients. The studies described eight different types of lymph node microarchitecture changes, categorized into three patterns: hyperplasia (SH, FH, PH), cell-specific infiltration (dendritic cells, T cells, neutrophils, macrophages), and differential gene expression. Meta-analysis of five GaC studies showed a positive association between SH in tumour-negative lymph nodes and better 5-year overall survival. Pooled risk ratios for all LNs showed increased 5-year overall survival for the presence of SH and PH. CONCLUSIONS This systematic review suggests that sinus histiocytosis and paracortical hyperplasia in regional tumour-negative lymph nodes may provide additional prognostic information for gastric and oesophageal cancer patients. Further studies are needed to better understand the lymph node reaction patterns and explore their impact of chemotherapy treatment and immunotherapy efficacy.
Collapse
Affiliation(s)
- Elzbieta Budginaite
- Department of Pathology, GROW School for Oncology and Reproduction, Maastricht University Medical Center+, P. Debyelaan 25, 6229 HX, Maastricht, The Netherlands
- The D-Lab: Decision Support for Precision Medicine, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Maximilian Kloft
- Department of Pathology, GROW School for Oncology and Reproduction, Maastricht University Medical Center+, P. Debyelaan 25, 6229 HX, Maastricht, The Netherlands
- Department of Internal Medicine, Justus-Liebig-University, Giessen, Germany
| | - Sander M J van Kuijk
- Department of Clinical Epidemiology and Medical Technology Assessment, Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Pedro A Canao
- Anatomical Pathology Department, Centro Hospitalar Universitário de São João, Porto, Portugal
- Faculty of Medicine of the University of Porto, Porto, Portugal
| | - Loes F S Kooreman
- Department of Pathology, GROW School for Oncology and Reproduction, Maastricht University Medical Center+, P. Debyelaan 25, 6229 HX, Maastricht, The Netherlands
| | - Alexander J Pennings
- Department of Surgery, GROW School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands
| | | | - Henry C Woodruff
- The D-Lab: Decision Support for Precision Medicine, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Heike I Grabsch
- Department of Pathology, GROW School for Oncology and Reproduction, Maastricht University Medical Center+, P. Debyelaan 25, 6229 HX, Maastricht, The Netherlands.
- Pathology and Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.
| |
Collapse
|
|
3
|
Watanabe S, Takagi A, Yuba E, Kojima C, Dei N, Matsumoto A, Tanikawa J, Kawamura T, De Silva NH, Izawa T, Akazawa T, Kanegi R, Hatoya S, Inaba T, Sugiura K. In vivo transfection of cytokine genes into tumor cells using a synthetic vehicle promotes antitumor immune responses in a visceral tumor model. FASEB J 2023; 37:e23228. [PMID: 37815518 DOI: 10.1096/fj.202202036r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 08/09/2023] [Accepted: 09/18/2023] [Indexed: 10/11/2023]
Abstract
The tumor microenvironment (TME) strongly affects the clinical outcomes of immunotherapy. This study aimed to activate the antitumor immune response by manipulating the TME by transfecting genes encoding relevant cytokines into tumor cells using a synthetic vehicle, which is designed to target tumor cells and promote the expression of transfected genes. Lung tumors were formed by injecting CT26.WT intravenously into BALB/c mice. Upon intravenous injection of the green fluorescent protein-coding plasmid encapsulated in the vehicle, 14.2% tumor-specific expression was observed. Transfection of the granulocyte-macrophage colony-stimulating factor (GM-CSF) and CD40 ligand (L)-plasmid combination and interferon gamma (IFNγ) and CD40L-plasmid combination showed 45.5% and 54.5% complete remission (CR), respectively, on day 60; alternate treatments with both the plasmid combinations elicited 66.7% CR, while the control animals died within 48 days. Immune status analysis revealed that the density of dendritic cells significantly increased in tumors, particularly after GM-CSF- and CD40L-gene transfection, while that of regulatory T cells significantly decreased. The proportion of activated killer cells and antitumoral macrophages significantly increased, specifically after IFNγ and CD40L transfection. Furthermore, the level of the immune escape molecule programmed death ligand-1 decreased in tumors after transfecting these cytokine genes. As a result, tumor cell-specific transfection of these cytokine genes by the synthetic vehicle significantly promotes antitumor immune responses in the TME, a key aim for visceral tumor therapy.
Collapse
Affiliation(s)
- Shunichi Watanabe
- Department of Advanced Pathobiology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Izumisano, Japan
| | - Ayaka Takagi
- Department of Advanced Pathobiology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Izumisano, Japan
| | - Eiji Yuba
- Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, Sakai, Japan
- Department of Applied Chemistry, Graduate School of Engineering, Osaka Metropolitan University, Sakai, Japan
| | - Chie Kojima
- Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, Sakai, Japan
- Department of Applied Chemistry, Graduate School of Engineering, Osaka Metropolitan University, Sakai, Japan
| | - Nanako Dei
- Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, Sakai, Japan
| | - Akikazu Matsumoto
- Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, Sakai, Japan
- Department of Applied Chemistry, Graduate School of Engineering, Osaka Metropolitan University, Sakai, Japan
| | - Jun Tanikawa
- Bioscience Research Laboratory, Sumitomo Chemical Company, Ltd., Osaka, Japan
| | - Tetsuya Kawamura
- Bioscience Research Laboratory, Sumitomo Chemical Company, Ltd., Osaka, Japan
| | - Nadeeka H De Silva
- Department of Advanced Pathobiology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Izumisano, Japan
| | - Takeshi Izawa
- Department of Integrated Structural Biosciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Izumisano, Japan
- Department of Integrated Structural Biosciences, Graduate School of Veterinary Science, Osaka Metropolitan University, Izumisano, Japan
| | - Takashi Akazawa
- Department of Cancer Drug Discovery and Development, Research Center, Osaka International Cancer Institute, Osaka, Japan
| | - Ryoji Kanegi
- Department of Advanced Pathobiology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Izumisano, Japan
- Department of Advanced Pathobiology, Graduate School of Veterinary Science, Osaka Metropolitan University, Izumisano, Japan
| | - Shingo Hatoya
- Department of Advanced Pathobiology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Izumisano, Japan
- Department of Advanced Pathobiology, Graduate School of Veterinary Science, Osaka Metropolitan University, Izumisano, Japan
| | - Toshio Inaba
- Department of Advanced Pathobiology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Izumisano, Japan
- Department of Advanced Pathobiology, Graduate School of Veterinary Science, Osaka Metropolitan University, Izumisano, Japan
| | - Kikuya Sugiura
- Department of Advanced Pathobiology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Izumisano, Japan
- Department of Advanced Pathobiology, Graduate School of Veterinary Science, Osaka Metropolitan University, Izumisano, Japan
| |
Collapse
|
|
4
|
Xiao J, Wang G, Zhu C, Liu K, Wang Y, Shen K, Fan H, Ma X, Xu Z, Yang L. A thirty-three gene-based signature predicts lymph node metastasis and prognosis in patients with gastric cancer. Heliyon 2023; 9:e17017. [PMID: 37484383 PMCID: PMC10361117 DOI: 10.1016/j.heliyon.2023.e17017] [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: 07/11/2022] [Revised: 06/01/2023] [Accepted: 06/04/2023] [Indexed: 07/25/2023] Open
Abstract
Recently, several studies have indicated the great potential of gene expression signature of the primary tumor in predicting lymph node metastasis; however, few current gene biomarkers can predict lymph node status and prognosis in gastric cancer (GC). Thus, we used the RNA-seq data from The Cancer Genome Atlas (TCGA) to identify differentially expressed genes between pathological lymph node-negative (pN0) and positive (pN+) patients and to establish a gene signature that could predict lymph node metastasis. Meanwhile, the robustness of identified gene signatures was validated in an independent dataset Asian Cancer Research Group (n = 300). In this study, our thirty-three gene-based signature was highly correlated with lymph node metastasis and could successfully discriminate pN + patients in the training set (Area under the receiver operating characteristic curve = 0.951). Moreover, Disease-free survival (P = 0.0029) and overall survival (P = 0.026) were significantly worse in high-risk compared with low-risk patients overall and when confined to pN0 patients only (P < 0.0001). Of note, this gene signature also proved useful in predicting lymph node status and survival in the validation cohort. The present study suggests a thirty-three gene-based signature that could effectively predict lymph node metastasis and prognosis in GC.
Collapse
Affiliation(s)
- Jian Xiao
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Gang Wang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Chuming Zhu
- Department of General Surgery, Liyang People's Hospital, Liyang Branch Hospital of Jiangsu Province Hospital, Liyang, Jiangsu Province, China
| | - Kanghui Liu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Yuanhang Wang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Kuan Shen
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Hao Fan
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Xiang Ma
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Zekuan Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Li Yang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
- Department of General Surgery, Liyang People's Hospital, Liyang Branch Hospital of Jiangsu Province Hospital, Liyang, Jiangsu Province, China
| |
Collapse
|
|
5
|
Dyduch G, Miążek A, Laskowicz Ł, Szpor J. Distribution of DC Subtypes: CD83+, DC-LAMP+, CD1a+, CD1c+, CD123+, and DC-SIGN+ in the Tumor Microenvironment of Endometrial Cancers-Correlation with Clinicopathologic Features. Int J Mol Sci 2023; 24:ijms24031933. [PMID: 36768258 PMCID: PMC9915342 DOI: 10.3390/ijms24031933] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 01/14/2023] [Accepted: 01/16/2023] [Indexed: 01/20/2023] Open
Abstract
Treatment options for endometrial cancer (EC) do not provide satisfactory survival improvement for advanced cases, hence the interest in novel therapies utilizing immunological regulatory mechanisms. Measures to modify the functionality of dendritic cells (DCs) found in TME are intensively investigated, given that DCs play a crucial role in inducing antitumor immunity. Samples of malignant endometrial neoplasms obtained from 94 patients were immunohistochemically stained with selected antibodies. Counts of positively identified DCs were correlated with clinical advancement and histological malignancy of cancers. The most prominent DC subtypes were immature DC-SIGN+ or CD123+. Mature CD83+ DCs were the fewest. We found a significant divergence of grade value distribution between cancers of different DCs' CD1a+ counts. The DC-LAMP+ count was positively associated with grade. Cancers with the least DC CD1c+ or DC CD123+ had higher pT scores than ones that were more heavily infiltrated. ECs can suppress immune cells, hence the predominance of immature DCs in our samples. Associations between DC counts and clinicopathological features of EC were observed only for a few subsets, which was plausibly due to the low diversity of the obtained samples or the small group size. Predictive abilities of particular DC immune subsets within EC's TME remain ambiguous, which calls for further research.
Collapse
Affiliation(s)
- Grzegorz Dyduch
- Department of Pathomorphology, Faculty of Medicine, Jagiellonian University Medical College, Grzegorzecka 16, 31-351 Krakow, Poland
- Correspondence:
| | - Apolonia Miążek
- Department of Pathomorphology, Faculty of Medicine, Jagiellonian University Medical College, Grzegorzecka 16, 31-351 Krakow, Poland
| | - Łukasz Laskowicz
- Gynaecology and Oncology Clinical Department, University Hospital, Jakubowskiego 2, 30-688 Krakow, Poland
| | - Joanna Szpor
- Department of Pathomorphology, Faculty of Medicine, Jagiellonian University Medical College, Grzegorzecka 16, 31-351 Krakow, Poland
| |
Collapse
|
|
6
|
Agnarelli A, Vella V, Samuels M, Papanastasopoulos P, Giamas G. Incorporating Immunotherapy in the Management of Gastric Cancer: Molecular and Clinical Implications. Cancers (Basel) 2022; 14:cancers14184378. [PMID: 36139540 PMCID: PMC9496849 DOI: 10.3390/cancers14184378] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/30/2022] [Accepted: 09/05/2022] [Indexed: 01/30/2023] Open
Abstract
Simple Summary Gastric cancer is one of the most common malignant tumours worldwide, with the fifth and third highest morbidity and mortality, respectively, of all cancers. Survival is limited, as most of the patients are diagnosed at an advanced stage, and are not suitable for surgery with a curative intent. Chemotherapy has only modestly improved patients’ outcomes and is mainly given with a palliative intent. Immunotherapy has improved overall survival of patients with gastric cancer, and has thus become a new standard of care in clinic. In this review we discuss the strong molecular rationale for the administration of immunotherapy in this disease and analyse the clinical data supporting its use. Abstract Gastric cancer has a median survival of 11 months, and this poor prognosis has not improved over the last 30 years. Recent pre-clinical data suggest that there is high tumour-related neoantigen expression in gastric cancer cells, suggesting that a clinical strategy that enhances the host’s immune system against cancer cells may be a successful approach to improve clinical outcomes. Additionally, there has been an increasing amount of translational evidence highlighting the relevance of PD-L1 expression in gastric cancer cells, indicating that PD-1/PD-L1 inhibitors may be useful. Several molecular subgroups of gastric cancer have been identified to respond with excellent outcomes to immunotherapy, including microsatellite instable tumours, tumours bearing a high tumour mutational burden, and tumours related to a chronic EBV infection. In gastric cancer, immunotherapy has produced durable responses in chemo-refractory patients; however, most recently there has been a lot of enthusiasm as several large-scale clinical trials highlight the improved survival noted from the incorporation of immunotherapy in the first line setting for advanced gastric cancer. Our review aims to discuss current pre-clinical and clinical data supporting the innovative role of immunotherapy in gastric cancer.
Collapse
|
|
7
|
Song J, Lin Z, Liu Q, Huang S, Han L, Fang Y, Zhong P, Dou R, Xiang Z, Zheng J, Zhang X, Wang S, Xiong B. MiR-192-5p/RB1/NF-κBp65 signaling axis promotes IL-10 secretion during gastric cancer EMT to induce Treg cell differentiation in the tumour microenvironment. Clin Transl Med 2022; 12:e992. [PMID: 35969010 PMCID: PMC9377151 DOI: 10.1002/ctm2.992] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 07/04/2022] [Accepted: 07/08/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Regulatory T (Treg) cells are important components of the tumour microenvironment (TME) that play roles in gastric cancer (GC) metastasis. Although tumour cells that undergo epithelial-mesenchymal transition (EMT) regulate Treg cell function, their regulatory mechanism in GC remains unclear. METHODS The miR-192-5p was identified by examining three Gene Expression Omnibus GC miRNA expression datasets. RNA immunoprecipitation (RIP) and dual-luciferase reporter assays were conducted to identify interactions between miR-192-5p and RB1. The role of miR-192-5p/RB1 in GC progression was evaluated based on EdU incorporation, wound healing and Transwell assays. An in vitro co-culture assay was performed to measure the effect of miR-192-5p/RB1 on Treg cell differentiation. In vivo experiments were conducted to explore the role of miR-192-5p in GC progression and Treg cell differentiation. RESULTS MiR-192-5p was overexpressed in tumour and was associated with poor prognosis in GC. MiR-192-5p bound to the RB1 3'-untranslated region, resulting in GC EMT, proliferation, migration and invasion. MiR-192-5p/RB1 mediated interleukin-10 (IL-10) secretion by regulating nuclear factor-kappaBp65 (NF-κBp65), affecting Treg cell differentiation. NF-κBp65, in turn, promoted miR-192-5p expression and formed a positive feedback loop. Furthermore, in vivo experiments confirmed that miR-192-5p/RB1 promotes GC growth and Treg cell differentiation. CONCLUSION Collectively, our studies indicate that miR-192-5p/RB1 promotes EMT of tumour cells, and the miR-192-5p/RB1/NF-κBp65 signaling axis induces Treg cell differentiation by regulating IL-10 secretion in GC. Our results suggest that targeting miR-192-5p/RB1/NF-κBp65 /IL-10 may pave the way for the development of new immune treatments for GC.
