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Issa H, Singh L, Lai KS, Parusheva-Borsitzky T, Ansari S. Dynamics of inflammatory signals within the tumor microenvironment. World J Exp Med 2025; 15:102285. [DOI: 10.5493/wjem.v15.i2.102285] [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] [Received: 10/13/2024] [Revised: 12/31/2024] [Accepted: 01/11/2025] [Indexed: 04/16/2025] Open
Abstract
Tumor stroma, or tumor microenvironment (TME), has been in the spotlight during recent years for its role in tumor development, growth, and metastasis. It consists of a myriad of elements, including tumor-associated macrophages, cancer-associated fibroblasts, a deregulated extracellular matrix, endothelial cells, and vascular vessels. The release of proinflammatory molecules, due to the inflamed microenvironment, such as cytokines and chemokines is found to play a pivotal role in progression of cancer and response to therapy. This review discusses the major key players and important chemical inflammatory signals released in the TME. Furthermore, the latest breakthroughs in cytokine-mediated crosstalk between immune cells and cancer cells have been highlighted. In addition, recent updates on alterations in cytokine signaling between chronic inflammation and malignant TME have also been reviewed.
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Affiliation(s)
- Hala Issa
- Division of Health Sciences, Higher Colleges of Technology, Abu Dhabi 25026, United Arab Emirates
| | - Lokjan Singh
- Department of Microbiology, Karnali Academy of Health Sciences, Jumla 21200, Karnali, Nepal
| | - Kok-Song Lai
- Division of Health Sciences, Higher Colleges of Technology, Abu Dhabi 25026, United Arab Emirates
| | - Tina Parusheva-Borsitzky
- Division of Health Sciences, Higher Colleges of Technology, Abu Dhabi 25026, United Arab Emirates
| | - Shamshul Ansari
- Division of Health Sciences, Higher Colleges of Technology, Abu Dhabi 25026, United Arab Emirates
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Zhang T, Tang X. Untangling immune cell contributions in the progression from GERD to Barrett's esophagus and esophageal cancer: Insights from genetic causal analysis. Int Immunopharmacol 2025; 150:114271. [PMID: 39965389 DOI: 10.1016/j.intimp.2025.114271] [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: 12/09/2024] [Revised: 01/30/2025] [Accepted: 02/07/2025] [Indexed: 02/20/2025]
Abstract
BACKGROUND Esophageal adenocarcinoma (EAC) is a rapidly increasing malignancy with significant morbidity and mortality. The progression from gastroesophageal reflux disease (GERD) to Barrett's esophagus (BE) and ultimately to EAC is thought to be influenced by chronic inflammation and immune cell dynamics. Despite the observed correlations in observational studies, the causal relationships between immune cell phenotypes and this disease continuum remain unclear. METHODS This study utilized a two-sample Mendelian Randomization (MR) approach to investigate the causal roles of 731 distinct immune cell phenotypes in the GERD-BE-EAC continuum. The analysis leveraged genome-wide association study (GWAS) data for immune phenotypes from a Sardinian cohort and data for GERD, BE, and EAC from the FinnGen and Open GWAS databases. A comprehensive set of MR methods, including inverse variance weighted (IVW), MR-Egger, and weighted median estimators, was employed to assess causality. Sensitivity analyses were conducted to evaluate heterogeneity and pleiotropy, ensuring the robustness of the findings. RESULTS The study revealed complex and multifaceted roles of immune cells across the GERD-BE-EAC continuum. In GERD, 34 immune phenotypes were found to be causally associated with either increased or decreased risk. Protective effects were observed in phenotypes such as Unswitched Memory B cells, while others like CD45RA- CD4+ T cells were linked to an elevated risk. In the context of BE, 28 immune phenotypes demonstrated significant causal associations, with the majority being protective, including Unswitched Memory B cells and CD62L on Granulocytes. Conversely, certain phenotypes, such as CD24 on Transitional B cells, were identified as risk factors for BE. For EAC, 34 immune phenotypes were implicated, with various B cell subsets, particularly those expressing BAFF-R and CD24, associated with an increased risk, while Switched Memory B cells and specific myeloid cell phenotypes showed protective effects. CONCLUSIONS This study provides novel insights into the complex role of immune cells in the pathogenesis of EAC, revealing a dynamic interplay where certain immune phenotypes may be protective in early stages but become risk-enhancing in later stages of disease progression. These findings highlight the potential of immune cell phenotypes to serve as biomarkers for early detection and targeted therapeutic interventions across the GERD-BE-EAC continuum. Further research is warranted to validate these findings in diverse populations and to explore the underlying mechanisms driving these immune-mediated effects.
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Affiliation(s)
- Tai Zhang
- Peking University Traditional Chinese Medicine Clinical Medical School (Xiyuan), Peking University Health Science Center, Beijing 100091, China; Peking University Health Science Center, Beijing 100191, China
| | - Xudong Tang
- Peking University Traditional Chinese Medicine Clinical Medical School (Xiyuan), Peking University Health Science Center, Beijing 100091, China; Institute of Digestive Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China.
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3
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Ye R, Li S, Li Y, Shi K, Li L. Revealing the role of regulatory b cells in cancer: development, function and treatment significance. Cancer Immunol Immunother 2025; 74:125. [PMID: 39998678 PMCID: PMC11861783 DOI: 10.1007/s00262-025-03973-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Accepted: 02/07/2025] [Indexed: 02/27/2025]
Abstract
B cells are essential components of the immune response, primarily recognized for their ability to produce antibodies. However, emerging research reveals their important roles in regulating immune responses and influencing tumor development, independent of antibodies. The connection between tumor progression and alterations in the tumor microenvironment is well-established, as immune infiltrating cells can enhance the survival of tumor cells by modifying their surroundings. Despite this, the majority of studies have focused on T cells and macrophages, creating a gap in our understanding of B cells. Regulatory B cells (Bregs) represent a crucial subpopulation that plays a significant role in maintaining immune balance. They may have a substantial impact on tumor immunity by negatively regulating tumor-infiltrating immune cells. This paper reviews the existing literature on Bregs, examining their development, phenotypes, functions, and the mechanisms through which they exert their regulatory effects. Furthermore, we highlight their potential interventional roles and prognostic significance in cancer therapy. By addressing the current gaps in knowledge regarding Bregs within tumors, we hope to inspire further research that could lead to innovative cancer treatments and improved outcomes for patients.
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Affiliation(s)
- Ruyu Ye
- Department of Hematology, The Second Hospital of Dalian Medical University, Dalian, People's Republic of China
| | - Sijia Li
- Department of Hematology, The Second Hospital of Dalian Medical University, Dalian, People's Republic of China
| | - Yuxiao Li
- Department of Hematology, The Second Hospital of Dalian Medical University, Dalian, People's Republic of China
| | - Kaixin Shi
- Department of Hematology, The Second Hospital of Dalian Medical University, Dalian, People's Republic of China
| | - Li Li
- Department of Hematology, The Second Hospital of Dalian Medical University, Dalian, People's Republic of China.