Collapse
Affiliation(s)
- Jialin Song
- Department of Gastrointestinal SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
- Hubei Key Laboratory of Tumour Biological BehavioursWuhanChina
- Hubei Cancer Clinical Study CenterWuhanChina
| | - Zaihuan Lin
- Department of Gastrointestinal SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
- Hubei Key Laboratory of Tumour Biological BehavioursWuhanChina
- Hubei Cancer Clinical Study CenterWuhanChina
| | - Qing Liu
- Department of Respiratory and Critical Care MedicineZhongnan Hospital of Wuhan UniversityWuhanChina
- Wuhan Research Center for Infectious Diseases and CancerChinese Academy of Medical SciencesWuhanChina
| | - Sihao Huang
- Department of Gastrointestinal SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
- Hubei Key Laboratory of Tumour Biological BehavioursWuhanChina
- Hubei Cancer Clinical Study CenterWuhanChina
| | - Lei Han
- Department of Gastrointestinal SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
- Hubei Key Laboratory of Tumour Biological BehavioursWuhanChina
- Hubei Cancer Clinical Study CenterWuhanChina
| | - Yan Fang
- Department of obstetrics and gynecologyGuangzhou Women and Children's Medical CenterGuangzhouChina
| | - Panyi Zhong
- Department of Gastrointestinal SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
- Hubei Key Laboratory of Tumour Biological BehavioursWuhanChina
- Hubei Cancer Clinical Study CenterWuhanChina
| | - Rongzhang Dou
- Department of Gastrointestinal SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
- Hubei Key Laboratory of Tumour Biological BehavioursWuhanChina
- Hubei Cancer Clinical Study CenterWuhanChina
| | - Zhenxian Xiang
- Department of Gastrointestinal SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
- Hubei Key Laboratory of Tumour Biological BehavioursWuhanChina
- Hubei Cancer Clinical Study CenterWuhanChina
| | - Jinsen Zheng
- Department of Gastrointestinal SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
- Hubei Key Laboratory of Tumour Biological BehavioursWuhanChina
- Hubei Cancer Clinical Study CenterWuhanChina
| | - Xinyao Zhang
- Department of Gastrointestinal SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
- Hubei Key Laboratory of Tumour Biological BehavioursWuhanChina
- Hubei Cancer Clinical Study CenterWuhanChina
| | - Shuyi Wang
- Department of Gastrointestinal SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
- Hubei Key Laboratory of Tumour Biological BehavioursWuhanChina
- Hubei Cancer Clinical Study CenterWuhanChina
| | - Bin Xiong
- Department of Gastrointestinal SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
- Hubei Key Laboratory of Tumour Biological BehavioursWuhanChina
- Hubei Cancer Clinical Study CenterWuhanChina
| |
Collapse
|
|
8
|
Inflammation and Gastric Cancer. Diseases 2022; 10:diseases10030035. [PMID: 35892729 PMCID: PMC9326573 DOI: 10.3390/diseases10030035] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 06/16/2022] [Accepted: 06/19/2022] [Indexed: 11/17/2022] Open
Abstract
Gastric cancer remains a major killer globally, although its incidence has declined over the past century. It is the fifth most common cancer and the third most common reason for cancer-related deaths worldwide. Gastric cancer is the outcome of a complex interaction between environmental, host genetic, and microbial factors. There is significant evidence supporting the association between chronic inflammation and the onset of cancer. This association is particularly robust for gastrointestinal cancers in which microbial pathogens are responsible for the chronic inflammation that can be a triggering factor for the onset of those cancers. Helicobacter pylori is the most prominent example since it is the most widespread infection, affecting nearly half of the world’s population. It is well-known to be responsible for inducing chronic gastric inflammation progressing to atrophy, metaplasia, dysplasia, and eventually, gastric cancer. This review provides an overview of the association of the factors playing a role in chronic inflammation; the bacterial characteristics which are responsible for the colonization, persistence in the stomach, and triggering of inflammation; the microbiome involved in the chronic inflammation process; and the host factors that have a role in determining whether gastritis progresses to gastric cancer. Understanding these interconnections may improve our ability to prevent gastric cancer development and enhance our understanding of existing cases.
Collapse
|
|
9
|
Zhao M, Duan X, Mi L, Shi J, Li N, Yin X, Han X, Wang J, Han G, Hou J, Yin F. Prognosis of hepatocellular carcinoma and its association with immune cells using systemic inflammatory response index. Future Oncol 2022; 18:2269-2288. [PMID: 35440159 DOI: 10.2217/fon-2021-1087] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 04/04/2022] [Indexed: 11/21/2022] Open
Abstract
Aim: To explore the prognostic value of the systemic inflammatory response index (SIRI) and peripheral blood T-cell subsets in patients with hepatocellular carcinoma (HCC) and the relationship between them. Materials & methods: We treated 352 patients with HCC with sorafenib and/or immune checkpoint inhibitors (ICIs) and analyzed SIRI and peripheral blood T cells. Results: SIRI was an independent prognostic factor for patients with HCC receiving systemic therapy. Patients with high SIRI and low baseline peripheral blood T-cell counts showed a poor response to ICIs. SIRI was significantly and negatively correlated with CD3+, CD4+ and CD8+ T-cell counts. Conclusion: SIRI markers can be employed to noninvasively assess the presence of cancer-promoting inflammation in the tumor microenvironment and predict the efficacy of targeted therapy and immunotherapy.
Collapse
Affiliation(s)
- Man Zhao
- Department of Gastroenterology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, Heibei, PR China
| | - Xiaoling Duan
- Department of Gastroenterology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, Heibei, PR China
| | - Lili Mi
- Department of Gastroenterology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, Heibei, PR China
| | - Jianfei Shi
- Department of Gastroenterology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, Heibei, PR China
| | - Ning Li
- Department of Gastroenterology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, Heibei, PR China
| | - Xiaolei Yin
- Department of Gastroenterology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, Heibei, PR China
| | - Xin Han
- Department of Gastroenterology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, Heibei, PR China
| | - Jinfeng Wang
- Department of Gastroenterology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, Heibei, PR China
| | - Guangjie Han
- Department of Gastroenterology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, Heibei, PR China
| | - Jiaojiao Hou
- Department of Gastroenterology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, Heibei, PR China
| | - Fei Yin
- Department of Gastroenterology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, Heibei, PR China
| |
Collapse
|
|
10
|
Gama-Cuellar AG, Francisco ALN, Scarini JF, Mariano FV, Kowalski LP, Gondak R. Decreased CD1a + and CD83 + cells in tonsillar squamous cell carcinoma regardless of HPV status. J Appl Oral Sci 2022; 30:e20210702. [PMID: 35584505 PMCID: PMC9126112 DOI: 10.1590/1678-7757-2020-0702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 04/06/2022] [Indexed: 11/22/2022] Open
Abstract
Dendritic cells (DCs) are specialized antigen-presenting cells that play a critical role in the immune response against human papillomavirus (HPV) infection, and represent a therapeutic target in cancer.
Collapse
Affiliation(s)
| | | | - João Figueira Scarini
- Universidade Estadual de Campinas - UNICAMP, Departamento de Anatomia-Patológica, Faculdade de Ciências Médicas, Campinas, SP, Brasil
| | - Fernanda Viviane Mariano
- Universidade Estadual de Campinas - UNICAMP, Departamento de Anatomia-Patológica, Faculdade de Ciências Médicas, Campinas, SP, Brasil
| | | | - Rogério Gondak
- Universidade Federal de Santa Catarina - UFSC, Departamento de Patologia, Florianópolis, SC, Brasil
| |
Collapse
|
|
11
|
Ni L. Advances in Human Dendritic Cell-Based Immunotherapy Against Gastrointestinal Cancer. Front Immunol 2022; 13:887189. [PMID: 35619702 PMCID: PMC9127253 DOI: 10.3389/fimmu.2022.887189] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 04/08/2022] [Indexed: 11/23/2022] Open
Abstract
Dendritic cells (DCs), the strongest antigen-presenting cells, are a focus for orchestrating the immune system in the fight against cancer. Basic scientific investigations elucidating the cellular biology of the DCs have resulted in new strategies in this fight, including cancer vaccinology, combination therapy, and adoptive cellular therapy. Although immunotherapy is currently becoming an unprecedented bench-to-bedside success, the overall response rate to the current immunotherapy in patients with gastrointestinal (GI) cancers is pretty low. Here, we have carried out a literature search of the studies of DCs in the treatment of GI cancer patients. We provide the advances in DC-based immunotherapy and highlight the clinical trials that indicate the therapeutic efficacies and toxicities related with each vaccine. Moreover, we also offer the yet-to-be-addressed questions about DC-based immunotherapy. This study focuses predominantly on the data derived from human studies to help understand the involvement of DCs in patients with GI cancers.
Collapse
Affiliation(s)
- Ling Ni
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China
| |
Collapse
|
|
12
|
Huang J, Chen W, Jie Z, Jiang M. Comprehensive Analysis of Immune Implications and Prognostic Value of SPI1 in Gastric Cancer. Front Oncol 2022; 12:820568. [PMID: 35237521 PMCID: PMC8882873 DOI: 10.3389/fonc.2022.820568] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 01/19/2022] [Indexed: 01/13/2023] Open
Abstract
Background The transcription factor Spi-1 proto-oncogene (SPI1, also known as PU.1) is a key regulator of signal communication in the immune system and is essential for the development of myeloid cells and lymphocytes. However, the potential role of SPI1 in gastric cancer (GC) and the correlations between SPI1 and immune infiltration remain unclear. Methods In the present study, multiple databases including ONCOMINE, TIMER, Kaplan–Meier Plotter, and The Cancer Genome Atlas were used to explore the expression levels and prognostic value of SPI1 in GC. cBioPortal was used to explore the possible reasons for the increased expression of SPI1 in GC. The correlations between SPI1 expression and tumor-infiltrating immune cells (TICs) were analyzed using CIBERSORT and TIMER. Gene set enrichment analysis was used to determine the biological function of SPI1 in the development of GC. In addition, a risk signature based on SPI1-related immunomodulators was constructed to accurately evaluate the prognosis of patients with GC. The upregulation of SPI1 expression in GC was further confirmed through immunohistochemistry, western blotting, and real-time quantitative PCR (RT-qPCR) assay. Results The expression of SPI1 was increased significantly in GC according to multiple databases, and high expression of SPI1 was related to poor prognosis and progression of GC. The main factor influencing the high expression of SPI1 mRNA in GC may be diploidy, not DNA methylation. Moreover, immunohistochemistry, western blotting, and RT-qPCR assays also confirmed the upregulated expression of SPI1 in GC. CIBERSORT analysis revealed that SPI1 expression was correlated with seven types of TICs (naive B cells, resting memory CD4 T cells, activated memory CD4 T cells, activated natural killer cells, resting natural killer cells, M2 macrophages, and resting dendritic cells). Gene set enrichment analysis indicated that SPI1 might be related to immune activation in GC and participate in cell cycle regulation. In addition, based on SPI1-related immunomodulators, we developed multiple-gene risk prediction signatures and constructed a nomogram that can independently predict the clinical outcome of GC. Conclusion The results of the present study suggest that SPI1 has a critical role in determining the prognosis of GC patients and may be a potential immunotherapeutic target.
Collapse
Affiliation(s)
- Jianfeng Huang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Wenzheng Chen
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Zhigang Jie
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
- *Correspondence: Mengmeng Jiang, ; Zhigang Jie,
| | - Mengmeng Jiang
- Department of Emergency Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
- *Correspondence: Mengmeng Jiang, ; Zhigang Jie,
| |
Collapse
|
|
13
|
López C, Bosch R, Korzynska A, García-Rojo M, Bueno G, García-Fontgivell JF, Martínez González S, Gras Navarro A, Sauras Colón E, Casanova Ribes J, Roszkowiak L, Mata D, Arenas M, Gómez J, Roso A, Berenguer M, Reverté-Villarroya S, Llobera M, Baucells J, Lejeune M. CD68 and CD83 immune populations in non-metastatic axillary lymph nodes are of prognostic value for the survival and relapse of breast cancer patients. Breast Cancer 2022; 29:618-635. [PMID: 35137329 DOI: 10.1007/s12282-022-01336-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 01/30/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND The foremost cause of death of breast cancer (BC) patients is metastasis, and the first site to which BC predominantly metastasizes is the axillary lymph node (ALN). Thus, ALN status is a key prognostic indicator at diagnosis. The immune system has an essential role in cancer progression and dissemination, so its evaluation in ALNs could have significant applications. In the present study we aimed to investigate the association of clinical-pathological and immune variables in the primary tumour and non-metastatic ALNs (ALNs-) of a cohort of luminal A and triple-negative BC (TNBC) patients with cancer-specific survival (CSS) and time to progression (TTP). METHODS We analysed the differences in the variables between patients with different outcomes, created univariate and multivariate Cox regression models, validated them by bootstrapping and multiple imputation of missing data techniques, and used Kaplan-Meier survival curves for a 10-years follow-up. RESULTS We found some clinical-pathological variables at diagnosis (tumour diameter, TNBC molecular profile and presence of ALN metastasis), and the levels of several immune markers in the two studied sites, to be associated with worse CSS and TTP. Nevertheless, only CD68 and CD83 in ALNs- were confirmed as independent prognostic factors for TTP. CONCLUSIONS The study identified the importance of macrophage and dendritic cell markers as prognostic factors of relapse for BC. We highlight the importance of studying the immune response in ALNs-, which could be relevant to the prediction of BC patients' outcome.
Collapse
Affiliation(s)
- Carlos López
- Department of Pathology, Oncological Pathology and Bioinformatics Research Group, Hospital de Tortosa Verge de la Cinta, ICS, IISPV, C/Esplanetes no 14, 43500, Tortosa, Spain. .,Universitat Rovira i Virgili (URV) - Campus Terres de l'Ebre, Avinguda Remolins no 13-15, 43500, Tortosa, Spain.
| | - Ramón Bosch
- Department of Pathology, Oncological Pathology and Bioinformatics Research Group, Hospital de Tortosa Verge de la Cinta, ICS, IISPV, C/Esplanetes no 14, 43500, Tortosa, Spain
| | - Anna Korzynska
- Laboratory of Processing and Analysis of Microscopic Images, Polish Academy of Sciences (IBIB PAN), Nalęcz Institute of Biocybernetics and Biomedical Engineering, Ks. Trojdena 4 St., 02-109, Warsaw, Poland
| | - Marcial García-Rojo
- Department of Pathology, Hospital Universitario Puerta del Mar, Avda. Ana de Viya, 21, 11009, Cádiz, Spain
| | - Gloria Bueno
- VISILAB, Universidad de Castilla-La Mancha, Av. Camilo José Cela, s/n, 13071, Ciudad Real, Spain
| | | | - Salomé Martínez González
- Department of Pathology, Hospital Universitari Joan XXIII, C/Dr. Mallafrè Guasch, 4, 43005, Tarragona, Spain
| | - Andrea Gras Navarro
- Department of Pathology, Oncological Pathology and Bioinformatics Research Group, Hospital de Tortosa Verge de la Cinta, ICS, IISPV, C/Esplanetes no 14, 43500, Tortosa, Spain.,Universitat Rovira i Virgili (URV) - Campus Terres de l'Ebre, Avinguda Remolins no 13-15, 43500, Tortosa, Spain
| | - Esther Sauras Colón
- Department of Pathology, Oncological Pathology and Bioinformatics Research Group, Hospital de Tortosa Verge de la Cinta, ICS, IISPV, C/Esplanetes no 14, 43500, Tortosa, Spain.
| | - Júlia Casanova Ribes
- Department of Pathology, Oncological Pathology and Bioinformatics Research Group, Hospital de Tortosa Verge de la Cinta, ICS, IISPV, C/Esplanetes no 14, 43500, Tortosa, Spain
| | - Lukasz Roszkowiak
- Laboratory of Processing and Analysis of Microscopic Images, Polish Academy of Sciences (IBIB PAN), Nalęcz Institute of Biocybernetics and Biomedical Engineering, Ks. Trojdena 4 St., 02-109, Warsaw, Poland
| | - Daniel Mata
- Department of Pathology, Oncological Pathology and Bioinformatics Research Group, Hospital de Tortosa Verge de la Cinta, ICS, IISPV, C/Esplanetes no 14, 43500, Tortosa, Spain
| | - Meritxell Arenas
- Institut d'Investigació Sanitària Pere Virgili, Radiation Oncology Department, Universitat Rovira i Virgili, Hospital Universitari Sant Joan de Reus, Reus, Spain
| | - Junior Gómez
- Institut d'Investigació Sanitària Pere Virgili, Radiation Oncology Department, Universitat Rovira i Virgili, Hospital Universitari Sant Joan de Reus, Reus, Spain
| | - Albert Roso
- Institut Universitari d'Investigació en Atenció Primària Jordi Gol (IDIAP Jordi Gol), Gran Via Corts Catalanes, 587, 08007, Barcelona, Spain
| | - Marta Berenguer
- Knowledge Management Department, Hospital de Tortosa Verge de la Cinta, ICS, IISPV, C/Esplanetes no 14, 43500, Tortosa, Spain
| | - Silvia Reverté-Villarroya
- Universitat Rovira i Virgili (URV) - Campus Terres de l'Ebre, Avinguda Remolins no 13-15, 43500, Tortosa, Spain.,Knowledge Management Department, Hospital de Tortosa Verge de la Cinta, ICS, IISPV, C/Esplanetes no 14, 43500, Tortosa, Spain
| | - Montserrat Llobera
- Department of Oncology, Hospital de Tortosa Verge de la Cinta, ICS, IISPV, C/Esplanetes no 14, 43500, Tortosa, Spain
| | - Jordi Baucells
- Informatics Department, Hospital de Tortosa Verge de la Cinta, ICS, IISPV, C/Esplanetes no 14, 43500, Tortosa, Spain
| | - Marylène Lejeune
- Department of Pathology, Oncological Pathology and Bioinformatics Research Group, Hospital de Tortosa Verge de la Cinta, ICS, IISPV, C/Esplanetes no 14, 43500, Tortosa, Spain.,Universitat Rovira i Virgili (URV) - Campus Terres de l'Ebre, Avinguda Remolins no 13-15, 43500, Tortosa, Spain
| |
Collapse
|
|
14
|
Yuan P, Zhou Y, Wang Z, Gui L, Ma B. Dendritic cell-targeting chemokines inhibit colorectal cancer progression. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2022; 3:828-840. [PMID: 36654820 PMCID: PMC9834269 DOI: 10.37349/etat.2022.00115] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Accepted: 10/29/2022] [Indexed: 12/29/2022] Open
Abstract
Aim Recent progress in cancer immunotherapy has shown its promise and prompted researchers to develop novel therapeutic strategies. Dendritic cells (DCs) are professional antigen-presenting cells crucial for initiating adaptive anti-tumor immunity, therefore a promising target for cancer treatment. Here, anti-tumor activities of DC-targeting chemokines were explored in murine colorectal tumor models. Methods The correlation of chemokine messenger RNA (mRNA) expression with DC markers was analyzed using The Cancer Genome Atlas (TCGA) dataset. Murine colorectal tumor cell lines (CT26 and MC38) stably overexpressing mouse C-C motif chemokine ligand 3 (CCL3), CCL19, CCL21, and X-C motif chemokine ligand 1 (XCL1) were established by lentiviral transduction. The effect of chemokines on tumor cell proliferation/survival was evaluated in vitro by cell counting kit-8 (CCK-8) assay and colony formation assay. Syngeneic subcutaneous tumor models were used to study the effects of these chemokines on tumor growth. Ki-67 expression in tumors was examined by immunohistochemistry. Immune cells in the tumor microenvironment (TME) and lymph nodes were analyzed by flow cytometry. Results Expression of the four chemokines was positively correlated with the two DC markers [integrin alpha X (ITGAX) and CLEC9A] in human colorectal tumor samples. Tumoral overexpression of DC-targeting chemokines had little or no effect on tumor cell proliferation/survival in vitro while significantly suppressing tumor growth in vivo. Fluorescence-activated cell sorting (FACS) analysis showed that CCL19, CCL21, and XCL1 boosted the ratios of DCs and T cells in CD45+ leukocytes while CCL3 increased the percentage of CD45+ leukocytes in total cells in MC38 tumor. XCL1 had an additional positive effect on antigen uptake by DCs in the TME and antigen transfer to tumor-draining lymph nodes. Conclusions CCL3, CCL19, CCL21, and XCL1 exhibited potent anti-tumor activities in vivo, although they might differentially regulate immune cells in the TME and antigen transfer to lymph nodes.
Collapse
Affiliation(s)
- Pengkun Yuan
- School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China,Clinical Stem Cell Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China,Zhejiang University–University of Edinburgh (ZJU-UoE) Institute, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang, China
| | - Yunyi Zhou
- School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China,Clinical Stem Cell Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Zhixue Wang
- School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China,Clinical Stem Cell Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Liming Gui
- School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China,Clinical Stem Cell Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Bin Ma
- School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China,Clinical Stem Cell Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China,Correspondence: Bin Ma, School of Biomedical Engineering Med-X Research Institute, Shanghai Jiao Tong University, No. 3 Teaching Building, 1954 Huashan RD, Xuhui District, Shanghai 200030, China.
| |
Collapse
|
|
15
|
Wang D, Cabalag CS, Clemons NJ, DuBois RN. Cyclooxygenases and Prostaglandins in Tumor Immunology and Microenvironment of Gastrointestinal Cancer. Gastroenterology 2021; 161:1813-1829. [PMID: 34606846 DOI: 10.1053/j.gastro.2021.09.059] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 09/03/2021] [Accepted: 09/19/2021] [Indexed: 12/21/2022]
Abstract
Chronic inflammation is a known risk factor for gastrointestinal cancer. The evidence that nonsteroidal anti-inflammatory drugs suppress the incidence, growth, and metastasis of gastrointestinal cancer supports the concept that a nonsteroidal anti-inflammatory drug target, cyclooxygenase, and its downstream bioactive lipid products may provide one of the links between inflammation and cancer. Preclinical studies have demonstrated that the cyclooxygenase-2-prostaglandin E2 pathway can promote gastrointestinal cancer development. Although the role of this pathway in cancer has been investigated extensively for 2 decades, only recent studies have described its effects on host defenses against transformed epithelial cells. Overcoming tumor-immune evasion remains one of the major challenges in cancer immunotherapy. This review summarizes the impacts of the cyclooxygenase-2-prostaglandin E2 pathway on gastrointestinal cancer development. Our focus was to highlight recent advances in our understanding of how this pathway induces tumor immune evasion.
Collapse
Affiliation(s)
- Dingzhi Wang
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina
| | - Carlos S Cabalag
- Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia
| | - Nicholas J Clemons
- Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
| | - Raymond N DuBois
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina.
| |
Collapse
|
|
16
|
Chen KHE, Ghosh M, Rivera L, Lin S, Kumar A, Swaminathan S, Lorenson MY, Walker AM. Prolactin enhances T regulatory cell promotion of breast cancer through the long form prolactin receptor. Transl Oncol 2021; 14:101195. [PMID: 34375938 PMCID: PMC8358703 DOI: 10.1016/j.tranon.2021.101195] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 08/03/2021] [Indexed: 12/13/2022] Open
Abstract
Systemic knockdown of the long form prolactin receptor in vivo increases survival in an aggressive, immunocompetent model of stage IV, triple negative breast cancer. Knockdown of the long form prolactin receptor reduces Treg recruitment to tumors by reducing tumor parenchymal production of CCL-17. Those Tregs still recruited to primary tumors have a substantial reduction in their ability to promote epithelial to mesenchymal transition of tumor parenchyma. For the Tregs in the primary tumor, there is transcript downregulation of components of the T cell receptor complex and CTLA-4. Tregs outside of the tumor have normal ability to suppress T effector cell proliferation after 1–5 months of treatment. Knockdown of the long form of the prolactin receptor therefore seems to have an intra-tumor immunotherapeutic effect without effect on peripheral Treg function. Previous work has shown systemic knockdown of the long form prolactin receptor (LFPRLR) in vivo markedly reduced metastasis in mouse models of breast cancer, but whether this translated to prolonged survival was unknown. Here we show that LFPRLR knockdown in the highly metastatic, immunocompetent 4T1 model prolonged survival and reduced recruitment of T regulatory cells (Tregs) to the tumor through effects on the production of CCL17. For the Tregs still recruited to the primary tumor, LFPRLR knockdown both directly and indirectly reduced their ability to promote tumor parenchymal epithelial to mesenchymal transition. Importantly, effects of prolactin on expression of mesenchymal genes by the tumor parenchyma were very different in the absence and presence of Tregs. While systemic knockdown of the LFPRLR downregulated transcripts important for immune synapse function in the remaining tumor Tregs, splenic Tregs seemed unaffected by LFPRLR knockdown, as demonstrated by their continued ability to suppress anti-CD3/CD28-stimulated effector cell proliferation at 1–5 months. These results demonstrate that knockdown of the LFPRLR achieves intra-tumor immunotherapeutic effects and suggest this occurs with reduced likelihood of peripheral inflammatory/autoimmune sequelae.
Collapse
Affiliation(s)
- Kuan-Hui Ethan Chen
- Division of Biomedical Sciences, University of California, Riverside, CA 92521, United States.
| | - Mrinal Ghosh
- Division of Biomedical Sciences, University of California, Riverside, CA 92521, United States
| | - Lorena Rivera
- Division of Biomedical Sciences, University of California, Riverside, CA 92521, United States
| | - Samuel Lin
- Division of Biomedical Sciences, University of California, Riverside, CA 92521, United States
| | - Anil Kumar
- Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010, United States
| | - Srividya Swaminathan
- Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010, United States
| | - Mary Y Lorenson
- Division of Biomedical Sciences, University of California, Riverside, CA 92521, United States
| | - Ameae M Walker
- Division of Biomedical Sciences, University of California, Riverside, CA 92521, United States.
| |
Collapse
|
|
17
|
Xue S, Ma M, Bei S, Li F, Wu C, Li H, Hu Y, Zhang X, Qian Y, Qin Z, Jiang J, Feng L. Identification and Validation of the Immune Regulator CXCR4 as a Novel Promising Target for Gastric Cancer. Front Immunol 2021; 12:702615. [PMID: 34322132 PMCID: PMC8311657 DOI: 10.3389/fimmu.2021.702615] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 06/10/2021] [Indexed: 12/24/2022] Open
Abstract
Immune checkpoint blockade has attracted a lot of attention in the treatment of human malignant tumors. We are trying to establish a prognostic model of gastric cancer (GC) based on the expression profile of immunoregulatory factor-related genes. Based on the TCGA database, we identified 234 differentially expressed immunoregulatory factors. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) conducted enrichment analysis to clarify the biological functions of differential expression of immunoregulatory factors. STRING database predicted the interaction network between 234 differently expressed immune regulatory factors. The expression of 11 immunoregulatory factors was significantly related to the overall survival of gastric cancer patients. Univariate Cox regression analysis, Kaplan–Meier analysis and multivariate Cox regression analysis found that immunomodulatory factors were involved in the progression of gastric cancer and promising biomarkers for predicting prognosis. Among them, CXCR4 was related to the low survival of GC patients and a key immunomodulatory factor in GC. Based on TCGA data, the high expression of CXCR4 in GC was positively correlated with the advanced stage and grade of gastric cancer and related to poor prognosis. Univariate analysis and multivariate analysis indicated that CXCR4 was an independent prognostic indicator for TCGA gastric cancer patients. In vitro functional studies had shown that CXCR4 promoted the proliferation, migration, and invasion of gastric cancer cells. In summary, this study has determined the prognostic value of 11 immunomodulatory factors in gastric cancer. CXCR4 is an independent prognostic indicator for gastric cancer patients, which may help to improve the individualized prognostic prediction of GC and provide candidates for the diagnosis and treatment of GC.
Collapse
Affiliation(s)
- Shuai Xue
- Endoscopy Center, Minhang Hospital, Fudan University, Shanghai, China
| | - Ming Ma
- Department of Gastroenterology, Minhang Hospital, Fudan University, Shanghai, China
| | - Songhua Bei
- Endoscopy Center, Minhang Hospital, Fudan University, Shanghai, China
| | - Fan Li
- Endoscopy Center, Minhang Hospital, Fudan University, Shanghai, China
| | - Chenqu Wu
- Endoscopy Center, Minhang Hospital, Fudan University, Shanghai, China
| | - Huanqing Li
- Endoscopy Center, Minhang Hospital, Fudan University, Shanghai, China
| | - Yanling Hu
- Institute of Fudan Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, China
| | - Xiaohong Zhang
- Endoscopy Center, Minhang Hospital, Fudan University, Shanghai, China
| | - YanQing Qian
- Endoscopy Center, Minhang Hospital, Fudan University, Shanghai, China
| | - Zhe Qin
- Endoscopy Center, Minhang Hospital, Fudan University, Shanghai, China
| | - Jun Jiang
- Endoscopy Center, Minhang Hospital, Fudan University, Shanghai, China
| | - Li Feng
- Endoscopy Center, Minhang Hospital, Fudan University, Shanghai, China
| |
Collapse
|
|
18
|
Yun S, Koh J, Nam SK, Kwak Y, Ahn SH, Do Park J, Kim HH, Kim WH, Lee HS. Immunoscore is a strong predictor of survival in the prognosis of stage II/III gastric cancer patients following 5-FU-based adjuvant chemotherapy. Cancer Immunol Immunother 2021; 70:431-441. [PMID: 32785776 PMCID: PMC10991343 DOI: 10.1007/s00262-020-02694-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Accepted: 08/04/2020] [Indexed: 12/25/2022]
Abstract
The prognostic impact of Immunoscore (IS) in gastric cancer (GC) patients treated with adjuvant chemotherapy remains unelucidated. We evaluated the CD3 + , CD8 + , and Foxp3 + T-lymphocyte densities in tumor centers and invasive margin regions of 389 patients with surgically resected stage II/III GC who received 5-FU-based adjuvant chemotherapy and investigated the impact of IS on survival. In univariate analysis, high CD3 + , CD8 + , and Foxp3 + T-lymphocyte densities in the invasive margin were correlated with better prognosis (all P < 0.05). Patients with high IS had significantly longer disease-free survival (DFS; P < 0.001) and overall survival (OS; P < 0.001). In multivariate analysis, IS demonstrated a powerful prognostic impact on patient outcome [DFS, hazard ratio (HR) = 0.465; 95% confidence interval (CI), 0.306-0.707, P < 0.001; OS, HR = 0.478; 95% CI, 0.308-0.743, P = 0.001]. Additionally, although all EBV-positive cases had high IS, IS was similar in both microsatellite instability (MSI)-high and microsatellite stable (MSS)/MSI-low groups (83.3% and 80.5%, respectively). Subgroup analysis according to MSI status revealed that high IS patients had significant DFS and OS benefits in both MSS/MSI-low (DFS, HR = 0.527, 95% CI, 0.341-0.816, P = 0.004; OS, HR = 0.528, 95% CI, 0.334-0.837, P = 0.007) and MSI-high (DFS, HR = 0.166, 95% CI, 0.033-0.826, P = 0.028; OS, HR = 0.177, 95% CI, 0.036-0.883, P = 0.035) groups. Thus, the assessment of immune cell infiltration based on IS may provide a strong indicator of survival in stage II/III GC patients with curative resection following 5-FU-based adjuvant chemotherapy.