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Yun H, Dong F, Wei X, Yan X, Zhang R, Zhang X, Wang Y. Role and value of the tumor microenvironment in the progression and treatment resistance of gastric cancer (Review). Oncol Rep 2025; 53:14. [PMID: 39611496 PMCID: PMC11622107 DOI: 10.3892/or.2024.8847] [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: 08/08/2024] [Accepted: 10/08/2024] [Indexed: 11/30/2024] Open
Abstract
Gastric cancer (GC) is characterized by a complex and heterogeneous tumor microenvironment (TME) that significantly influences disease progression and treatment outcomes. The tumor stroma, which is composed of a variety of cell types such as cancer‑associated fibroblasts, immune cells and vascular components, displays significant spatial and temporal diversity. These stromal elements engage in dynamic crosstalk with cancer cells, shaping their proliferative, invasive and metastatic potential. Furthermore, the TME is instrumental in facilitating resistance to traditional chemotherapy, specific treatments and immunotherapy strategies. Understanding the underlying mechanisms by which the GC microenvironment evolves and supports tumor growth and therapeutic resistance is critical for developing effective treatment strategies. The present review explores the latest progress in understanding the intricate interactions between cancer cells and their immediate environment in GC, highlighting the implications for disease pathogenesis and therapeutic interventions.
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Affiliation(s)
- Heng Yun
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, Gansu 730900, P.R. China
| | - Fangde Dong
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, Gansu 730900, P.R. China
| | - Xiaoqin Wei
- Department of Pain, The Second People's Hospital of Baiyin, Baiyin, Gansu 730900, P.R. China
| | - Xinyong Yan
- Department of Proctology, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, Gansu 730900, P.R. China
| | - Ronglong Zhang
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, Gansu 730900, P.R. China
| | - Xiuyu Zhang
- Department of Gastroenterology, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, Gansu 730900, P.R. China
| | - Yulin Wang
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, Gansu 730900, P.R. China
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Shi X, Cheng X, Jiang A, Shi W, Zhu L, Mou W, Glaviano A, Liu Z, Cheng Q, Lin A, Wang L, Luo P. Immune Checkpoints in B Cells: Unlocking New Potentials in Cancer Treatment. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2403423. [PMID: 39509319 PMCID: PMC11653663 DOI: 10.1002/advs.202403423] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 08/26/2024] [Indexed: 11/15/2024]
Abstract
B cells are crucial component of humoral immunity, and their role in the tumor immune microenvironment (TME) has garnered significant attention in recent years. These cells hold great potential and application prospects in the field of tumor immunotherapy. Research has demonstrated that the TME can remodel various B cell functions, including proliferation, differentiation, antigen presentation, and antibody production, thereby invalidating the anti-tumor effects of B cells. Concurrently, numerous immune checkpoints (ICs) on the surface of B cells are upregulated. Aberrant B-cell IC signals not only impair the function of B cells themselves, but also modulate the tumor-killing effects of other immune cells, ultimately fostering an immunosuppressive TME and facilitating tumor immune escape. Blocking ICs on B cells is beneficial for reversing the immunosuppressive TME and restoring anti-tumor immune responses. In this paper, the intricate connection between B-cell ICs and the TME is delved into, emphasizing the critical role of targeting B-cell ICs in anti-tumor immunity, which may provide valuable insights for the future development of tumor immunotherapy based on B cells.
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Affiliation(s)
- Xiaoye Shi
- Department of OncologyZhujiang HospitalSouthern Medical UniversityGuangzhouGuangdong510282China
- The Second School of Clinical MedicineSouthern Medical UniversityGuangzhouGuangdong510515China
| | - Xiangshu Cheng
- College of Bioinformatics Science and TechnologyHarbin Medical University157 Baojian Road. Nangang District, HarbinHeilongiiang150076China
| | - Aimin Jiang
- Department of UrologyChanghai HospitalNaval Medical University (Second Military Medical University)Shanghai200433China
| | - Wenjie Shi
- Molecular and Experimental SurgeryUniversity Clinic for General‐Visceral‐Vascular‐ and Trans‐Plantation SurgeryMedical Faculty University Hospital MagdeburgOtto‐von Guericke University39120MagdeburgGermany
| | - Lingxuan Zhu
- Department of OncologyZhujiang HospitalSouthern Medical UniversityGuangzhouGuangdong510282China
| | - Weiming Mou
- Department of OncologyZhujiang HospitalSouthern Medical UniversityGuangzhouGuangdong510282China
- Department of UrologyShanghai General HospitalShanghai Jiao Tong University School of MedicineShanghai200080China
| | - Antonino Glaviano
- Department of BiologicalChemical and Pharmaceutical Sciences and TechnologiesUniversity of PalermoPalermo90123Italy
| | - Zaoqu Liu
- Institute of Basic Medical SciencesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100730China
| | - Quan Cheng
- Department of NeurosurgeryXiangya HospitalCentral South UniversityChangsha410008China
- National Clinical Research Center for Geriatric DisordersXiangya HospitalCentral South UniversityChangsha410008China
| | - Anqi Lin
- Department of OncologyZhujiang HospitalSouthern Medical UniversityGuangzhouGuangdong510282China
| | - Linhui Wang
- Department of UrologyChanghai HospitalNaval Medical University (Second Military Medical University)Shanghai200433China
| | - Peng Luo
- Department of OncologyZhujiang HospitalSouthern Medical UniversityGuangzhouGuangdong510282China
- Cancer Centre and Institute of Translational MedicineFaculty of Health SciencesUniversity of MacauMacau SAR999078China
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Yang C, Zhang Y, Wang R, Cheng B, Wu Y, Fu X. IL-10 +CD19 + regulatory B cells induce CD4 +Foxp3 +regulatory T cells in serum of cervical cancer patients. Autoimmunity 2024; 57:2290909. [PMID: 38084896 DOI: 10.1080/08916934.2023.2290909] [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: 11/01/2022] [Accepted: 11/27/2023] [Indexed: 12/18/2023]
Abstract
Increase of regulatory T cells (Tregs) in the tumour microenvironment predicts worse survival of patients with various types of cancer. Recently, B cells play a significant role in the maintenance of Treg cells. However, the relevance of regulatory B cells (Bregs) to tumour immunity in humans remains elusive. Flow cytometry analysis was used to detect the Bregs and Tregs. Double staining results illustrated that the proportion of Bregs and Tregs were prominently higher in cervical cancer than normal tissues. Increase of Bregs and Tregs in cervical cancer microenvironment was associated with poor survival. Furthermore, Bregs cocultured with cervical cancer cell lines increased and induced Tregs. To sum up, the increased expression of Bregs contributes to the differentiation of CD4+ T cells into Tregs in the cervical cancer.