Collapse
Affiliation(s)
- Sumi Yun
- Department of Diagnostic Pathology, Samkwang Medical Laboratories, Seoul, Republic of Korea
| | - Jiwon Koh
- Department of Pathology, Seoul National University Hospital, Seoul, Republic of Korea
| | - Soo Kyung Nam
- Department of Pathology, Seoul National University Bundang Hospital, 173-82 Gumiro, Bundang-gu, Gyeonggi-do, Seongnam-si, 463-707, Republic of Korea
| | - Yoonjin Kwak
- Department of Pathology, Seoul National University Hospital, Seoul, Republic of Korea
- Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Sang-Hoon Ahn
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Joong Do Park
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Hyung-Ho Kim
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Woo Ho Kim
- Department of Pathology, Seoul National University Hospital, Seoul, Republic of Korea
- Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University Bundang Hospital, 173-82 Gumiro, Bundang-gu, Gyeonggi-do, Seongnam-si, 463-707, Republic of Korea.
- Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea.
| |
Collapse
|
|
19
|
Rocha S, Basto AP, Ijsselsteijn ME, Teles SP, Azevedo MM, Gonçalves G, Gullo I, Almeida GM, Maqueda JJ, Oliveira MI, Carneiro F, Barata JT, Graça L, de Miranda NFCC, Carvalho J, Oliveira C. Immunophenotype of Gastric Tumors Unveils a Pleiotropic Role of Regulatory T Cells in Tumor Development. Cancers (Basel) 2021; 13:cancers13030421. [PMID: 33498681 PMCID: PMC7865950 DOI: 10.3390/cancers13030421] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 01/19/2021] [Accepted: 01/20/2021] [Indexed: 01/26/2023] Open
Abstract
Gastric cancer (GC) patients display increased regulatory T cell (Tregs) numbers in peripheral blood and among tumor-infiltrating lymphocytes. Nevertheless, the role of Tregs in GC progression remains controversial. Here, we sought to explore the impact of Tregs in GCs with distinct histology, and whether Tregs can directly influence tumor cell behavior and GC development. We performed a comprehensive immunophenotyping of 82 human GC cases, through an integrated analysis of multispectral immunofluorescence detection of T cells markers and patient clinicopathological data. Moreover, we developed 3D in vitro co-cultures with Tregs and tumor cells that were followed by high-throughput and light-sheet imaging, and their biological features studied with conventional/imaging flow cytometry and Western blotting. We showed that Tregs located at the tumor nest were frequent in intestinal-type GCs but did not associate with increased levels of effector T cells. Our in vitro results suggested that Tregs preferentially infiltrated intestinal-type GC spheroids, induced the expression of IL2Rα and activation of MAPK signaling pathway in tumor cells, and promoted spheroid growth. Accumulation of Tregs in intestinal-type GCs was increased at early stages of the stomach wall invasion and in the absence of vascular and perineural invasion. In this study, we proposed a non-immunosuppressive mechanism through which Tregs might directly modulate GC cells and thereby promote tumor growth. Our findings hold insightful implications for therapeutic strategies targeting intestinal-type GCs and other tumors with similar immune context.
Collapse
Affiliation(s)
- Sara Rocha
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (S.R.); (S.P.T.); (M.M.A.); (I.G.); (G.M.A.); (J.J.M.); (F.C.); (J.C.)
- Ipatimup—Institute of Molecular Pathology and Immunology of University of Porto, 4200-135 Porto, Portugal
- Doctoral Program on Cellular and Molecular Biotechnology Applied to Health Sciences, ICBAS—Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal
| | - Afonso P Basto
- iMM—Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, 1649-028 Lisbon, Portugal; (A.P.B.); (J.T.B.); (L.G.)
- Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal
| | - Marieke E Ijsselsteijn
- Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (M.E.I.); (N.F.C.C.d.M.)
| | - Sara P Teles
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (S.R.); (S.P.T.); (M.M.A.); (I.G.); (G.M.A.); (J.J.M.); (F.C.); (J.C.)
- Ipatimup—Institute of Molecular Pathology and Immunology of University of Porto, 4200-135 Porto, Portugal
| | - Maria M Azevedo
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (S.R.); (S.P.T.); (M.M.A.); (I.G.); (G.M.A.); (J.J.M.); (F.C.); (J.C.)
| | - Gilza Gonçalves
- Department of Pathology, Faculty of Medicine of the University of Porto (FMUP), 4200-319 Porto, Portugal;
| | - Irene Gullo
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (S.R.); (S.P.T.); (M.M.A.); (I.G.); (G.M.A.); (J.J.M.); (F.C.); (J.C.)
- Ipatimup—Institute of Molecular Pathology and Immunology of University of Porto, 4200-135 Porto, Portugal
- Department of Pathology, Faculty of Medicine of the University of Porto (FMUP), 4200-319 Porto, Portugal;
- Department of Pathology, Centro Hospitalar Universitário de São João, 4200-319 Porto, Portugal
| | - Gabriela M Almeida
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (S.R.); (S.P.T.); (M.M.A.); (I.G.); (G.M.A.); (J.J.M.); (F.C.); (J.C.)
- Ipatimup—Institute of Molecular Pathology and Immunology of University of Porto, 4200-135 Porto, Portugal
- Department of Pathology, Faculty of Medicine of the University of Porto (FMUP), 4200-319 Porto, Portugal;
| | - Joaquín J Maqueda
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (S.R.); (S.P.T.); (M.M.A.); (I.G.); (G.M.A.); (J.J.M.); (F.C.); (J.C.)
- Ipatimup—Institute of Molecular Pathology and Immunology of University of Porto, 4200-135 Porto, Portugal
| | - Marta I Oliveira
- International Iberian Nanotechnology Laboratory, 4715-330 Braga, Portugal;
| | - Fátima Carneiro
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (S.R.); (S.P.T.); (M.M.A.); (I.G.); (G.M.A.); (J.J.M.); (F.C.); (J.C.)
- Ipatimup—Institute of Molecular Pathology and Immunology of University of Porto, 4200-135 Porto, Portugal
- Department of Pathology, Faculty of Medicine of the University of Porto (FMUP), 4200-319 Porto, Portugal;
- Department of Pathology, Centro Hospitalar Universitário de São João, 4200-319 Porto, Portugal
| | - João T Barata
- iMM—Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, 1649-028 Lisbon, Portugal; (A.P.B.); (J.T.B.); (L.G.)
| | - Luís Graça
- iMM—Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, 1649-028 Lisbon, Portugal; (A.P.B.); (J.T.B.); (L.G.)
- Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal
| | - Noel F C C de Miranda
- Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (M.E.I.); (N.F.C.C.d.M.)
| | - Joana Carvalho
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (S.R.); (S.P.T.); (M.M.A.); (I.G.); (G.M.A.); (J.J.M.); (F.C.); (J.C.)
- Ipatimup—Institute of Molecular Pathology and Immunology of University of Porto, 4200-135 Porto, Portugal
| | - Carla Oliveira
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (S.R.); (S.P.T.); (M.M.A.); (I.G.); (G.M.A.); (J.J.M.); (F.C.); (J.C.)
- Ipatimup—Institute of Molecular Pathology and Immunology of University of Porto, 4200-135 Porto, Portugal
- Department of Pathology, Faculty of Medicine of the University of Porto (FMUP), 4200-319 Porto, Portugal;
- Correspondence: ; Tel.: +351-225-570-785
| |
Collapse
|
|
20
|
The impaired anti-tumoral effect of immune surveillance cells in the immune microenvironment of gastric cancer. Clin Immunol 2020; 219:108551. [DOI: 10.1016/j.clim.2020.108551] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 07/07/2020] [Accepted: 07/28/2020] [Indexed: 12/11/2022]
|
|
21
|
Batool A, Liu H, Liu YX, Chen SR. CD83, a Novel MAPK Signaling Pathway Interactor, Determines Ovarian Cancer Cell Fate. Cancers (Basel) 2020; 12:cancers12082269. [PMID: 32823589 PMCID: PMC7465057 DOI: 10.3390/cancers12082269] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 08/07/2020] [Accepted: 08/11/2020] [Indexed: 12/12/2022] Open
Abstract
Ovarian cancer is a leading cause of death from gynecologic malignancies worldwide. Although CD83 is widely described as a solid marker for mature dendritic cells, emerging pieces of evidence indicate the expression of membrane protein CD83 by various tumor cells, including ovarian cancer cells. However, the potential role of CD83 in ovarian cancer cell properties and development remains absolutely unknown. By using human CD83 stable overexpression and knockdown sublines of several ovarian cancer cells, we observed that CD83 advanced the growth proliferation, colony formation ability, spheroid formation, and in vivo tumorigenicity of ovarian cancer cells; surprisingly, CD83 limited their migration and invasion potentials. Positive regulation of proliferation/stemness factors (e.g., cyclin-CDKs and KIT/CD44) but negative regulation of matrix metallopeptidases (e.g., MMP1 and 7) by CD83 were revealed by the integrated analysis of transcriptome and proteome. Furthermore, immunoprecipitation-mass spectrometry (IP-MS) and co-immunoprecipitation (Co-IP) first identified the association of CD83 with MAP3K7 (also known as TAK1) and MAP3K7-binding protein TAB1 on the cell membrane. Moreover, CD83 functions through the activation of MAP3K7-MEK1/2-ERK1/2 cascades to further regulate downstream FOXO1/p21/CDK2/CCNB1 and STAT3/DKK1 signaling pathways, thus activating proliferation and spheroid formation of ovarian cancer cells, respectively. Collectively, our findings define a CD83-MAPK pathway in the regulation of proliferation and stemness in ovarian cancer cells, with potential therapeutic applications in blocking their progression.
Collapse
Affiliation(s)
- Aalia Batool
- Laboratory of Cell Proliferation & Regulation Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, China; (A.B.); (H.L.)
- Laboratory of Reproductive Neuroendocrinology, Department of Zoology, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China;
| | - Hao Liu
- Laboratory of Cell Proliferation & Regulation Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, China; (A.B.); (H.L.)
| | - Yi-Xun Liu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China;
| | - Su-Ren Chen
- Laboratory of Cell Proliferation & Regulation Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, China; (A.B.); (H.L.)
- Correspondence:
| |
Collapse
|
|
22
|
Zhang N, Wang D, Duan Y, Ayarick VA, Cao M, Wang Y, Zhang G, Wang Y. The special immune microenvironment of tumor budding and its impact on prognosis in gastric adenocarcinoma. Pathol Res Pract 2020; 216:152926. [PMID: 32327282 DOI: 10.1016/j.prp.2020.152926] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 02/23/2020] [Accepted: 03/14/2020] [Indexed: 12/30/2022]
Abstract
Recent studies showed that the tumor-infiltrating lymphocytes (TILs) are not randomly distributed, but organized to accumulate more or less densely in different regions within tumors, which have provoked new thoughts on cancer management. In this study we explored the characteristics of tumor immunemicroenvironment (TIME) for the tumor budding (TB) and lymphocytes in patients with gastric adenocarcinoma (GAC) as well as their prognostic significance. The TILs around the TB at the invasive margin were assessed by double-immunohistochemistry staining for the CD8, FOXP3, OX40 and GrB phenotypes. Results showed that there was a negative correlation between the density of TB and TILs in the budding area, tumor stroma and parenchyma. And the number of TILs around the TB was evidently reduced, compared with TILs in the non-budding region (P < 0.001). Additionally, the number of TILs in turn changed from non-budding area CD8+>FOXP3+>OX40+> GrB + T cells to FOXP3+>CD8+>OX40 + T > GrB + T cells in budding area. Survival rate was significantly lower in patients who had a higher density of TB (P < 0.001) and a lower density of TILs (P = 0.013). We concluded that TB was surrounded by a weak immune surveillance and immunosuppressive response supported the spatial heterogeneity in the TIME of gastric adenocarcinomas. The regional heterogeneity should be attached importance for identifying the influence of the TIME on cancer development and evolution.
Collapse
Affiliation(s)
- Nana Zhang
- Institute for Cancer Research, School of Basic Medical Science, Health Science Center of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Depu Wang
- Department of Science and Technology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Yixin Duan
- Institute for Cancer Research, School of Basic Medical Science, Health Science Center of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Vivian Adiila Ayarick
- Institute for Cancer Research, School of Basic Medical Science, Health Science Center of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Meng Cao
- Institute for Cancer Research, School of Basic Medical Science, Health Science Center of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Ying Wang
- Institute for Cancer Research, School of Basic Medical Science, Health Science Center of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Guanjun Zhang
- Department of Pathology, The First Affiliated Hospital of Xi'an Jiaotong University, Xian, Shaanxi, 710061, China.
| | - Yili Wang
- Institute for Cancer Research, School of Basic Medical Science, Health Science Center of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China.
| |
Collapse
|
|
23
|
Liposomal TLR9 Agonist Combined with TLR2 Agonist-Fused Antigen Can Modulate Tumor Microenvironment through Dendritic Cells. Cancers (Basel) 2020; 12:cancers12040810. [PMID: 32231003 PMCID: PMC7225995 DOI: 10.3390/cancers12040810] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 03/23/2020] [Accepted: 03/26/2020] [Indexed: 12/14/2022] Open
Abstract
Dendritic cells (DCs) are antigen-presenting cells involved in T cell activation and differentiation to regulate immune responses. Lipoimmunogens can be developed as pharmaceutical lipoproteins for cancer immunotherapy to target DCs via toll-like receptor 2 (TLR2) signaling. Previously, we constructed a lipoimmunogen, a lipidated human papillomavirus (HPV) E7 inactive mutant (rlipoE7m), to inhibit the growth of HPV16 E7-expressing tumor cells in a murine model. Moreover, this antitumor effect could be enhanced by a combinatory treatment with CpG oligodeoxynucleotides (ODN). To improve safety, we developed a rlipoE7m plus DOTAP liposome-encapsulated native phosphodiester CpG (POCpG/DOTAP) treatment to target DCs to enhance antitumor immunity. We optimized the formulation of rlipoE7m and POCpG/DOTAP liposomes to promote conventional DC and plasmacytoid DC maturation in vitro and in vivo. Combination of rlipoE7m plus POCpG/DOTAP could activate conventional DCs and plasmacytoid DCs to augment IL-12 production to promote antitumor responses by intravenous injection. In addition, the combination of rlipoE7m plus POCpG/DOTAP could elicit robust cytotoxic T lymphocytes (CTLs) by intravenous immunization. Interestingly, the combination of rlipoE7m plus POCpG/DOTAP could efficiently inhibit tumor growth via intravenous immunization. Moreover, rlipoE7m plus POCpG/DOTAP combined reduced the number of tumor-infiltrating regulatory T cells dramatically due to downregulation of IL-10 production by DCs. These results showed that the combination of rlipoE7m plus POCpG/DOTAP could target DCs via intravenous delivery to enhance antitumor immunity and reduce the number of immunosuppressive cells in the tumor microenvironment.