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Affiliation(s)
- Chunfeng Yang
- Department of Obstetrics and Gynecology, Guangdong Provincial Key Laboratory for Major Obstetric Diseases; Guangdong Province Clinical Research Center for Obstetrics and Gynecology; Guangdong-Hong Kong-Macoa Greater Bay Area Higher Educaiton Joint Laboratory of Maternal-Fetal Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Department of Obstetrics and Gynecology, Shenzhen Baoan Maternal and Child Health Hospital, Shenzhen, China
| | - Yuanyuan Zhang
- Department of Gynecologic Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, PR China
| | - Rui Wang
- Department of Obstetrics and Gynecology, Guangdong Provincial Key Laboratory for Major Obstetric Diseases; Guangdong Province Clinical Research Center for Obstetrics and Gynecology; Guangdong-Hong Kong-Macoa Greater Bay Area Higher Educaiton Joint Laboratory of Maternal-Fetal Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Bing Cheng
- Department of Obstetrics and Gynecology, Guangdong Provincial Key Laboratory for Major Obstetric Diseases; Guangdong Province Clinical Research Center for Obstetrics and Gynecology; Guangdong-Hong Kong-Macoa Greater Bay Area Higher Educaiton Joint Laboratory of Maternal-Fetal Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - You Wu
- Department of Gynecologic Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, PR China
| | - Xi Fu
- Department of Obstetrics and Gynecology, Guangdong Provincial Key Laboratory for Major Obstetric Diseases; Guangdong Province Clinical Research Center for Obstetrics and Gynecology; Guangdong-Hong Kong-Macoa Greater Bay Area Higher Educaiton Joint Laboratory of Maternal-Fetal Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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Ahsan NF, Lourenço S, Psyllou D, Long A, Shankar S, Bashford-Rogers R. The current understanding of the phenotypic and functional properties of human regulatory B cells (Bregs). OXFORD OPEN IMMUNOLOGY 2024; 5:iqae012. [PMID: 39346706 PMCID: PMC11427547 DOI: 10.1093/oxfimm/iqae012] [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: 02/14/2024] [Revised: 06/13/2024] [Accepted: 09/10/2024] [Indexed: 10/01/2024] Open
Abstract
B cells can have a wide range of pro- and anti- inflammatory functions. A subset of B cells called regulatory B cells (Bregs) can potently suppress immune responses. Bregs have been shown to maintain immune homeostasis and modulate inflammatory responses. Bregs are an exciting cellular target across a range of diseases, including Breg induction in autoimmunity, allergy and transplantation, and Breg suppression in cancers and infection. Bregs exhibit a remarkable phenotypic heterogeneity, rendering their unequivocal identification a challenging task. The lack of a universally accepted and exclusive surface marker set for Bregs across various studies contributes to inconsistencies in their categorization. This review paper presents a comprehensive overview of the current understanding of the phenotypic and functional properties of human Bregs while addressing the persisting ambiguities and discrepancies in their characterization. Finally, the paper examines the promising therapeutic opportunities presented by Bregs as their immunomodulatory capacities have gained attention in the context of autoimmune diseases, allergic conditions, and cancer. We explore the exciting potential in harnessing Bregs as potential therapeutic agents and the avenues that remain open for the development of Breg-based treatment strategies.
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Affiliation(s)
- Nawara Faiza Ahsan
- Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom
- Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom
| | - Stella Lourenço
- Keizo Asami Institute, Federal University of Pernambuco, Recife 50740-520, Brazil
| | - Dimitra Psyllou
- Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom
| | - Alexander Long
- Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom
| | - Sushma Shankar
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 7DQ, United Kingdom
| | - Rachael Bashford-Rogers
- Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom
- Oxford Cancer Centre, University of Oxford, Oxford OX3 7LH, United Kingdom
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8
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Jung YJ, Woo JS, Hwang SH, Yang S, Kim SJ, Jhun J, Lee SY, Lee KH, Cho ML, Song KY. Effect of IL-10-producing B cells in peripheral blood and tumor tissue on gastric cancer. Cell Commun Signal 2023; 21:320. [PMID: 37946227 PMCID: PMC10634038 DOI: 10.1186/s12964-023-01174-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 05/25/2023] [Indexed: 11/12/2023] Open
Abstract
BACKGROUND Interleukin (IL)-10-producing B (B10) cells are generated in response to signals from the tumor microenvironment and promote tumor growth by interacting with B10 cells. We investigated the distributions of immune cells in peripheral blood and tumor tissue samples from patients with gastric cancer (GC). METHODS Patients with GC who underwent radical gastrectomy in Seoul St. Mary's Hospital between August 2020 and May 2021 were enrolled in this study. Forty-two samples of peripheral blood were collected, and a pair of gastric mucosal samples (normal and cancerous mucosa; did not influence tumor diagnosis or staging) was collected from each patient after surgery. B10 cells in peripheral blood and cancer mucosa samples were investigated by flow cytometry and immunofluorescence. AGS cells, gastric cancer cell line, were cultured with IL-10 and measured cell death and cytokine secretion. Also, AGS cells were co-cultured with CD19 + B cells and measured cytokine secretion. RESULTS The population of B10 cells was significantly larger in the blood of patients with GC compared with controls. In confocal images of gastric mucosal tissues, cancerous mucosa contained more B10 cells than normal mucosa. The population of B10 cells in cancerous mucosa increased with cancer stage. When AGS cells were cultured under cell-death conditions, cellular necrosis was significantly decreased, and proliferation was increased, for 1 day after IL-10 stimulation. Tumor necrosis factor (TNF)-α, IL-8, IL-1β, and vascular endothelial growth factor secretion by cancer cells was significantly increased by coculture of AGS cells with GC-derived CD19+ B cells. CONCLUSIONS B cells may be one of the populations that promote carcinogenesis by inducing the production of inflammatory mediators, such as IL-10, in GC. Targeting B10 cells activity could improve the outcomes of antitumor immunotherapy. Video Abstract.
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Affiliation(s)
- Yoon Ju Jung
- Division of Gastrointestinal Surgery, Department of Surgery, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, 07345, Korea
| | - Jin Seok Woo
- Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, 06591, Korea
- Lab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, 06591, Korea
| | - Sun-Hee Hwang
- Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, 06591, Korea
- Lab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, 06591, Korea
| | - SeungCheon Yang
- Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, 06591, Korea
- Lab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, 06591, Korea
| | - So Jung Kim
- Division of Gastrointestinal Surgery, Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, 06591, Korea
| | - JooYeon Jhun
- Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, 06591, Korea
- Lab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, 06591, Korea
- Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, 06591, Korea
| | - Seung Yoon Lee
- Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, 06591, Korea
- Lab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, 06591, Korea
- Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, 06591, Korea
| | - Kun Hee Lee
- Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, 06591, Korea
- Lab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, 06591, Korea
- Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, 06591, Korea
| | - Mi-La Cho
- Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, 06591, Korea.
- Lab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, 06591, Korea.
- Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, 06591, Korea.
- Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul, 06591, Korea.
| | - Kyo Young Song
- Division of Gastrointestinal Surgery, Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, 06591, Korea.
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Bao J, Betzler AC, Hess J, Brunner C. Exploring the dual role of B cells in solid tumors: implications for head and neck squamous cell carcinoma. Front Immunol 2023; 14:1233085. [PMID: 37868967 PMCID: PMC10586314 DOI: 10.3389/fimmu.2023.1233085] [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: 06/01/2023] [Accepted: 09/06/2023] [Indexed: 10/24/2023] Open
Abstract
In the tumor milieu of head and neck squamous cell carcinoma (HNSCC), distinct B cell subpopulations are present, which exert either pro- or anti-tumor activities. Multiple factors, including hypoxia, cytokines, interactions with tumor cells, and other immune infiltrating lymphocytes (TILs), alter the equilibrium between the dual roles of B cells leading to cancerogenesis. Certain B cell subsets in the tumor microenvironment (TME) exhibit immunosuppressive function. These cells are known as regulatory B (Breg) cells. Breg cells suppress immune responses by secreting a series of immunosuppressive cytokines, including IL-10, IL-35, TGF-β, granzyme B, and adenosine or dampen effector TILs by intercellular contacts. Multiple Breg phenotypes have been discovered in human and mouse cancer models. However, when compartmentalized within a tertiary lymphoid structure (TLS), B cells predominantly play anti-tumor effects. A mature TLS contains a CD20+ B cell zone with several important types of B cells, including germinal-center like B cells, antibody-secreting plasma cells, and memory B cells. They kill tumor cells via antibody-dependent cytotoxicity and phagocytosis, and local complement activation effects. TLSs are also privileged sites for local T and B cell coordination and activation. Nonetheless, in some cases, TLSs may serve as a niche for hidden tumor cells and indicate a bad prognosis. Thus, TIL-B cells exhibit bidirectional immune-modulatory activity and are responsive to a variety of immunotherapies. In this review, we discuss the functional distinctions between immunosuppressive Breg cells and immunogenic effector B cells that mature within TLSs with the focus on tumors of HNSCC patients. Additionally, we review contemporary immunotherapies that aim to target TIL-B cells. For the development of innovative therapeutic approaches to complement T-cell-based immunotherapy, a full understanding of either effector B cells or Breg cells is necessary.
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Affiliation(s)
- Jiantong Bao
- Department of Otorhinolaryngology and Head & Neck Surgery, University Medical Center Ulm, Head & Neck Cancer Center of the Comprehensive Cancer Center Ulm, Ulm, Germany
- School of Medicine, Southeast University, Nanjing, China
| | - Annika C. Betzler
- Department of Otorhinolaryngology and Head & Neck Surgery, University Medical Center Ulm, Head & Neck Cancer Center of the Comprehensive Cancer Center Ulm, Ulm, Germany
| | - Jochen Hess
- Department of Otorhinolaryngology, Head and Neck Surgery, Heidelberg University Hospital, Heidelberg, Germany
- Molecular Mechanisms of Head and Neck Tumors, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Cornelia Brunner
- Department of Otorhinolaryngology and Head & Neck Surgery, University Medical Center Ulm, Head & Neck Cancer Center of the Comprehensive Cancer Center Ulm, Ulm, Germany
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10
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Shao MM, Zhai K, Huang ZY, Yi FS, Zheng SC, Liu YL, Qiao X, Chen QY, Wang Z, Shi HZ. Characterization of the alternative splicing landscape in lung adenocarcinoma reveals novel prognosis signature associated with B cells. PLoS One 2023; 18:e0279018. [PMID: 37432957 DOI: 10.1371/journal.pone.0279018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Accepted: 11/07/2022] [Indexed: 07/13/2023] Open
Abstract
BACKGROUND Lung cancer is the second most commonly diagnosed cancer and the leading cause of cancer-related death. Malignant pleural effusion (MPE) is a special microenvironment for lung cancer metastasis. Alternative splicing, which is regulated by splicing factors, affects the expression of most genes and influences carcinogenesis and metastasis. METHODS mRNA-seq data and alternative splicing events in lung adenocarcinoma (LUAD) were obtained from The Cancer Genome Atlas (TCGA). A risk model was generated by Cox regression analyses and LASSO regression. Cell isolation and flow cytometry were used to identify B cells. RESULTS We systematically analyzed the splicing factors, alternative splicing events, clinical characteristics, and immunologic features of LUAD in the TCGA cohort. A risk signature based on 23 alternative splicing events was established and identified as an independent prognosis factor in LUAD. Among all patients, the risk signature showed a better prognostic value in metastatic patients. By single-sample gene set enrichment analysis, we found that among tumor-infiltrating lymphocytes, B cells were most significantly correlated to the risk score. Furthermore, we investigated the classification and function of B cells in MPE, a metastatic microenvironment of LUAD, and found that regulatory B cells might participate in the regulation of the immune microenvironment of MPE through antigen presentation and promotion of regulatory T cell differentiation. CONCLUSIONS We evaluated the prognostic value of alternative splicing events in LUAD and metastatic LUAD. We found that regulatory B cells had the function of antigen presentation, inhibited naïve T cells from differentiating into Th1 cells, and promoted Treg differentiation in LUAD patients with MPE.
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Affiliation(s)
- Ming-Ming Shao
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Kan Zhai
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Zhong-Yin Huang
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Feng-Shuang Yi
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Sheng-Cai Zheng
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Ya-Lan Liu
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Xin Qiao
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Qing-Yu Chen
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Zhen Wang
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Huan-Zhong Shi
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
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11
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Moreira H, Dobosz A, Cwynar-Zając Ł, Nowak P, Czyżewski M, Barg M, Reichert P, Królikowska A, Barg E. Unraveling the role of Breg cells in digestive tract cancer and infectious immunity. Front Immunol 2022; 13:981847. [PMID: 36618354 PMCID: PMC9816437 DOI: 10.3389/fimmu.2022.981847] [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: 06/29/2022] [Accepted: 12/02/2022] [Indexed: 12/25/2022] Open
Abstract
Over the past two decades, regulatory B cells (Breg cells or Bregs) have emerged as an immunosuppressive subset of B lymphocytes playing a key role in inflammation, infection, allergy, transplantation, and cancer. However, the involvement of Bregs in various pathological conditions of the gastrointestinal tract is not fully understood and is the subject of much recent research. In this review, we aimed to summarize the current state of knowledge about the origin, phenotype, and suppressive mechanisms of Bregs. The relationship between the host gut microbiota and the function of Bregs in the context of the disturbance of mucosal immune homeostasis is also discussed. Moreover, we focused our attention on the role of Bregs in certain diseases and pathological conditions related to the digestive tract, especially Helicobacter pylori infection, parasitic diseases (leishmaniasis and schistosomiasis), and gastrointestinal neoplasms. Increasing evidence points to a relationship between the presence and number of Bregs and the severity and progression of these pathologies. As the number of cases is increasing year by year, also among young people, it is extremely important to understand the role of these cells in the digestive tract.
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Affiliation(s)
- Helena Moreira
- Department of Medical Sciences Foundation, Wroclaw Medical University, Wroclaw, Poland,*Correspondence: Helena Moreira, ; Agnieszka Dobosz,
| | - Agnieszka Dobosz
- Department of Medical Sciences Foundation, Wroclaw Medical University, Wroclaw, Poland,*Correspondence: Helena Moreira, ; Agnieszka Dobosz,
| | - Łucja Cwynar-Zając
- Department of Medical Sciences Foundation, Wroclaw Medical University, Wroclaw, Poland
| | - Paulina Nowak
- Faculty of Pharmacy, Wroclaw Medical University, Wroclaw, Poland
| | - Marek Czyżewski
- Faculty of Medicine, Wroclaw Medical University, Wroclaw, Poland
| | - Marta Barg
- Faculty of Medicine, Wroclaw Medical University, Wroclaw, Poland
| | - Paweł Reichert
- Department of Trauma Surgery, Clinical Department of Trauma and Hand Surgery, Faculty of Medicine, Wroclaw Medical University, Wroclaw, Poland
| | - Aleksandra Królikowska
- Ergonomics and Biomedical Monitoring Laboratory, Department of Physiotherapy, Faculty of Health Sciences, Wroclaw Medical University, Wroclaw, Poland
| | - Ewa Barg
- Department of Medical Sciences Foundation, Wroclaw Medical University, Wroclaw, Poland
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12
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Post-Intervention Plasma IL-10 Level Predicts Early Tumor Response in Hepatocellular Carcinoma Treated with Transarterial Chemoembolization. HEPATITIS MONTHLY 2022. [DOI: 10.5812/hepatmon-129104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Background: Cytokines play an important role in tumor progression, but studies have shown mixed results regarding the role of cytokines in predicting the early response to transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC). Objectives: This study aimed to explore the correlation between plasma levels of cytokines and early tumor response in HCC patients undergoing TACE. Methods: Thirty HCC patients enrolled in this study from the department of liver disease of a general hospital from June 2020 to January 2021. Plasma samples were sampled at baseline and 7 days after TACE for cytokine detection by cytometric bead array (CBA). At 4 - 6 weeks after TACE, the objective response of HCC patients was confirmed according to response evaluation criteria in solid tumors (RECIST). Potential factors such as various cytokines and some clinical parameters were analyzed by univariate and multivariate analysis. The predictive effects of different factors in HCC patients undergoing TACE were analyzed by the receiver operating characteristic (ROC) curve. Results: Plasma levels of post-TACE interleukin-10 (IL-10) were statistically significantly higher than baseline IL-10 levels. The level of plasma IL-10 after TACE was an independent risk factor for early tumor response. The patients with low plasma IL-10 levels after TACE had a favorable prognosis. Receiver operating characteristic curve analysis showed that post-TACE IL-10 had a high predictive value (area under the curve = 0.769, 95% confidence interval (CI): 0.598 - 0.939). A high level of plasma IL-10 after TACE was correlated with alpha-fetoprotein (AFP) level (P = 0.037) and post-TACE alanine aminotransferase (ALT) (r = 0.368, P = 0.045). Post-TACE plasma IL-10 did not correlate with age or tumor metastasis. Conclusions: Our findings demonstrated that post-intervention plasma IL-10 levels could predict short-term outcomes independently after TACE. These findings were helpful in identifying the patients who might benefit from TACE.