Collapse
|
|
24
|
Notch1/2/3/4 are prognostic biomarker and correlated with immune infiltrates in gastric cancer. Aging (Albany NY) 2020; 12:2595-2609. [PMID: 32028262 PMCID: PMC7041744 DOI: 10.18632/aging.102764] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 01/12/2020] [Indexed: 02/06/2023]
Abstract
Notch refers to a set of genes encoding a family of transmembrane receptors in mammalian cells. Previous evidence indicated that Notch receptors were implicated in the onset of gastric cancer. However, there is little evidence on the different genetic expression patterns of the four Notch receptors and their values for patient prognosis. Most recently, we investigated the transcriptional data of Notch receptors and related patient survival in patients with GC based on several databases, including ONCOMINE, GEPIA, Kaplan–Meier Plotter, cBioPortal and TIMER. According to our findings, gastric cancer tissues, compared with adjacent normal tissues presented a higher level of expression of Notch1/2/3. We also performed a survival analysis and noted that gastric cancer patients with high transcription levels of Notch1/2/3/4 had a low relapse-free survival. In gastric cancer patients, higher levels of infiltration in their CD4+ T cells, macrophages, neutrophils, and dendritic cells were positive associated with the expression of Notch receptors. Notch expression had significant association with diverse immune marker sets in gastric cancer. Overall, this study provides evidence that Notch1/2/3/4 could become the potential targets for precision treatment and new biomarkers in the prognosis of gastric cancer.
Collapse
|
|
25
|
Wijesekera DPH, Yuba E, De Silva NH, Watanabe SI, Tsukamoto M, Ichida C, Izawa T, Itoh K, Kanegi R, Hatoya S, Yamate J, Inaba T, Sugiura K. Manipulation of the tumor microenvironment by cytokine gene transfection enhances dendritic cell-based immunotherapy. FASEB Bioadv 2020; 2:5-17. [PMID: 32123853 PMCID: PMC6996313 DOI: 10.1096/fba.2019-00052] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 06/21/2019] [Accepted: 11/06/2019] [Indexed: 01/21/2023] Open
Abstract
The tumor microenvironment strongly influences clinical outcomes of immunotherapy. By transfecting genes of relevant cytokines into tumor cells, we sought to manipulate the microenvironment so as to elicit activation of T helper type 1 (Th1) responses and the maturation of dendritic cells (DCs). Using a synthetic vehicle, the efficiency of in vivo transfection of GFP-cDNA into tumor cells was about 7.5% by intratumoral injection and about 11.5% by intravenous injection. Survival was significantly improved by both intratumoral and intravenous injection of the plasmid containing cDNA of interferon-gamma, followed by intratumoral injection of DCs presenting the tumor antigens. Also, tumor growth was inhibited by these treatments. A more significant effect on survival and tumor growth inhibition was observed following injection of the plasmid containing cDNA of CD40 ligand, which is a potent inducer of DC-maturation. Furthermore, the co-injection of both IFNγ- and CD40 ligand-encoding cDNA-plasmids, followed by DC treatment, gave rise to further marked and enhancement, including 100% survival and more than 50% complete remission. This treatment regimen elicited significant increases in mature DCs and types of cells contributing to Th1 responses, and significant decreases in immune suppressor cells in the tumor. In the spleen, the treatment significantly increased activities of tumor-specific killer and natural killer cells, but no alteration was observed in mature DCs or suppressor cells. These results indicate that transfection of these cytokine genes into tumor cells significantly alter the tumor microenvironment and improve the therapeutic results of DC-based immunotherapy.
Collapse
Affiliation(s)
- Daluthgamage Patsy Himali Wijesekera
- Department of Advanced Pathobiology Graduate School of Life and Environmental Sciences Osaka Prefecture University Izumisano Japan
- Present address: Department of Pathobiology Faculty of Veterinary Medicine and Animal Science University of Peradeniya Peradeniya Sri Lanka
| | - Eiji Yuba
- Department of Applied Chemistry Graduate School of Engineering Osaka Prefecture University Sakai Japan
| | - Nadeeka Harshini De Silva
- Department of Advanced Pathobiology Graduate School of Life and Environmental Sciences Osaka Prefecture University Izumisano Japan
| | - Shun-Ichi Watanabe
- Department of Advanced Pathobiology Graduate School of Life and Environmental Sciences Osaka Prefecture University Izumisano Japan
| | - Masaya Tsukamoto
- Department of Advanced Pathobiology Graduate School of Life and Environmental Sciences Osaka Prefecture University Izumisano Japan
| | - Chihiro Ichida
- Department of Advanced Pathobiology Graduate School of Life and Environmental Sciences Osaka Prefecture University Izumisano Japan
| | - Takeshi Izawa
- Department of Integrated Structural Biosciences Graduate School of Life and Environmental Sciences Osaka Prefecture University Izumisano Osaka Japan
| | - Kazuyuki Itoh
- Research Institute Nozaki Tokushukai Daitou City Japan
| | - Ryoji Kanegi
- Department of Advanced Pathobiology Graduate School of Life and Environmental Sciences Osaka Prefecture University Izumisano Japan
| | - Shingo Hatoya
- Department of Advanced Pathobiology Graduate School of Life and Environmental Sciences Osaka Prefecture University Izumisano Japan
| | - Jyoji Yamate
- Department of Integrated Structural Biosciences Graduate School of Life and Environmental Sciences Osaka Prefecture University Izumisano Osaka Japan
| | - Toshio Inaba
- Department of Advanced Pathobiology Graduate School of Life and Environmental Sciences Osaka Prefecture University Izumisano Japan
| | - Kikuya Sugiura
- Department of Advanced Pathobiology Graduate School of Life and Environmental Sciences Osaka Prefecture University Izumisano Japan
| |
Collapse
|
|
26
|
Li F, Sun Y, Huang J, Xu W, Liu J, Yuan Z. CD4/CD8 + T cells, DC subsets, Foxp3, and IDO expression are predictive indictors of gastric cancer prognosis. Cancer Med 2019; 8:7330-7344. [PMID: 31631566 PMCID: PMC6885892 DOI: 10.1002/cam4.2596] [Citation(s) in RCA: 96] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Revised: 08/28/2019] [Accepted: 09/17/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The tumor microenvironment represents an abnormal niche containing numerous factors, such as T cells, dendritic cells (DCs), regulatory T cells (Tregs), and indoleamine 2,3-dioxygenase (IDO), involved in maintaining immune homeostasis and tolerance. All these factors may influence the choice of therapy and the clinical outcomes. METHODS Flow cytometry was performed to identify CD4+/CD8 + T cells and DCs, and immunohistochemistry was used to evaluate IDO and Forkhead Box P3 (Foxp3) expression; these experiments were performed in order to explore the clinical and prognostic significance of CD4/CD8 + T cells, DCs, Tregs, and IDO expression in gastric carcinoma. RESULTS Smaller tumor size was correlated with higher expression levels of peripheral CD4 + T cells (P = .003) and CD8 + T cells (P = .002), and lower IDO expression (P = .044) in tumors. Well-differentiated gastric carcinomas displayed higher peripheral (P = .029) and tumor-infiltrating CD4 + T cell (P = .009) populations and a higher tumor-infiltrating DC1/DC2 ratio (P = .048). Gastric cancer in the early T stages exhibited higher populations of peripheral DC2s (P = .044) and a higher tumor-infiltrating DC1/DC2 ratio (P = .012). Gastric cancer at the N0 stage had lower tumor-infiltrating DC2s (P = .032) and a higher DC1/DC2 ratio (P = .037). IDO expression was positively correlated with tumor-infiltrating Foxp3 + Tregs (P < .001) as well as DC2s (P < .001), whereas it was negatively correlated with the tumor-infiltrating CD4/CD8 + T cell ratio (P = .023). Tumor-infiltrating Foxp3 + Treg was positively correlated with tumor-infiltrating DC2s (r2 = 0.772; P < .001). At T, N, and TNM stages, the expression levels of peripheral DC2s, tumor-infiltrating DC1/DC2 ratios, Foxp3 + Tregs, and IDO were significantly correlated with prognosis (P < .05). The T stage and peripheral DC2s were significant risk factors for overall survival. CONCLUSION Immunocompetent cells and humoral immune factors, including DC2s, CD4+/CD8 + T cells, Foxp3 + Tregs, and IDO, interact with each other to compose a complex community of tumor immune microenvironment, ultimately affecting tumor progression and survival of gastric cancer.
Collapse
Affiliation(s)
- Fangxuan Li
- Department of Radiotherapy, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Department of Cancer Prevention, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Yao Sun
- Department of Radiotherapy, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China
| | - Jinchao Huang
- Department of Cancer Prevention, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,Department of Molecular Imaging and Nuclear Medicine, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Wengui Xu
- Department of Molecular Imaging and Nuclear Medicine, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Juntian Liu
- Department of Cancer Prevention, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Zhiyong Yuan
- Department of Radiotherapy, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China
| |
Collapse
|
|
27
|
Zhang N, Cao M, Duan Y, Bai H, Li X, Wang Y. Prognostic role of tumor-infiltrating lymphocytes in gastric cancer: a meta-analysis and experimental validation. Arch Med Sci 2019; 16:1092-1103. [PMID: 32863998 PMCID: PMC7444703 DOI: 10.5114/aoms.2019.86101] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Accepted: 02/15/2018] [Indexed: 02/06/2023] Open
Abstract
INTRODUCTION We performed a meta-analysis and an experimental validation to investigate the association between tumor infiltrating lymphocytes (TILs) and the outcome of gastric cancer (GC) patients to provide prognostic indicators for clinical practice. MATERIAL AND METHODS The relative literature of TILs in tumor tissue from patients with gastric cancer was searched from PubMed, Embase, NIH databases, from April 2000 to 31 December 2016. Studies on the prognostic value of TILs as CD3+, CD4+, CD8+, GrB+, and FOXP3+ lymphocytes for GC were retrieved, and also the related references were traced as supplements. Independent screening documents, extracting information and evaluating quality were implemented independently by 2 evaluators according to the inclusion and exclusion criteria, which were then analyzed by meta-analysis using STATA version 12.0 software. RESULTS The results indicated that high levels of intratumoral CD8+, CD3+ and CD4+ T cell infiltration were associated with better overall survival(OS) in gastric cancer patients, while high density of intratumoral FOXP3+ T cells was not closely associated with a worse outcome. Additionally, in our study, higher density of granzyme B+ (GrB+) T cell infiltration indicated an optimistic prognosis, and infiltration of a larger number of general TILs also suggested a favorable prognosis by log-rank test analysis. CONCLUSIONS This meta-analysis clarified that high levels of CD8+, CD3+, and CD4+ T cell infiltration in tumor tissue showed better OS in GC patients, whereas high density of FOXP3+ T cell infiltration may not be recognized as a negative prognostic factor. These results may provide some useful prognostic indicators for clinical application in gastric cancer.
Collapse
Affiliation(s)
- Nana Zhang
- Institute of Cancer Research, School of Basic Medical Science, Xi'an Jiaotong University Xi'an, China
| | - Meng Cao
- Institute of Cancer Research, School of Basic Medical Science, Xi'an Jiaotong University Xi'an, China
| | - Yixin Duan
- Institute of Cancer Research, School of Basic Medical Science, Xi'an Jiaotong University Xi'an, China
| | - Haixia Bai
- Institute of Cancer Research, School of Basic Medical Science, Xi'an Jiaotong University Xi'an, China
| | - Xiang Li
- Institute of Cancer Research, School of Basic Medical Science, Xi'an Jiaotong University Xi'an, China
| | - Yili Wang
- Institute of Cancer Research, School of Basic Medical Science, Xi'an Jiaotong University Xi'an, China
| |
Collapse
|
|
28
|
Recent advances in the study of regulatory T cells in gastric cancer. Int Immunopharmacol 2019; 73:560-567. [PMID: 31181438 DOI: 10.1016/j.intimp.2019.05.009] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Revised: 05/05/2019] [Accepted: 05/06/2019] [Indexed: 12/15/2022]
Abstract
Gastric cancer (GC), which features a complex pathogenesis and mechanism, remains refractory. FOXP3+ regulatory T cells (Tregs), which have been implicated in the progression of gastric cancer, play an immunosuppressive role in the tumor microenvironment. However, the prognostic value of Treg infiltration is still controversial in GC patients. Recently, the association of Tregs with the clinicopathological characteristics of GC patients, the prognostic value of Tregs alone or its combination with other factors to GC patients, the role of Tregs in GC tumor microenvironment, clinical applications and Tregs-targeted therapies for GC patients have become hot issues. In this review, we are going to discuss these scientific researches which focused on these topics.
Collapse
|
|
29
|
Li Z, Ju X, Silveira PA, Abadir E, Hsu WH, Hart DNJ, Clark GJ. CD83: Activation Marker for Antigen Presenting Cells and Its Therapeutic Potential. Front Immunol 2019; 10:1312. [PMID: 31231400 PMCID: PMC6568190 DOI: 10.3389/fimmu.2019.01312] [Citation(s) in RCA: 99] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Accepted: 05/23/2019] [Indexed: 12/17/2022] Open
Abstract
CD83 is a member of the immunoglobulin (Ig) superfamily and is expressed in membrane bound or soluble forms. Membrane CD83 (mCD83) can be detected on a variety of activated immune cells, although it is most highly and stably expressed by mature dendritic cells (DC). mCD83 regulates maturation, activation and homeostasis. Soluble CD83 (sCD83), which is elevated in the serum of patients with autoimmune disease and some hematological malignancies is reported to have an immune suppressive function. While CD83 is emerging as a promising immune modulator with therapeutic potential, some important aspects such as its ligand/s, intracellular signaling pathways and modulators of its expression are unclear. In this review we discuss the recent biological findings and the potential clinical value of CD83 based therapeutics in various conditions including autoimmune disease, graft-vs.-host disease, transplantation and hematological malignancies.
Collapse
Affiliation(s)
- Ziduo Li
- Dendritic Cell Research, ANZAC Research Institute, Sydney, NSW, Australia
- Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
| | - Xinsheng Ju
- Dendritic Cell Research, ANZAC Research Institute, Sydney, NSW, Australia
- Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
| | - Pablo A. Silveira
- Dendritic Cell Research, ANZAC Research Institute, Sydney, NSW, Australia
- Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
| | - Edward Abadir
- Dendritic Cell Research, ANZAC Research Institute, Sydney, NSW, Australia
- Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
| | - Wei-Hsun Hsu
- Dendritic Cell Research, ANZAC Research Institute, Sydney, NSW, Australia
- Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
| | - Derek N. J. Hart
- Dendritic Cell Research, ANZAC Research Institute, Sydney, NSW, Australia
- Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
| | - Georgina J. Clark
- Dendritic Cell Research, ANZAC Research Institute, Sydney, NSW, Australia
- Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
| |
Collapse
|
|
30
|
Izumi D, Gao F, Toden S, Sonohara F, Kanda M, Ishimoto T, Kodera Y, Wang X, Baba H, Goel A. A genomewide transcriptomic approach identifies a novel gene expression signature for the detection of lymph node metastasis in patients with early stage gastric cancer. EBioMedicine 2019; 41:268-275. [PMID: 30772302 PMCID: PMC6441863 DOI: 10.1016/j.ebiom.2019.01.057] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Revised: 01/29/2019] [Accepted: 01/30/2019] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Although identification of lymph node (LN) metastasis is a well-recognized strategy for improving outcomes in patients with gastric cancer (GC), currently there is lack of availability of adequate molecular biomarkers that can identify such metastasis. Herein we have developed a robust gene-expression signature for detecting LN metastasis in early stage GC by using a transcriptome-wide biomarker discovery and subsequent validation in multiple clinical cohorts. METHODS A total of 532 patients with pathological T1 and T2 GC from 4 different cohorts were analyzed. Two independent datasets (n = 96, and n = 188) were used to establish a gene signature for the identification of LN metastasis in GC patients. The diagnostic performance of our gene-expression signature was subsequently assessed in two independent clinical cohorts using qRT-PCR assays (n = 101, and n = 147), and subsequently compared against conventional tumor markers and image-based diagnostics. FINDINGS We established a 15-gene signature by analyzing multiple high throughput datasets, which robustly distinguished LN status in both training (AUC = 0.765, 95% CI 0.667-0.863) and validation cohorts (AUC = 0.742, 95% CI 0.630-0.852). Notably, the 15-gene signature was significantly superior compared to the conventional tumor markers, CEA (P = .04) and CA19-9 (P = .005), as well as computed tomography-based imaging (P = .04). INTERPRETATION We have established and validated a 15-gene signature for detecting LN metastasis in GC patients, which offers a robust diagnostic tool for potentially improving treatment outcomes in gastric cancer patients. FUND: NIH: CA72851, CA181572, CA14792, CA202797, CA187956; CPRIT: RP140784: Baylor Sammons Cancer Center polot grants (AG), VPRT: 9610337, CityU 21101115, 11102317, 11103718; JCYJ20170307091256048 (XW).
Collapse
Affiliation(s)
- Daisuke Izumi
- Center for Gastrointestinal Research, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA; Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Department of Surgery, Kumamoto General Hospital, Kumamoto, Japan
| | - Feng Gao
- Department of Biomedical Sciences, Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Hong Kong, China
| | - Shusuke Toden
- Center for Gastrointestinal Research, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA
| | - Fuminori Sonohara
- Center for Gastrointestinal Research, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA; Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mitsuro Kanda
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takatsugu Ishimoto
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; The International Research Center for Medicine Sciences, Kumamoto University, Kumamoto, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Xin Wang
- Department of Biomedical Sciences, Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Hong Kong, China; Shenzhen Research Institute, City University of Hong Kong, Shenzhen, China.
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Ajay Goel
- Center for Gastrointestinal Research, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA.
| |
Collapse
|
|
31
|
Lybaert L, Vermaelen K, De Geest BG, Nuhn L. Immunoengineering through cancer vaccines – A personalized and multi-step vaccine approach towards precise cancer immunity. J Control Release 2018; 289:125-145. [DOI: 10.1016/j.jconrel.2018.09.009] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Revised: 09/11/2018] [Accepted: 09/12/2018] [Indexed: 02/07/2023]
|
|
32
|
Lee JS, Won HS, Sun DS, Hong JH, Ko YH. Prognostic role of tumor-infiltrating lymphocytes in gastric cancer: A systematic review and meta-analysis. Medicine (Baltimore) 2018; 97:e11769. [PMID: 30095632 PMCID: PMC6133557 DOI: 10.1097/md.0000000000011769] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Accepted: 07/11/2018] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND The potential prognostic value of tumor-infiltrating lymphocytes (TILs) in gastric cancer remains controversial. This meta-analysis examines the association between TILs and survival outcomes in gastric cancer. METHODS Twenty-two eligible studies were identified using the PubMed and Google Scholar databases. The combined sample size of the 22 studies was 2941, and the median sample size of the individual studies was 122 patients (52-220). The main clinical outcomes examined were overall cancer survival (OCS) and overall cancer relapse-free survival (OCRFS). RESULTS Tumor tissue CD3(+) TILs, indicative of pan-T-cell expression, had a positive effect on survival with a hazard ratio (HR) of 0.64 (95% confidence interval [CI] 0.52-0.78) for OCS, as did the non-FOXP3(+) T-cell subgroup with an HR of 0.66 (95% CI 0.57-0.75), particularly in CD8(+) lymphocytes (HR = 0.63, 95% CI 0.48-0.83). On the contrary, high FOXP3(+) T-cell expression was correlated with reduced OCS, with an HR of 1.75 (95% CI 1.26-2.42). Analysis of the seven studies evaluating OCRFS revealed improved OCRFS with infiltration of non-FOXP3(+) TILs with an HR of 0.59 (95% CI 0.42-0.81) but not FOXP3(+) T lymphocytes with an HR of 1.82 (95% CI 1.30-2.53). CONCLUSION The results from this meta-analysis suggest that high expression of TILs, mainly by CD8 lymphocytes, may be a potential prognostic biomarker in patients with gastric cancer.
Collapse
Affiliation(s)
| | - Hye Sung Won
- Division of Oncology, Department of Internal Medicine
| | - Der Sheng Sun
- Division of Oncology, Department of Internal Medicine
| | - Ji Hyung Hong
- Division of Oncology, Department of Internal Medicine
| | - Yoon Ho Ko
- Division of Oncology, Department of Internal Medicine
- Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| |
Collapse
|
|
33
|
Yu PC, Long D, Liao CC, Zhang S. Association between density of tumor-infiltrating lymphocytes and prognoses of patients with gastric cancer. Medicine (Baltimore) 2018; 97:e11387. [PMID: 29979429 PMCID: PMC6076141 DOI: 10.1097/md.0000000000011387] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
INTRODUCTION Tumor-infiltrating lymphocytes (TILs) have been shown to be of prognostic significance in patients with gastric cancer. This study aims to investigate the association between density of TILs and prognoses of patients with gastric cancer. METHODS The relative studies of tumor-infiltrating lymphocytes in tumor tissue from patients with gastric cancer were systematically searched from PubMed and Embase until October 31, 2017. The pooled hazard ratios (HRs) and their 95% confidence intervals (95%CI) for overall survival (OS) were estimated. RESULTS Twenty-nine studies involving 4,942 patients were included into analyses. Subset of TILs included CD8, CD3, CD4, and FOXP3 T cell density. Results from meta-analyses revealed that high density of intratumoral CD8 T cells (HR = 0.77, 95% CI 0.63-0.95) and CD3 (HR = 0.62, 95% CI 0.49-0.77) were associated with significantly higher OS than those with low density in patients with gastric cancer. Moreover, a larger number of general TILs density also suggested a favorable prognosis (HR 0.75, 95% CI 0.67-0.84). However, patients with high density of intratumoral FOXP3 T or CD4 T cells were not statistically associated with higher or lower OS than those with low density (HR 1.41, 95% CI 0.97-2.05; HR = 0.86, 95% CI 0.47-1.57). Sample size and follow-up period seemed to influence study outcomes. CONCLUSION The present study revealed that high density of intratumoral CD8 and CD3 T cells were associated with better OS in patients with gastric cancer.
Collapse
Affiliation(s)
- Peng-Cheng Yu
- Department of Colorectal Anal Surgery, the First Affiliated Hospital of Guangxi Medical University
| | - Di Long
- Department of Colorectal Anal Surgery, the First Affiliated Hospital of Guangxi Medical University
| | - Cheng-Cheng Liao
- Department of Chemotherapy, the Affiliated Tumor Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Sen Zhang
- Department of Colorectal Anal Surgery, the First Affiliated Hospital of Guangxi Medical University
| |
Collapse
|
|
34
|
Abstract
Chronic inflammation is a risk factor for gastrointestinal cancer and other diseases. Most studies have focused on cytokines and chemokines as mediators connecting chronic inflammation to cancer, whereas the involvement of lipid mediators, including prostanoids, has not been extensively investigated. Prostanoids are among the earliest signaling molecules released in response to inflammation. Multiple lines of evidence suggest that prostanoids are involved in gastrointestinal cancer. In this Review, we discuss how prostanoids impact gastrointestinal cancer development. In particular, we highlight recent advances in our understanding of how prostaglandin E2 induces the immunosuppressive microenvironment in gastrointestinal cancers.
Collapse
Affiliation(s)
- Dingzhi Wang
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Raymond N DuBois
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA.,Department of Research and Division of Gastroenterology, Mayo Clinic, Scottsdale, Arizona, USA
| |
Collapse
|
|
35
|
Wei M, Shen D, Mulmi Shrestha S, Liu J, Zhang J, Yin Y. The Progress of T Cell Immunity Related to Prognosis in Gastric Cancer. BIOMED RESEARCH INTERNATIONAL 2018; 2018:3201940. [PMID: 29682534 PMCID: PMC5848132 DOI: 10.1155/2018/3201940] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Accepted: 12/06/2017] [Indexed: 02/07/2023]
Abstract
Gastric cancer is the fifth most common malignancy all over the world, and the factors that can affect progress and prognosis of the gastric cancer patients are various, such as TNM stages, invasive depth, and lymph node metastasis ratio. T cell immunity is important component of human immunity system and immunity responding to tumor and dysfunction or imbalance of T cell immunity will lead to serious outcomes for body. T cell immunity includes many different types of cells, CD4+ T cell, CD8+ T cell, memory cell, and so on, and each of them has special function on antitumor response or tumor immune escape which is revealed in lung cancer, colorectal cancer, breast cancer, ovarian cancer, and so on. But its correlation with gastric cancer is not clear. Our review was preformed to explore the relationship between the progress and prognosis of gastric cancer (GC) and T cell immunity. According to recent researches, T cell immunity may have an important role in the progress and prognosis of GCs, but its function is affected by location, category, related molecule, and interaction between the cells, and some effects still are controversial. More researches are needed to clarify this correlation.
Collapse
Affiliation(s)
- Ming Wei
- Gastroenterology Department, Affiliated Zhongda Hospital of Southeast University, Nanjing, China
| | - Duo Shen
- Gastroenterology Department, Affiliated Zhongda Hospital of Southeast University, Nanjing, China
| | - Sachin Mulmi Shrestha
- Gastroenterology Department, Affiliated Zhongda Hospital of Southeast University, Nanjing, China
| | - Juan Liu
- Gastroenterology Department, Affiliated Zhongda Hospital of Southeast University, Nanjing, China
| | - Junyi Zhang
- Department of Critical Care Medicine, Affiliated Zhongda Hospital of Southeast University, Nanjing, China
| | - Ying Yin
- Gastroenterology Department, Affiliated Zhongda Hospital of Southeast University, Nanjing, China
| |
Collapse
|
|
36
|
Liu W, Zhao J, Li Q, Wang Q, Zhou Y, Tong Z. Gastric cancer patients have elevated plasmacytoid and CD1c + dendritic cells in the peripheral blood. Oncol Lett 2018; 15:5087-5092. [PMID: 29552142 DOI: 10.3892/ol.2018.7990] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Accepted: 12/13/2017] [Indexed: 12/14/2022] Open
Abstract
Dendritic cells (DCs) are important in tumor immunology. Identifying DC subset markers in the peripheral blood, which are informative for gastric cancer stages, is not only useful for prognosis but may also provide mechanistic insights into processes facilitating therapy. The present study investigated plasmacytoid dendritic cells (pDCs) and myeloid CD1c+ dendritic cells (mDC1s) in the peripheral blood of patients with gastric cancer and healthy controls using flow cytometry. Using peripheral DC staining and subset analysis, patients with gastric cancer were identified to have substantially higher numbers of peripheral pDCs and mDC1s. In addition, there was a trend of elevated circulating pDCs with advanced stages and lymph node metastasis in gastric cancer, whereas no differences in circulating mDC1s were observed among the various groups. The results suggested that circulating pDCs are a positive prognostic indicator in patients with gastric cancer of different stages and highlighted the critical role of pDCs immunity in the development of gastric cancer.
Collapse
Affiliation(s)
- Weihuang Liu
- School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Jie Zhao
- School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Qiaoqi Li
- School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Qiaona Wang
- School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Ying Zhou
- School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Zan Tong
- School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei 430071, P.R. China
| |
Collapse
|
|
37
|
Jiang W, Liu K, Guo Q, Cheng J, Shen L, Cao Y, Wu J, Shi J, Cao H, Liu B, Tao K, Wang G, Cai K. Tumor-infiltrating immune cells and prognosis in gastric cancer: a systematic review and meta-analysis. Oncotarget 2017; 8:62312-62329. [PMID: 28977947 PMCID: PMC5617507 DOI: 10.18632/oncotarget.17602] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Accepted: 04/11/2017] [Indexed: 12/29/2022] Open
Abstract
Tumor-infiltrating immune cells are a pivotal component of the tumor microenvironment (TME), but their indicative role remains poorly defined. A meta-analysis was performed to reveal the prognostic efficiency of tumor-infiltrating immune cells in gastric cancer (GC). By searching PubMed and Embase, we identified a total of 35 eligible articles that involved 4888 patients. Random or fixed effect models were employed to extract pooled hazard ratios (HRs) with 95% confidence intervals (CIs). Our results indicated that high CD3+ lymphocyte infiltration in all the locations (AG), the tumor nest (TN), and the tumor stroma (TS) predicted better overall survival (OS) (HR=0.71, 95% CI=0.57-0.90; HR=0.58, 95% CI=0.42-0.80; and HR=0.50, 95% CI=0.37-0.68, respectively). CD8+ T cell infiltration in AG and FoxP3+ regulatory T cells (Tregs) in the tumor invasive margin (TM) were also associated with improved OS (HR=0.90, 95% CI=0.83-0.97; HR=0.65, 95% CI=0.48-0.87, respectively). However, contrasting results were found in the macrophage subset, with M2 in AG (HR=1.45, 95% CI=1.13-1.86) and the TN (HR=1.67, 95% CI=1.12-2.48) associated with worse OS. In summary, the combination of the densities and locations of tumor-infiltrating immune cells can be useful for predicting survival for GC patients, but additional research is needed to reinforce the reliability of this study's conclusions.
Collapse
Affiliation(s)
- Wen Jiang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ke Liu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qing Guo
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ji Cheng
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liming Shen
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yinghao Cao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jing Wu
- MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Maternal and Child Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jianguo Shi
- Department of Gastrointestinal Surgery, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Heng Cao
- Department of Gastrointestinal Surgery, Xinyang Central Hospital, Xinyang, China
| | - Bo Liu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kaixiong Tao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guobin Wang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kailin Cai
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
|
38
|
Lopez A, Hansmannel F, Kokten T, Bronowicki JP, Melhem H, Sokol H, Peyrin-Biroulet L. Microbiota in digestive cancers: our new partner? Carcinogenesis 2017; 38:1157-1166. [DOI: 10.1093/carcin/bgx087] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Accepted: 08/09/2017] [Indexed: 01/01/2023] Open
|
|
39
|
Pellicioli ACA, Bingle L, Farthing P, Lopes MA, Martins MD, Vargas PA. Immunosurveillance profile of oral squamous cell carcinoma and oral epithelial dysplasia through dendritic and T-cell analysis. J Oral Pathol Med 2017; 46:928-933. [PMID: 28585308 DOI: 10.1111/jop.12597] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/29/2017] [Indexed: 12/30/2022]
Abstract
Oral squamous cell carcinomas (OSCCs) can arise from potentially malignant disorders, such as leukoplakia. The immune system plays an important role recognizing tumour precursor cells. However, due to immuno-editing mechanisms cancer cells are able to escape immune system surveillance. OBJECTIVE To evaluate the profile of dendritic (Langerhans and plasmacytoid) and T cells in OSCC and oral epithelial dysplasia (OED) and correlate these findings with clinical data. MATERIALS AND METHODS Fifty cases of OSCC and 48 of OED were immunostained for CD1a and CD83 dendritic Langerhans cells (DLC), CD303 plasmacytoid dendritic cells (pDC) and CD8 followed by quantitative analysis. RESULTS Analysis revealed a significant decrease in the number of mature CD83 DLC in OSCC compared with OED. CD303 positivity was significantly increased in the OSCC group when compared to OED. CD8-positive lymphocytes were significantly decreased in OSCC compared with OED lesions. No statistical correlation was found with clinical data. CONCLUSION The number of mature dendritic cells (DC) was decreased in OSCC compared with OED lesions suggesting that either these cells might have migrated to lymph nodes to present the tumour antigens and activate the immune system or cytokines secreted by the tumour microenvironment are inhibiting the adequate maturation of DLC. The numbers of pDC were significantly increased in the OSCC group compared with the OED group. This suggests they may play an important role in the defence against tumours although it is not clear whether this is promoting or inhibiting malignant progression.