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13
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Kovaleva OV, Podlesnaya PA, Chang VL, Ognerubov NA, Gratchev AN, Kozlov NA, Stilidi IS, Kushlinskii NE. Comprehensive Analysis of Stromal and Serum Markers in Gastric Cancer. Acta Naturae 2022; 14:75-83. [PMID: 36694901 PMCID: PMC9844092 DOI: 10.32607/actanaturae.11753] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 10/20/2022] [Indexed: 01/22/2023] Open
Abstract
A comprehensive analysis of the cell phenotype of the inflammatory infiltrate of the tumor stroma represents a promising area of molecular oncology. The study of not only soluble forms of various immunoregulatory molecules, but also their membrane-bound forms is also considered highly relevant. We performed a comprehensive analysis of tissue and circulating forms of the PD-1 and PD-L1 proteins, as well as macrophage and B-cell markers in the tumor stroma of gastric cancer, to assess their clinical and prognostic significance. The tumor and blood plasma samples from 63 gastric cancer patients were studied using ELISA and immunohistochemistry. Malignant gastric tumors were shown to be strongly infiltrated by B-cells, and their number was comparable to that of macrophages. For PU.1 expression, an association with tumor size was observed; i.e., larger tumors were characterized by fewer PU.1+ infiltrating cells (p = 0.005). No clinical significance was found for CD20 and CD163, but their numbers were higher at earlier stages of the disease and in the absence of metastases. It was also demonstrated that the PD-L1 content in tumor cells was not associated with the clinical and morphological characteristics of GC. At the same time, PD-L1 expression in tumor stromal cells was associated with the presence of distant metastases. The analysis of the prognostic significance of all the markers studied demonstrated that CD163 was statistically significantly associated with a poor prognosis for the disease (p = 0.019). In addition, PD-L1 expression in tumor cells tended to indicate a favorable prognosis (p = 0.122). The results obtained in this work indicate that the study of soluble and tissue markers of tumor stroma is promising in prognosticating the course of GC. The search for combinations of markers seems to be highly promising, with their comprehensive analysis capable of helping personalize advanced antitumor therapy.
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Affiliation(s)
- O. V. Kovaleva
- N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russian Federation, Moscow, 115552 Russia
| | - P. A. Podlesnaya
- N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russian Federation, Moscow, 115552 Russia
| | - V. L. Chang
- Medical Institute of G.P. Derzhavin Tambov State University, Tambov, 392000 Russia
| | - N. A. Ognerubov
- Medical Institute of G.P. Derzhavin Tambov State University, Tambov, 392000 Russia
| | - A. N. Gratchev
- N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russian Federation, Moscow, 115552 Russia
| | - N. A. Kozlov
- N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russian Federation, Moscow, 115552 Russia
| | - I. S. Stilidi
- N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russian Federation, Moscow, 115552 Russia
| | - N. E. Kushlinskii
- N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russian Federation, Moscow, 115552 Russia
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14
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Qin Y, Lu F, Lyu K, Chang AE, Li Q. Emerging concepts regarding pro- and anti tumor properties of B cells in tumor immunity. Front Immunol 2022; 13:881427. [PMID: 35967441 PMCID: PMC9366002 DOI: 10.3389/fimmu.2022.881427] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 07/07/2022] [Indexed: 12/26/2022] Open
Abstract
Controversial views regarding the roles of B cells in tumor immunity have existed for several decades. However, more recent studies have focused on its positive properties in antitumor immunity. Many studies have demonstrated a close association of the higher density of intratumoral B cells with favorable outcomes in cancer patients. B cells can interact with T cells as well as follicular dendritic cells within tertiary lymphoid structures, where they undergo a series of biological events, including clonal expansion, somatic hypermutation, class switching, and tumor-specific antibody production, which may trigger antitumor humoral responses. After activation, B cells can function as effector cells via direct tumor-killing, antigen-presenting activity, and production of tumor-specific antibodies. At the other extreme, B cells can obtain inhibitory functions by relevant stimuli, converting to regulatory B cells, which serve as an immunosuppressive arm to tumor immunity. Here we summarize our current understanding of the bipolar properties of B cells within the tumor immune microenvironment and propose potential B cell-based immunotherapeutic strategies, which may help promote cancer immunotherapy.
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Affiliation(s)
- You Qin
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, United States
| | - Furong Lu
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Kexing Lyu
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, United States
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Alfred E. Chang
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, United States
- *Correspondence: Qiao Li, ; Alfred E. Chang,
| | - Qiao Li
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, United States
- *Correspondence: Qiao Li, ; Alfred E. Chang,
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15
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Abstract
The tumor microenvironment (TME) is a heterogeneous, complex organization composed of tumor, stroma, and endothelial cells that is characterized by cross talk between tumor and innate and adaptive immune cells. Over the last decade, it has become increasingly clear that the immune cells in the TME play a critical role in controlling or promoting tumor growth. The function of T lymphocytes in this process has been well characterized. On the other hand, the function of B lymphocytes is less clear, although recent data from our group and others have strongly indicated a critical role for B cells in antitumor immunity. There are, however, a multitude of populations of B cells found within the TME, ranging from naive B cells all the way to terminally differentiated plasma cells and memory B cells. Here, we characterize the role of B cells in the TME in both animal models and patients, with an emphasis on dissecting how B cell heterogeneity contributes to the immune response to cancer.