Collapse
Affiliation(s)
| | - Lynne Bingle
- Piracicaba Dental School, University of Campinas, Piracicaba, Brazil.,School of Clinical Dentistry, University of Sheffield, Sheffield, UK
| | - Paula Farthing
- School of Clinical Dentistry, University of Sheffield, Sheffield, UK
| | | | - Manoela Domingues Martins
- Piracicaba Dental School, University of Campinas, Piracicaba, Brazil.,School of Dentistry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | | |
Collapse
|
|
40
|
Sun X, Feng Z, Wang Y, Qu Y, Gai Y. Expression of Foxp3 and its prognostic significance in colorectal cancer. Int J Immunopathol Pharmacol 2017; 30:201-206. [PMID: 28560891 PMCID: PMC5806801 DOI: 10.1177/0394632017710415] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
The aim of this study was to explore the expression and clinical significance of Foxp3 in colorectal tumor cells. An immunohistochemistry assay was used to detect the expression of Foxp3 in 173 cases of colorectal cancer. The relationship between the clinicopathological factors and the prognosis of colorectal cancer was analyzed. The rate of positive Foxp3 expression in tumor cells was 89.7%. There were no significant differences between cases with and without expression of Foxp3 with regard to sex, age, primary cancer sites, and distal metastasis. The expression of Foxp3 was negatively correlated with lymph node metastasis and pathological tumor, node, metastasis (pTNM) stage in tumor cells (P < 0.05), which reflects the depth of invasion. Foxp3 expression also had a positive correlation with the degree of differentiation (P < 0.01). A high level of Foxp3 expression was observed more often in tumor cells compared to tumor-surrounding tissues (P = 0.003). High expression of Foxp3 was also associated with longer overall and disease-free survival (P ⩽ 0.001). Foxp3 expression in colorectal cancer cells correlates with many clinicopathological characteristics; moreover, high expression of Foxp3 may be a promising potential prognostic factor for patients with colorectal cancer.
Collapse
Affiliation(s)
- Xiuwei Sun
- 1 Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Zhanjun Feng
- 1 Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yunxuan Wang
- 1 Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yao Qu
- 1 Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yunzhu Gai
- 2 Department of Oncology, Guangzhou First People's Hospital, Guangzhou, China
| |
Collapse
|
|
41
|
Kalinski P, Talmadge JE. Tumor Immuno-Environment in Cancer Progression and Therapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 1036:1-18. [PMID: 29275461 DOI: 10.1007/978-3-319-67577-0_1] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The approvals of Provenge (Sipuleucel-T), Ipilimumab (Yervoy/anti-CTLA-4) and blockers of the PD-1 - PD-L1/PD-L2 pathway, such as nivolumab (Opdivo), pembrolizumab (Keytruda), or atezolizumab (Tecentriq), have established immunotherapy as a key component of comprehensive cancer care. Further, murine mechanistic studies and studies in immunocompromised patients have documented the critical role of immunity in effectiveness of radio- and chemotherapy. However, in addition to the ability of the immune system to control cancer progression, it can also promote tumor growth, via regulatory T cells (Tregs), myeloid-derived dendritic cells (MDSCs) and tumor associated macrophages (TAM), which can enhance survival of cancer cells directly or via the regulation of the tumor stroma.An increasing body of evidence supports a central role for the tumor microenvironment (TME) and the interactions between tumor stroma, infiltrating immune cells and cancer cells during the induction and effector phase of anti-cancer immunity, and the overall effectiveness of immunotherapy and other forms of cancer treatment. In this chapter, we discuss the roles of key TME components during tumor progression, metastatic process and cancer therapy-induced tumor regression, as well as opportunities for their modulation to enhance the overall therapeutic benefit.
Collapse
Affiliation(s)
- Pawel Kalinski
- Department of Medicine and Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, NY, USA.
| | - James E Talmadge
- University of Nebraska Medical Center, 986495 Nebraska Medical Center, Omaha, NE, USA
| |
Collapse
|
|
42
|
Chen WM, Wu CS, Liu JL, Yeh CM, Tseng L, Huang HC, Chang PJ, Wu SF. Expression of Helios in gastric tumor cells predicts better survival in gastric cancer patients. J Cancer Res Clin Oncol 2016; 142:2375-82. [PMID: 27576507 DOI: 10.1007/s00432-016-2223-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Accepted: 08/20/2016] [Indexed: 12/25/2022]
Abstract
PURPOSE Helios belongs to Ikaros family, which plays an important role in the cell-fate decision and control cell proliferation; abnormal expressions in leukemia are associated with poor prognosis. In this study, we investigated the Helios expression between Helicobacter pylori infection and prognosis in gastric cancer patients. METHODS A total of 67 gastric cancer patients who received partial or full gastrectomies were enrolled. Helios expression by immunohistochemistry and mRNA was investigated with the clinical stage, Helicobacter pylori infection, CD4 expression, FoxP3 expression and prognosis. RESULTS From the immunohistochemistry stain, we found that the Helios was expressed in both cancer cell and tumor-infiltrated lymphocytes. The high expression of Helios in gastric tumor cells had a better median overall survival rate in gastric cancer patients (50.7 ± 3.2 vs. 34.1 ± 4.9 months; P = 0.015), Helicobacter pylori-infected patients (51.1 ± 3.5 vs. 30.4 ± 5.1 months; P = 0.007) and advanced gastric cancer patients (42.1 ± 5.5 vs. 23.2 ± 4.8 months; P = 0.043). From multivariate analysis, the Helios expression in gastric tumor cells was an independent factor to predict better survival in all gastric cancers (HR = 2.78; 95 % confidence interval [CI], 1.09-7.09; P = 0.032) and advanced gastric cancer patients (HR = 2.85; 95 % confidence interval [CI], 1.00-8.13; P = 0.03). CONCLUSIONS Higher expression of Helios in gastric tumor cells predicts better survival in gastric cancer patients, especially for Helicobacter pylori-infected and advanced-stage gastric cancer patients.
Collapse
Affiliation(s)
- Wei-Ming Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Cheng-Shyong Wu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Jing-Lan Liu
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Pathology, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Chia-Ming Yeh
- Department of Life Science and Institute of Molecular Biology, National Chung Cheng University, No.168, University Rd., Min-Hsiung, Chia-Yi, 62247, Taiwan, Republic of China
| | - Libby Tseng
- Department of Life Science and Institute of Molecular Biology, National Chung Cheng University, No.168, University Rd., Min-Hsiung, Chia-Yi, 62247, Taiwan, Republic of China
| | - Hao-Chun Huang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Pey-Jium Chang
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Shu-Fen Wu
- Department of Life Science and Institute of Molecular Biology, National Chung Cheng University, No.168, University Rd., Min-Hsiung, Chia-Yi, 62247, Taiwan, Republic of China.
| |
Collapse
|
|
43
|
Becht E, Giraldo NA, Germain C, de Reyniès A, Laurent-Puig P, Zucman-Rossi J, Dieu-Nosjean MC, Sautès-Fridman C, Fridman WH. Immune Contexture, Immunoscore, and Malignant Cell Molecular Subgroups for Prognostic and Theranostic Classifications of Cancers. Adv Immunol 2016; 130:95-190. [DOI: 10.1016/bs.ai.2015.12.002] [Citation(s) in RCA: 126] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
|
|
44
|
Schlößer HA, Drebber U, Kloth M, Thelen M, Rothschild SI, Haase S, Garcia-Marquez M, Wennhold K, Berlth F, Urbanski A, Alakus H, Schauss A, Shimabukuro-Vornhagen A, Theurich S, Warnecke-Ebertz U, Stippel DL, Zippelius A, Büttner R, Hallek M, Hölscher AH, Zander T, Mönig SP, von Bergwelt-Baildon M. Immune checkpoints programmed death 1 ligand 1 and cytotoxic T lymphocyte associated molecule 4 in gastric adenocarcinoma. Oncoimmunology 2015; 5:e1100789. [PMID: 27467911 DOI: 10.1080/2162402x.2015.1100789] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Revised: 09/14/2015] [Accepted: 09/22/2015] [Indexed: 12/14/2022] Open
Abstract
Remarkable efficacy of immune checkpoint inhibition has been reported for several types of solid tumors and early studies in gastric adenocarcinoma are promising. A detailed knowledge about the natural biology of immune checkpoints in gastric adenocarcinoma is essential for clinical and translational evaluation of these drugs. This study is a comprehensive analysis of cytotoxic T lymphocyte associated molecule 4 (CTLA-4) and programmed death 1 ligand 1 (PD-L1) expression in gastric adenocarcinoma. PD-L1 and CTLA-4 were stained on tumor sections of 127 Caucasian patients with gastric adenocarcinoma by immunohistochemistry (IHC) and somatic mutation profiling was performed using targeted next-generation sequencing. Expression of PD-L1 and CTLA-4 on lymphocytes in tumor sections, tumor-draining lymph nodes (TDLN) and peripheral blood were studied by flow-cytometry and immune-fluorescence microscopy in an additional cohort. PD-L1 and CTLA-4 were expressed in 44.9% (57/127) and 86.6% (110/127) of the analyzed gastric adenocarcinoma samples, respectively. Positive tumor cell staining for PD-L1 or CTLA-4 was associated with inferior overall survival. Somatic mutational analysis did not reveal a correlation to expression of PD-L1 or CTLA-4 on tumor cells. Expression of PD-1 (52.2%), PD-L1 (42.2%) and CTLA-4 (1.6%) on tumor infiltrating T cells was significantly elevated compared to peripheral blood. Of note, PD-1 and PD-L1 were expressed far higher by tumor-infiltrating lymphocytes than CTLA-4. In conclusion, specific immune checkpoint-inhibitors should be evaluated in this disease and the combination with molecular targeted therapies might be of benefit. An extensive immune monitoring should accompany these studies to better understand their mode of action in the tumor microenvironment.
Collapse
Affiliation(s)
- Hans A Schlößer
- Department of General, Visceral and Cancer Surgery, University of Cologne, Germany; Cologne Interventional Immunology, University of Cologne, Germany; Gastrointestinal Cancer Group Cologne, University of Cologne, Germany
| | - Uta Drebber
- Institute of Pathology, University of Cologne , Germany
| | - Michael Kloth
- Gastrointestinal Cancer Group Cologne, University of Cologne, Germany; Institute of Pathology, University of Cologne, Germany
| | - Martin Thelen
- Cologne Interventional Immunology, University of Cologne , Germany
| | - Sacha I Rothschild
- Cologne Interventional Immunology, University of Cologne, Germany; Department of Internal Medicine I, University of Cologne, Germany; Department of Internal Medicine, Medical Oncology, University Hospital Basel, Switzerland
| | - Simon Haase
- Department of General, Visceral and Cancer Surgery, University of Cologne , Germany
| | - Maria Garcia-Marquez
- Cologne Interventional Immunology, University of Cologne, Germany; Department of Internal Medicine I, University of Cologne, Germany
| | - Kerstin Wennhold
- Cologne Interventional Immunology, University of Cologne, Germany; Department of Internal Medicine I, University of Cologne, Germany
| | - Felix Berlth
- Department of General, Visceral and Cancer Surgery, University of Cologne , Germany
| | - Alexander Urbanski
- Department of General, Visceral and Cancer Surgery, University of Cologne , Germany
| | - Hakan Alakus
- Department of General, Visceral and Cancer Surgery, University of Cologne, Germany; Gastrointestinal Cancer Group Cologne, University of Cologne, Germany
| | - Astrid Schauss
- Cluster of Excellence in Aging-Associated Disease, Core Facility Imaging, University of Cologne , Germany
| | - Alexander Shimabukuro-Vornhagen
- Cologne Interventional Immunology, University of Cologne, Germany; Department of Internal Medicine I, University of Cologne, Germany
| | - Sebastian Theurich
- Cologne Interventional Immunology, University of Cologne, Germany; Department of Internal Medicine I, University of Cologne, Germany; Max-Planck-Institute for Metabolism Research, Cologne, Germany
| | - Ute Warnecke-Ebertz
- Department of General, Visceral and Cancer Surgery, University of Cologne , Germany
| | - Dirk L Stippel
- Department of General, Visceral and Cancer Surgery, University of Cologne , Germany
| | - Alfred Zippelius
- Department of Internal Medicine, Medical Oncology, University Hospital Basel , Switzerland
| | | | - Michael Hallek
- Department of Internal Medicine I, University of Cologne , Germany
| | - Arnulf H Hölscher
- Department of General, Visceral and Cancer Surgery, University of Cologne , Germany
| | - Thomas Zander
- Gastrointestinal Cancer Group Cologne, University of Cologne, Germany; Department of Internal Medicine I, University of Cologne, Germany
| | - Stefan P Mönig
- Department of General, Visceral and Cancer Surgery, University of Cologne, Germany; Gastrointestinal Cancer Group Cologne, University of Cologne, Germany
| | - Michael von Bergwelt-Baildon
- Cologne Interventional Immunology, University of Cologne, Germany; Department of Internal Medicine I, University of Cologne, Germany
| |
Collapse
|
|
45
|
Zhao Y, Huo M, Xu Z, Wang Y, Huang L. Nanoparticle delivery of CDDO-Me remodels the tumor microenvironment and enhances vaccine therapy for melanoma. Biomaterials 2015; 68:54-66. [PMID: 26264646 DOI: 10.1016/j.biomaterials.2015.07.053] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Revised: 07/26/2015] [Accepted: 07/31/2015] [Indexed: 12/30/2022]
Abstract
Lipid-calcium-phosphate nanoparticle (NP) delivery of Trp2 peptide vaccine is one of the most effective vaccine strategies against melanoma. However, due to the immunosuppressive microenvironment in the tumor, the achievement of potent immune responses remains a major challenge. NP delivery systems provide an opportunity to deliver chemotherapy agent to modulate the tumor microenvironment (TME) and improve the vaccine activity. Anti-inflammatory triterpenoid methyl-2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate (CDDO-Me) is a broad spectrum inhibitor of several signaling pathways that are important in both cancer cells and cells in the TME. Intravenous delivery of CDDO-Me using poly-lactic-glycolic-acid NP combination with subcutaneous Trp2 vaccine resulted in an increase of antitumor efficacy and apoptotic tumor tissue than Trp2 vaccine alone in B16F10 melanoma. There was a significant decrease of both Treg cells and MDSCs and a concomitant increase in the cytotoxic T-lymphocyte infiltration in TEM of the vaccinated animals. Also, CDDO-Me remodeled the tumor associated fibroblasts, collagen and vessel in TME, meanwhile, enhanced the Fas signaling pathway which could sensitize the tumor cells for cytotoxic T lymphocyte mediated killing. The combination of systemic induction of antigen-specific immune response using Trp2 nanovaccine and targeted modification of the TME with the NP delivered CDDO-Me offers a powerful combination therapy for melanoma.