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Affiliation(s)
- Stephanie M Downs-Canner
- Department of Surgery, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.,Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - Jeremy Meier
- Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA;
| | - Benjamin G Vincent
- Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA; .,Bioinformatics and Computational Biology Program, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.,Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - Jonathan S Serody
- Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA; .,Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
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16
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Mirlekar B. Tumor promoting roles of IL-10, TGF-β, IL-4, and IL-35: Its implications in cancer immunotherapy. SAGE Open Med 2022; 10:20503121211069012. [PMID: 35096390 PMCID: PMC8793114 DOI: 10.1177/20503121211069012] [Citation(s) in RCA: 122] [Impact Index Per Article: 40.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 12/07/2021] [Indexed: 12/23/2022] Open
Abstract
Cytokines play a critical role in regulating host immune response toward cancer and determining the overall fate of tumorigenesis. The tumor microenvironment is dominated mainly by immune-suppressive cytokines that control effector antitumor immunity and promote survival and the proliferation of cancer cells, which ultimately leads to enhanced tumor growth. In addition to tumor cells, the heterogeneous immune cells present within the tumor milieu are the significant source of immune-suppressive cytokines. These cytokines are classified into a broad range; however, in most tumor types, the interleukin-10, transforming growth factor-β, interleukin-4, and interleukin-35 are consistently reported as immune-suppressive cytokines that help tumor growth and metastasis. The most emerging concern in cancer treatment is hijacking and restraining the activity of antitumor immune cells in the tumor niche due to a highly immune-suppressive environment. This review summarizes the role and precise functions of interleukin-10, transforming growth factor-β, interleukin-4, and interleukin-35 in modulating tumor immune contexture and its implication in developing effective immune-therapeutic approaches. CONCISE CONCLUSION Recent effort geared toward developing novel immune-therapeutic approaches faces significant challenges due to sustained mutations in tumor cells and a highly immune-suppressive microenvironment present within the tumor milieu. The cytokines play a crucial role in developing an immune-suppressive environment that ultimately dictates the fate of tumorigenesis. This review critically covers the novel aspects of predominant immune-suppressive cytokines such as interleukin-10, transforming growth factor-β, interleukin-4, and interleukin-35 in dictating the fate of tumorigenesis and how targeting these cytokines can help the development of better immune-therapeutic drug regimens for the treatment of cancer.
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Affiliation(s)
- Bhalchandra Mirlekar
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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17
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Ma ES, Wang ZX, Zhu MQ, Zhao J. Immune evasion mechanisms and therapeutic strategies in gastric cancer. World J Gastrointest Oncol 2022; 14:216-229. [PMID: 35116112 PMCID: PMC8790417 DOI: 10.4251/wjgo.v14.i1.216] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 06/22/2021] [Accepted: 12/10/2021] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is a malignancy with a high incidence and mortality. The tumor immune microenvironment plays an important role in promoting cancer development and supports GC progression. Accumulating evidence shows that GC cells can exert versatile mechanisms to remodel the tumor immune microenvironment and induce immune evasion. In this review, we systematically summarize the intricate crosstalk between GC cells and immune cells, including tumor-associated macrophages, neutrophils, myeloid-derived suppressor cells, natural killer cells, effector T cells, regulatory T cells, and B cells. We focus on how GC cells alter these immune cells to create an immunosuppressive microenvironment that protects GC cells from immune attack. We conclude by compiling the latest progression of immune checkpoint inhibitor-based immunotherapies, both alone and in combination with conventional therapies. Anti-cytotoxic T-lymphocyte-associated protein 4 and anti-programmed cell death protein 1/programmed death-ligand 1 therapy alone does not provide substantial clinical benefit for GC treatment. However, the combination of immune checkpoint inhibitors with chemotherapy or targeted therapy has promising survival advantages in refractory and advanced GC patients. This review provides a comprehensive understanding of the immune evasion mechanisms of GC, and highlights promising immunotherapeutic strategies.
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Affiliation(s)
- En-Si Ma
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
- Institute of Organ Transplantation, Fudan University, Shanghai 200040, China
| | - Zheng-Xin Wang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
- Institute of Organ Transplantation, Fudan University, Shanghai 200040, China
| | - Meng-Qi Zhu
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Jing Zhao
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
- Cancer Metastasis Institute, Fudan University, Shanghai 200040, China
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18
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Lue JK, Downs-Canner S, Chaudhuri J. The role of B cells in the development, progression, and treatment of lymphomas and solid tumors. Adv Immunol 2022; 154:71-117. [PMID: 36038195 DOI: 10.1016/bs.ai.2022.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
B cells are integral components of the mammalian immune response as they have the ability to generate antibodies against an almost infinite array of antigens. Over the past several decades, significant scientific progress has been made in understanding that this enormous B cell diversity contributes to pathogen clearance. However, our understanding of the humoral response to solid tumors and to tumor-specific antigens is unclear. In this review, we first discuss how B cells interact with other cells in the tumor microenvironment and influence the development and progression of various solid tumors. The ability of B lymphocytes to generate antibodies against a diverse repertoire of antigens and subsequently tailor the humoral immune response to specific pathogens relies on their ability to undergo genomic alterations during their development and differentiation. We will discuss key transforming events that lead to the development of B cell lymphomas. Overall, this review provides a foundation for innovative therapeutic interventions for both lymphoma and solid tumor malignancies.
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Affiliation(s)
- Jennifer K Lue
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
| | - Stephanie Downs-Canner
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
| | - Jayanta Chaudhuri
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
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19
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Collagenous Gastritis in Primary Selective IgM Deficiency: Transition to EBV+ Gastric Adenocarcinoma. Case Reports Immunol 2021; 2021:5574944. [PMID: 34123443 PMCID: PMC8172285 DOI: 10.1155/2021/5574944] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 05/14/2021] [Indexed: 12/18/2022] Open
Abstract
Selective IgM deficiency (SIgMD) and isolated collagenous gastritis are two independent rare disorders. Our purpose is to report the 1st case of SIgMD and isolated collagenous gastritis and collagenous gastritis that has transitioned to EBV + gastric adenocarcinoma. Gastric biopsy tissue was analyzed by EBV-related encoded RNA in situ hybridization assay. Subsets of CD4, CD8, T follicular helper cells (TFH), and members of the “regulatory lymphocytes club” were measured with multiple panels of monoclonal antibodies and isotype controls by multicolor flow cytometry. The patient was diagnosed with SIgMD (extremely low serum IgM 9 mg/dl and normal IgG and IgA and exclusion of secondary causes of low IgM). Soon after SIgMD diagnosis, the patient developed collagenous gastritis and, 8 years later, developed gastric adenocarcinoma that was positive for EBV. An extensive immunological analysis revealed reduced naïve CD4 and CD8 effector memory T cells and increased naïve and central memory CD8 T cells. Among the circulating follicular helper T cells (cTFH), TFH1 and TFH2 were increased whereas TFH17 was decreased. CD4 Treg cells and TFR cells were increased, whereas Breg and CD8 Treg were comparable to control. In conclusion, SIgMD may be associated with isolated collagenous gastritis, and collagenous gastritis may transition to EBV + gastric adenocarcinoma. A role of regulatory lymphocytes in gastric cancer is discussed.
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20
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Catalán D, Mansilla MA, Ferrier A, Soto L, Oleinika K, Aguillón JC, Aravena O. Immunosuppressive Mechanisms of Regulatory B Cells. Front Immunol 2021; 12:611795. [PMID: 33995344 PMCID: PMC8118522 DOI: 10.3389/fimmu.2021.611795] [Citation(s) in RCA: 209] [Impact Index Per Article: 52.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 02/19/2021] [Indexed: 12/12/2022] Open
Abstract
Regulatory B cells (Bregs) is a term that encompasses all B cells that act to suppress immune responses. Bregs contribute to the maintenance of tolerance, limiting ongoing immune responses and reestablishing immune homeostasis. The important role of Bregs in restraining the pathology associated with exacerbated inflammatory responses in autoimmunity and graft rejection has been consistently demonstrated, while more recent studies have suggested a role for this population in other immune-related conditions, such as infections, allergy, cancer, and chronic metabolic diseases. Initial studies identified IL-10 as the hallmark of Breg function; nevertheless, the past decade has seen the discovery of other molecules utilized by human and murine B cells to regulate immune responses. This new arsenal includes other anti-inflammatory cytokines such IL-35 and TGF-β, as well as cell surface proteins like CD1d and PD-L1. In this review, we examine the main suppressive mechanisms employed by these novel Breg populations. We also discuss recent evidence that helps to unravel previously unknown aspects of the phenotype, development, activation, and function of IL-10-producing Bregs, incorporating an overview on those questions that remain obscure.
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Affiliation(s)
- Diego Catalán
- Programa Disciplinario de Inmunología, Facultad de Medicina, Instituto de Ciencias Biomédicas (ICBM), Universidad de Chile, Santiago, Chile.,Instituto Milenio en Inmunología e Inmunoterapia, Santiago, Chile
| | - Miguel Andrés Mansilla
- Programa Disciplinario de Inmunología, Facultad de Medicina, Instituto de Ciencias Biomédicas (ICBM), Universidad de Chile, Santiago, Chile
| | - Ashley Ferrier
- Programa Disciplinario de Inmunología, Facultad de Medicina, Instituto de Ciencias Biomédicas (ICBM), Universidad de Chile, Santiago, Chile.,Instituto Milenio en Inmunología e Inmunoterapia, Santiago, Chile
| | - Lilian Soto
- Programa Disciplinario de Inmunología, Facultad de Medicina, Instituto de Ciencias Biomédicas (ICBM), Universidad de Chile, Santiago, Chile.,Unidad de Dolor, Hospital Clínico, Universidad de Chile (HCUCH), Santiago, Chile
| | | | - Juan Carlos Aguillón
- Programa Disciplinario de Inmunología, Facultad de Medicina, Instituto de Ciencias Biomédicas (ICBM), Universidad de Chile, Santiago, Chile
| | - Octavio Aravena
- Programa Disciplinario de Inmunología, Facultad de Medicina, Instituto de Ciencias Biomédicas (ICBM), Universidad de Chile, Santiago, Chile
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21
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Jing Y, Xu F, Liang W, Liu J, Zhang L. Role of regulatory B cells in gastric cancer: Latest evidence and therapeutics strategies. Int Immunopharmacol 2021; 96:107581. [PMID: 33812259 DOI: 10.1016/j.intimp.2021.107581] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Revised: 03/07/2021] [Accepted: 03/09/2021] [Indexed: 12/16/2022]
Abstract
Gastric cancer (GC) is the second most common cancer globally and kills about 700,000 people annually. Today's knowledge clearly shows a close and complicated relationship between the tumor microenvironment (TME) and the immune system. The immune system components can both stimulate tumor growth and inhibit tumor cells. However, numerous of these mechanisms are not yet fully understood. As an essential immune cell in humoral immunity, B lymphocytes can play a dual role during various pathologic states, including infections, autoimmune diseases, and cancer, depending on their phenotype and environmental signals. Inherently, B cells can inhibit tumor growth by producing antibodies as well as the presentation of tumor antigens. However, evidence suggests that a subset of these cells termed regulatory B cells (Bregs) with an inhibitory phenotype can suppress anti-tumor responses and support the tumor growth by producing anti-inflammatory cytokines and the expression of inhibitory molecules. Therefore, in this review, the role of Bregs in the microenvironment of GC and treatment strategies based on targeting this subset of B cells have been investigated.
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Affiliation(s)
- Yuanming Jing
- Department of Gastrointestinal Surgery, Shaoxing People's Hospital, Shaoxing Hospital, The First Affiliated Hospital of Shaoxing University, Shaoxing 312000, Zhejiang Province, PR China.
| | - Fangming Xu
- Department of Orthopedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, 355 Xinqiao Road, Dinghai District, Zhoushan 316000, Zhejiang Province, PR China
| | - Wenqing Liang
- Department of Orthopedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, 355 Xinqiao Road, Dinghai District, Zhoushan 316000, Zhejiang Province, PR China
| | - Jian Liu
- Department of Hepatobiliary Surgery, Shanghai Oriental Hepatobiliary Hospital, Shanghai 200438, PR China
| | - Lin Zhang
- Department of Pharmacy, Shaoxing People's Hospital, Shaoxing Hospital, The First Affiliated Hospital of Shaoxing University, Shaoxing 312000, Zhejiang Province, PR China.
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22
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Jian Y, Yang K, Sun X, Zhao J, Huang K, Aldanakh A, Xu Z, Wu H, Xu Q, Zhang L, Xu C, Yang D, Wang S. Current Advance of Immune Evasion Mechanisms and Emerging Immunotherapies in Renal Cell Carcinoma. Front Immunol 2021; 12:639636. [PMID: 33767709 PMCID: PMC7985340 DOI: 10.3389/fimmu.2021.639636] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 02/08/2021] [Indexed: 12/16/2022] Open
Abstract
Renal cell carcinoma is a highly heterogeneous cancer group, and the complex microenvironment of the tumor provides appropriate immune evasion opportunities. The molecular mechanism of immune escape in renal cell carcinoma is currently a hot issue, focusing primarily on the major complex of histocompatibility, immunosuppressive cells, their secreted immunosuppressive cytokines, and apoptosis molecule signal transduction. Immunotherapy is the best treatment option for patients with metastatic or advanced renal cell carcinoma and combination immunotherapy based on a variety of principles has shown promising prospects. Comprehensive and in-depth knowledge of the molecular mechanism of immune escape in renal cell carcinoma is of vital importance for the clinical implementation of effective therapies. The goal of this review is to address research into the mechanisms of immune escape in renal cell carcinoma and the use of the latest immunotherapy. In addition, we are all looking forward to the latest frontiers of experimental combination immunotherapy.
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Affiliation(s)
- Yuli Jian
- Department of Biochemistry and Molecular Biology, Institute of Glycobiology, Dalian Medical University, Dalian, China
| | - Kangkang Yang
- Department of Biochemistry and Molecular Biology, Institute of Glycobiology, Dalian Medical University, Dalian, China
| | - Xiaoxin Sun
- Department of Biochemistry and Molecular Biology, Institute of Glycobiology, Dalian Medical University, Dalian, China
| | - Jun Zhao
- Department of Urology, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Kai Huang
- Department of Urology, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Abdullah Aldanakh
- Department of Urology, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Zhongyang Xu
- Department of Biochemistry and Molecular Biology, Institute of Glycobiology, Dalian Medical University, Dalian, China
| | - Haotian Wu
- Department of Urology, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Qiwei Xu
- Department of Biochemistry and Molecular Biology, Institute of Glycobiology, Dalian Medical University, Dalian, China
| | - Lin Zhang
- Department of Biochemistry and Molecular Biology, Institute of Glycobiology, Dalian Medical University, Dalian, China
| | - Chunyan Xu
- Department of Biochemistry and Molecular Biology, Institute of Glycobiology, Dalian Medical University, Dalian, China
| | - Deyong Yang
- Department of Urology, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Shujing Wang
- Department of Biochemistry and Molecular Biology, Institute of Glycobiology, Dalian Medical University, Dalian, China
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23
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Lv Q, Xia Q, Li A, Wang Z. The Potential Role of IL1RAP on Tumor Microenvironment-Related Inflammatory Factors in Stomach Adenocarcinoma. Technol Cancer Res Treat 2021; 20:1533033821995282. [PMID: 33602046 PMCID: PMC7897808 DOI: 10.1177/1533033821995282] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
This study was performed to investigate the role of interleukin-1 receptor accessory protein (IL1RAP) in stomach carcinoma in vitro and in vivo, determine whether IL1RAP knockdown could regulate the development of stomach carcinoma, and elucidate the relationship between IL1RAP knockdown and inflammation by tumor microenvironment-related inflammatory factors in stomach carcinoma. We first used TCGA and GEPIA systems to predict the potential function of IL1RAP. Second, western blot and RT-PCR were used to analyze the expression, or mRNA level, of IL1RAP at different tissue or cell lines. Third, the occurrence and development of stomach carcinoma in vitro and in vivo were observed by using IL1RAP knockdown lentivirus. Finally, the inflammation of stomach carcinoma in vitro and in vivo was observed. Results show that in GEPIA and TCGA systems, IL1RAP expression in STAD tumor tissue was higher than normal, and high expression of IL1RAP in STAD patients had a worse prognostic outcome. Besides, GSEA shown IL1RAP was negative correlation of apopopsis, TLR4 and NF-κB signaling pathway. We also predicted that IL1RAP may related to IL-1 s, IL-33, and IL-36 s in STAD. The IL1RAP expression and mRNA level in tumor, or MGC803, cells were increased. Furthermore, IL1RAP knockdown by lentivirus could inhibit stomach carcinoma development in vitro and in vivo through weakening tumor cell proliferation, migration, invasion, therefore reducing tumor volume, weight, and biomarker levels, and increasing apoptotic level. Finally, we found IL1RAP knockdown could increase inflammation of tumor microenvironment-related inflammatory factors of stomach carcinoma, in vitro and in vivo. Our study demonstrates that IL1RAP is possibly able to regulate inflammation and apoptosis in stomach carcinoma. Furthermore, TLR4, NF-κB, IL-1 s, IL-33, and IL-36 s maybe the downstream target factor of IL1RAP in inflammation. These results may provide a new strategy for stomach carcinoma development by regulating inflammation.