Collapse
Affiliation(s)
- Yan Zhao
- Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States; Department of Pharmaceutics, School of Pharmacy, China Medical University, Shenyang 110122, China
| | - Meirong Huo
- Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States; State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Zhenghong Xu
- Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
| | - Yuhua Wang
- Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States.
| | - Leaf Huang
- Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States.
| |
Collapse
|
|
46
|
Halvorsen EC, Mahmoud SM, Bennewith KL. Emerging roles of regulatory T cells in tumour progression and metastasis. Cancer Metastasis Rev 2015; 33:1025-41. [PMID: 25359584 DOI: 10.1007/s10555-014-9529-x] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The metastasis of cancer is a complex and life-threatening process that is only partially understood. Immune suppressive cells are recognized as important contributors to tumour progression and may also promote the development and growth of tumour metastases. Specifically, regulatory T cells (Tregs) have been found to promote primary tumour progression, and emerging pre-clinical data suggests that Tregs may promote metastasis and metastatic tumour growth. While the precise role that Tregs play in metastatic progression is understudied, recent findings have indicated that by suppressing innate and adaptive anti-tumour immunity, Tregs may shield tumour cells from immune detection, and thereby allow tumour cells to survive, proliferate and acquire characteristics that facilitate dissemination. This review will highlight our current understanding of Tregs in metastasis, including an overview of pre-clinical findings and discussion of clinical data regarding Tregs and therapeutic outcome. Evolving strategies to directly ablate Tregs or to inhibit their function will also be discussed. Improving our understanding of how Tregs may influence tumour metastasis may lead to novel treatments for metastatic cancer.
Collapse
Affiliation(s)
- Elizabeth C Halvorsen
- Department of Integrative Oncology, British Columbia Cancer Agency, 9-202, 675 West 10th Avenue, Vancouver, British Columbia, V5Z 1L3, Canada
| | | | | |
Collapse
|
|
47
|
Heeren AM, Koster BD, Samuels S, Ferns DM, Chondronasiou D, Kenter GG, Jordanova ES, de Gruijl TD. High and interrelated rates of PD-L1+CD14+ antigen-presenting cells and regulatory T cells mark the microenvironment of metastatic lymph nodes from patients with cervical cancer. Cancer Immunol Res 2014; 3:48-58. [PMID: 25361854 DOI: 10.1158/2326-6066.cir-14-0149] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
A better understanding of the microenvironment in relation to lymph node metastasis is essential for the development of effective immunotherapeutic strategies against cervical cancer. In the present study, we investigated the microenvironment of tumor-draining lymph nodes of patients with cervical cancer by comprehensive flow cytometry-based phenotyping and enumeration of immune-cell subsets in tumor-negative (LN(-), n = 20) versus tumor-positive lymph nodes (LN(+), n = 8), and by the study of cytokine release profiles (n = 4 for both LN(-) and LN(+)). We found significantly lower CD4(+) and higher CD8(+) T-cell frequencies in LN(+) samples, accompanied by increased surface levels of activation markers (HLA-DR; ICOS; PD-1; CTLA-4) and the memory marker CD45RO. Furthermore, in LN(+), we found increased rates of a potentially regulatory antigen-presenting cell (APC) subset (CD11c(hi)CD14(+)PD-L1(+)) and of myeloid-derived suppressor cell subsets; the LN(+) APC subset correlated with significantly elevated frequencies of FoxP3(+) regulatory T cells (Treg). After in vitro stimulation with different Toll-like receptor (TLR) ligands (PGN; Poly-IC; R848), we observed higher production levels of IL6, IL10, and TNFα but lower levels of IFNγ in LN(+) samples. We conclude that, despite increased T-cell differentiation and activation, a switch to a profound immune-suppressive microenvironment in LN(+) of patients with cervical cancer will enable immune escape. Our data indicate that the CD14(+)PD-L1(+) APC/Treg axis is a particularly attractive and relevant therapeutic target to specifically tackle microenvironmental immune suppression and thus enhances the efficacy of immunotherapy in patients with metastasized cervical cancer.
Collapse
Affiliation(s)
- A Marijne Heeren
- Department of Medical Oncology, VU University Medical Center-Cancer Center Amsterdam, Amsterdam, the Netherlands. Center Gynecological Oncology Amsterdam (CGOA), Department of Obstetrics and Gynecology, VU University Medical Center, Amsterdam, the Netherlands
| | - Bas D Koster
- Department of Medical Oncology, VU University Medical Center-Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Sanne Samuels
- Center Gynecological Oncology Amsterdam (CGOA), Department of Gynecology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, the Netherlands
| | - Debbie M Ferns
- Center Gynecological Oncology Amsterdam (CGOA), Department of Obstetrics and Gynecology, VU University Medical Center, Amsterdam, the Netherlands
| | - Dafni Chondronasiou
- Department of Medical Oncology, VU University Medical Center-Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Gemma G Kenter
- Center Gynecological Oncology Amsterdam (CGOA), Department of Obstetrics and Gynecology, VU University Medical Center, Amsterdam, the Netherlands. Center Gynecological Oncology Amsterdam (CGOA), Department of Gynecology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, the Netherlands
| | - Ekaterina S Jordanova
- Center Gynecological Oncology Amsterdam (CGOA), Department of Obstetrics and Gynecology, VU University Medical Center, Amsterdam, the Netherlands
| | - Tanja D de Gruijl
- Department of Medical Oncology, VU University Medical Center-Cancer Center Amsterdam, Amsterdam, the Netherlands.
| |
Collapse
|
|
48
|
Zhao LW, Li C, Zhang RL, Xue HG, Zhang FX, Zhang F, Gai XD. B7-H1 and B7-H4 expression in colorectal carcinoma: correlation with tumor FOXP3(+) regulatory T-cell infiltration. Acta Histochem 2014; 116:1163-8. [PMID: 25053455 DOI: 10.1016/j.acthis.2014.06.003] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2014] [Revised: 06/08/2014] [Accepted: 06/09/2014] [Indexed: 12/12/2022]
Abstract
B7-H1 and B7-H4 are newly discovered members of the B7-CD28 family. They can inhibit T cell activation and proliferation and regulate T cell immune response negatively. Both B7-H1 and B7-H4 are expressed in many tumors and are classified as co-inhibitors of cell-mediated immunity. FOXP3(+) regulatory T cells (Tregs) play an important role in the maintenance of tumor immunity tolerance. However, the implication of B7-H1 and B7-H4 expression and their interaction with Tregs infiltration in colorectal cancer are unknown. The present study aimed to determine the expression of B7-H1 and B7-H4 as well as Tregs infiltration in colorectal cancer and to explore the clinical and pathological implication of suppressor immune cells and molecules. Frozen sections and immunohistochemical assay were undertaken to assess B7-H1, B7-H4 expression and Tregs infiltration in fresh specimens collected from 56 patients with colorectal carcinoma. The results showed that expression of B7-H1 and B7-H4 in colorectal carcinoma tissues was significantly higher than in adjacent normal mucosa (P<0.001). B7-H1 expression was positively correlated to the infiltration depth, lymph node metastasis and advanced Duke's stage (P<0.05, P<0.05 and P<0.05, respectively), whereas B7-H4 expression was positively related to the infiltration depth and lymph node metastasis (P<0.01 and P<0.05, respectively). Furthermore, Tregs infiltration was more frequent in tumor tissue than in adjacent normal mucosa and was associated with poor differentiation and positive lymph node metastasis (P<0.01, and P<0.01, respectively). The statistical analysis indicated a significant correlation between Tregs infiltration and B7-H1 or B7-H4 expression respectively. These results suggest that over-expression of B7-H1 and B7-H4 has stronger prognostic significance and promote tumor tolerance, and they might contribute to Tregs development in the colorectal carcinoma tolerogenic milieu.
Collapse
Affiliation(s)
- Li-wei Zhao
- Department of Pathology, School of Basic Medical Sciences, Beihua University, Jilin, Jilin 132013, People's Republic of China; Department of Pathology, School of Basic Medical Sciences, Jilin Medical College, Jilin, Jilin 132013, People's Republic of China
| | - Chun Li
- Department of Pathology, School of Basic Medical Sciences, Beihua University, Jilin, Jilin 132013, People's Republic of China
| | - Rui-lan Zhang
- Department of Pathology, School of Basic Medical Sciences, Beihua University, Jilin, Jilin 132013, People's Republic of China
| | - Hao-gang Xue
- Department of Surgery, Affiliated Hospital of Beihua University, Jilin, Jilin 132013, People's Republic of China
| | - Fu-xi Zhang
- Department of Surgery, Affiliated Hospital of Beihua University, Jilin, Jilin 132013, People's Republic of China
| | - Fan Zhang
- Department of Pathology, School of Basic Medical Sciences, Beihua University, Jilin, Jilin 132013, People's Republic of China
| | - Xiao-dong Gai
- Department of Pathology, School of Basic Medical Sciences, Beihua University, Jilin, Jilin 132013, People's Republic of China.
| |
Collapse
|
|
49
|
Tsurikisawa N, Saito H, Oshikata C, Tsuburai T, Ishiyama M, Mitomi H, Akiyama K. An increase of CD83+ dendritic cells ex vivo correlates with increased regulatory T cells in patients with active eosinophilic granulomatosis and polyangiitis. BMC Immunol 2014; 15:32. [PMID: 25174446 PMCID: PMC4159546 DOI: 10.1186/s12865-014-0032-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2014] [Accepted: 08/08/2014] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare disease characterized by the presence of allergic granulomatosis and necrotizing vasculitis with eosinophilic infiltration. The etiology of EGPA is unknown. Dendritic cells (DCs) are not only critical for the induction of primary immune responses; they may also be important for the induction of immunological tolerance and the regulation of the type of T-cell-mediated immune response. To investigate whether DC maturation is associated with EGPA disease status, we examined the relationship between the maturation of DCs and the differentiation of regulatory T (Treg) cells in EGPA patients. We exposed the CD14+ blood monocytes of 19 patients with EGPA in remission or relapse to stimulation with GM-CSF and IL-4 for 6 d and lipopolysaccharide for 24 h to obtain mature CD83+ DCs and immature CD206+ DCs. Using immunohistochemistry, we examined four patients for the presence of CD83+ and CD206+ DCs in the lung at the onset of EGPA. RESULTS The percentage of CD83+ cells among DCs differentiated from CD14+ monocytes was lower for EGPA patients in relapse than in remission. The percentage of CD83+ DCs was inversely correlated with the percentage of CD206+ DCs and was significantly correlated with the numbers of naturally occurring CD4+ regulatory Treg (nTreg; FOXP3+CD4+) cells and inducible Treg (iTreg; CD4+CD25+ T cells producing IL-10 or TGF-β) cells but not the number of eosinophils. The percentage of CD206+ DCs was significantly inversely correlated with the percentages of nTreg and iTreg cells but not the number of eosinophils. Immunohistochemistry revealed both CD206+ DCs and CD83+ DCs in alveoli and interstitial spaces at the onset of EGPA. CONCLUSION The maturation of DCs from monocytes was related to disease activity in patients with EGPA. Increased CD83+ DCs in EGPA patients may induce the differentiation of iTreg and nTreg cells, thereby suppressing inflammation and disease activity.
Collapse
Affiliation(s)
- Naomi Tsurikisawa
- />Departments of Allergy and Respirology, 18-1 Sakuradai, Minami-ku Sagamihara, Kanagawa 252-0392 Japan
| | - Hiroshi Saito
- />Clinical Research Center for Allergy and Rheumatology, National Hospital Organization, Sagamihara National Hospital, 18-1 Sakuradai, Minami-ku Sagamihara, Kanagawa 252-0392 Japan
| | - Chiyako Oshikata
- />Departments of Allergy and Respirology, 18-1 Sakuradai, Minami-ku Sagamihara, Kanagawa 252-0392 Japan
| | - Takahiro Tsuburai
- />Departments of Allergy and Respirology, 18-1 Sakuradai, Minami-ku Sagamihara, Kanagawa 252-0392 Japan
| | - Miyako Ishiyama
- />Laboratory Medicine, Kanagawa Rehabilitation Hospital, 516 Nanasawa Atsugi, Kanagawa, 243-0121 Japan
| | - Hiroyuki Mitomi
- />Department of Surgical and Molecular Pathology, Dokkyo Medical University, 880 Kitakobayashi, Shimotsuga-gun, Mibu-machi, Tochigi 321-0293 Japan
| | - Kazuo Akiyama
- />Departments of Allergy and Respirology, 18-1 Sakuradai, Minami-ku Sagamihara, Kanagawa 252-0392 Japan
- />Clinical Research Center for Allergy and Rheumatology, National Hospital Organization, Sagamihara National Hospital, 18-1 Sakuradai, Minami-ku Sagamihara, Kanagawa 252-0392 Japan
| |
Collapse
|
|
50
|
Li RL, Zhou S, Qin J, Liang CM, Luo GR. Effect of administration of BMDC vaccine sensitized by heat shocked hepal-6 cell proteins on intratumoral CD25 +Foxp3 + Tregs in mouse hepatocellular carcinoma. Shijie Huaren Xiaohua Zazhi 2014; 22:2081-2090. [DOI: 10.11569/wcjd.v22.i15.2081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine whether the bone marrow derived dendritic cell (BMDC) vaccine sensitized by heat shocked hepal-6 cell proteins affects the infiltration of intratumoral CD25+Foxp3+ Tregs in a mouse hepatocellular carcinoma (HCC) model.
METHODS: In the presence of GM-CSF and IL-4, BMDCs were induced in vitro. BMDCs were sensitized by heat shocked hepal-6 cell proteins to generate a vaccine for HCC. The expression of CD11c, CCR7, CD80 and CD86 on these sensitized BMDCs were analyzed by FACS. The anti-tumor effect of this vaccine was evaluated using a mouse HCC model established by subcutaneous injection of Hepal-6 cells. Eight days later, the tumor-bearing mice were divided into four groups, which underwent intratumoral injection of BMDCs sensitized by heat shocked hepal-6 cell proteins, serum-free culture medium, BMDCs without sensitization and BMDCs sensitized by unheated hepal-6 cell proteins (once every 7 d, 2 times altogether), respectively. Nine days after final administration, the mice were sacrificed and the tumor samples were taken for immunofluorescence staining for CD8+ cells and intratumoral CD25+Foxp3+ Tregs.
RESULTS: Light microscopy and scanning electron microscopy showed that BMDCs propagated in the presence of GM-CSF and IL-4 displayed the typical morphological characteristics of dendritic cells. Immunocytochemical staining showed that they expressed the dendritic cell marks including CD11c, CCR7, CD80 and CD86. Compared with the controls (BMDCs without sensitization or sensitized by unheated hepal-6 cells proteins), the BMDCs sensitized by heat shocked hepal-6 cells proteins showed increased expression of CD11c (67.2 ± 4.49 vs 52.4 ± 5.20, 58.4 ± 4.43), CCR7 (65.4 ± 5.34 vs 45.9 ± 5.04, 57.0 ± 3.46), CD80 (62.9 ± 4.69 vs 46.9 ± 4.75, 54.4 ± 3.47) and CD86 (73.3 ± 3.58 vs 60.1 ± 2.98, 63.7 ± 3.10) (P < 0.01 for all). Compared with the controls, the mice administrated with the BMDC vaccine sensitized by heat shocked Hepal-6 cell proteins showed increased CD8+ T cells (55.0 ± 4.11 vs 38.2 ± 3.34, 44.6 ± 4.29, 45.6 ± 4.92, P < 0.01 for all) and decreased intratumoral CD25+Foxp3+ Tregs (0.37 ± 0.028 vs 1.31 ± 0.020, 0.77 ± 0.057, 0.57 ± 0.062, P < 0.05 for all).
CONCLUSION: Heat shocked hepal-6 cell protein sensitization can upregulate the expression of CD11c, CCR7, CD80 and CD86 on BMDCs in vitro. Administration with this BMDC vaccine can increase CD8+ T cells and decrease intratumoral CD25+Foxp3+ Tregs in HCC mice.
Collapse
|