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Affiliation(s)
- Qing Lv
- Department of Gastrointestinal Surgery, Wuhan Union Hospital, Wuhan, Hubei, China
| | - Qinghua Xia
- Department of Gastrointestinal Surgery, Wuhan Union Hospital, Wuhan, Hubei, China
| | - Anshu Li
- Department of Gastrointestinal Surgery, Wuhan Union Hospital, Wuhan, Hubei, China
| | - Zhiyong Wang
- Department of Gastrointestinal Surgery, Wuhan Union Hospital, Wuhan, Hubei, China
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24
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Ni Z, Xing D, Zhang T, Ding N, Xiang D, Zhao Z, Qu J, Hu C, Shen X, Xue X, Zhou J. Tumor-infiltrating B cell is associated with the control of progression of gastric cancer. Immunol Res 2020; 69:43-52. [PMID: 33236222 DOI: 10.1007/s12026-020-09167-z] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 11/16/2020] [Indexed: 01/13/2023]
Abstract
This study aimed to further explore the clinicopathological correlation of B cell infiltration in gastric cancer (GC) and its impact on prognostic. By immunohistochemical method, CD20+ B cells, CD3+ T cells, CD66b+ tumor-associated neutrophils, CD163+ tumor-associated macrophages, and CD57+ natural killer cells were analyzed in consecutive sections of 584 GC tissues and 69 normal adjacent tissues. Kaplan-Meier and Cox regression analyses determined the relationship between clinical relevance or prognosis and B cell infiltration. The correlation between total B cell infiltration and various T cell subtype infiltration in GC tissues from 407 patients in the TCGA data was also analyzed. Kaplan-Meier and Cox regression analyses determined the effects of total B cell infiltration and various B cell subtype infiltration on the prognosis of patients with GC. The infiltration level of CD20+ B cells was positively correlated with that of T cells (risk ratio [RR] = 0.0930), especially CD4+ T cells and CD8+ T cells (P < 0.05). A high level of CD20+ B cell infiltration was significantly associated with low lymph node involvement and low TNM stage (P < 0.05). High levels of CD20+ B cell infiltration were significantly associated with improvements in overall survival and disease-free survival. Univariate Cox regression and multivariate Cox regression analysis showed that CD20+ B cell infiltration was an independent protective factor of prognosis. Higher levels of class-switched memory B cell and plasma cell also reflected better overall survival, and class-switched memory B cell and plasma cell were independent protective factors for prognosis. The findings indicate that B cell infiltration in GC, especially switched memory B cells and plasma cells, has a significant effect on tumor progression and prognosis.
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Affiliation(s)
- Zhonglin Ni
- Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, No. 1838 North Guangzhou Avenue, Guangzhou, 510515, Guangdong Province, China
| | - Dong Xing
- Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, School of Basic Medical Sciences, Wenzhou Medical University, University Town, Chashan, Wenzhou, 325035, Zhejiang Province, China
| | - Teming Zhang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, Zhejiang Province, China
| | - Ning Ding
- Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, School of Basic Medical Sciences, Wenzhou Medical University, University Town, Chashan, Wenzhou, 325035, Zhejiang Province, China
| | - Dan Xiang
- Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, School of Basic Medical Sciences, Wenzhou Medical University, University Town, Chashan, Wenzhou, 325035, Zhejiang Province, China
| | - Zhiguang Zhao
- Department of Pathology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, No. 109 West Xueyuan Road, Lucheng District, Wenzhou, 325027, Zhejiang Province, China.
| | - Jinmiao Qu
- Department of Oncology, The First Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang Province, China
| | - Changyuan Hu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, China
| | - Xian Shen
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, Zhejiang Province, China
| | - Xiangyang Xue
- Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, School of Basic Medical Sciences, Wenzhou Medical University, University Town, Chashan, Wenzhou, 325035, Zhejiang Province, China.
| | - Jie Zhou
- Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, No. 1838 North Guangzhou Avenue, Guangzhou, 510515, Guangdong Province, China.
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25
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Shang J, Zha H, Sun Y. Phenotypes, Functions, and Clinical Relevance of Regulatory B Cells in Cancer. Front Immunol 2020; 11:582657. [PMID: 33193391 PMCID: PMC7649814 DOI: 10.3389/fimmu.2020.582657] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 10/02/2020] [Indexed: 12/11/2022] Open
Abstract
In immune system, B cells are classically positive modulators that regulate inflammation and immune responses. Regulatory B cells (Bregs) are a subset of B cells which play crucial roles in various conditions, including infection, allergies, autoimmune diseases, transplantation, and tumors. Until now, unequivocal surface markers for Bregs still lack consensus, although numerous Breg subsets have been identified. Generally, Bregs exert their immunoregulatory functions mainly through cytokine secretion and intercellular contact. In the tumor microenvironment, Bregs suppress effector T cells, induce regulatory T cells and target other tumor-infiltrating immune cells, such as myeloid-derived suppressor cells, natural killer cells and macrophages, to hamper anti-tumor immunity. Meanwhile, the cross-regulations between Bregs and tumor cells often result in tumor escape from immunosurveillance. In addition, accumulating evidence suggests that Bregs are closely associated with many clinicopathological factors of cancer patients and might be potential biomarkers for accessing patient survival. Thus, Bregs are potential therapeutic targets for future immunotherapy in cancer patients. In this review, we will discuss the phenotypes, functions, and clinical relevance of Bregs in cancer.
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Affiliation(s)
- Jin Shang
- Department of Health Service, Guard Bureau of the Joint Staff Department, Central Military Commission of PLA, Beijing, China
| | - Haoran Zha
- Department of Oncology, PLA Rocket Force Characteristic Medical Center, Beijing, China
| | - Yufa Sun
- Department of Health Service, Guard Bureau of the Joint Staff Department, Central Military Commission of PLA, Beijing, China
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