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Guo P, Zhu B, Bai T, Guo X, Shi D, Jiang C, Kong J, Huang Q, Shi J, Shao D. Nanomaterial-Interleukin Combination for Boosting NK Cell-Based Tumor Immunotherapy. ACS Biomater Sci Eng 2025. [PMID: 40340300 DOI: 10.1021/acsbiomaterials.4c01725] [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: 05/10/2025]
Abstract
The use of natural killer (NK) cell-based immunotherapy has been extensively explored in clinical trials for multiple types of tumors and has surfaced as a promising approach in tumor immunotherapy. Interleukins (ILs), a vital class of cytokines, play a crucial role in regulating several functions of NK cells, thereby becoming a focal point in the advancement of NK cell-based therapies. Nonetheless, the use of ILs as single agents is significantly constrained by their short half-life, limited efficacy, and adverse reactions. Currently, nanomaterials are being progressively employed in the delivery of ILs to enhance NK cell-based immunotherapy. However, there is currently a lack of comprehensive reviews summarizing the design of NK-cell-targeted nanomaterials and related systems for delivery of ILs. Furthermore, certain nanomaterials, either alone or in conjunction with other therapeutics, can also promote the secretion of ILs, representing a promising avenue for further exploration. Accordingly, this review begins by outlining various types of ILs and subsequently discusses the advancements in applying nanomaterials for IL delivery. It also examines the potential of nanomaterials to enhance IL secretion from other immune cells, thereby influencing the NK cell functionality. Lastly, this review addresses the challenges associated with using nanomaterials in these contexts and offers perspectives for future research. This study aims to provide valuable insights into the development of NK cell immunotherapy and innovative nanomaterial-based drug delivery systems.
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Affiliation(s)
- Ping Guo
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, China
| | - Bobo Zhu
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, China
| | - Ting Bai
- School of Bioengineering and Health, Wuhan Textile University, Wuhan, 430200, China
| | - Xiaojia Guo
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, China
| | - Dingyu Shi
- School of Materials Science and Engineering, Northwestern Polytechnical University, Xi'an, 710072, China
| | - Chunmei Jiang
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, China
| | - Jie Kong
- Shaanxi Key Laboratory of Macromolecular Science and Technology, School of Chemistry and Chemical Engineering, Northwestern Polytechnical University, Xi'an, 710072, China
| | - Qingsheng Huang
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, China
| | - Junling Shi
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, China
| | - Dongyan Shao
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, China
- Research & Development Institute of Northwestern Polytechnical University in Shenzhen, No. 45th, Gaoxin South Ninth Road, Nanshan District, Shenzhen City, 518063, P. R. China
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Masmoudi D, Villalba M, Alix-Panabières C. Natural killer cells: the immune frontline against circulating tumor cells. J Exp Clin Cancer Res 2025; 44:118. [PMID: 40211394 PMCID: PMC11983744 DOI: 10.1186/s13046-025-03375-x] [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: 01/10/2025] [Accepted: 03/25/2025] [Indexed: 04/14/2025] Open
Abstract
Natural killer (NK) play a key role in controlling tumor dissemination by mediating cytotoxicity towards cancer cells without the need of education. These cells are pivotal in eliminating circulating tumor cells (CTCs) from the bloodstream, thus limiting cancer spread and metastasis. However, aggressive CTCs can evade NK cell surveillance, facilitating tumor growth at distant sites. In this review, we first discuss the biology of NK cells, focusing on their functions within the tumor microenvironment (TME), the lymphatic system, and circulation. We then examine the immune evasion mechanisms employed by cancer cells to inhibit NK cell activity, including the upregulation of inhibitory receptors. Finally, we explore the clinical implications of monitoring circulating biomarkers, such as NK cells and CTCs, for therapeutic decision-making and emphasize the need to enhance NK cell-based therapies by overcoming immune escape mechanisms.
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Affiliation(s)
- Doryan Masmoudi
- Laboratory of Rare Circulating Human Cells, University Medical Center of Montpellier, Montpellier, France
| | - Martin Villalba
- IRMB, Univ Montpellier, INSERM, CHU Montpellier, CNRS, Montpellier, France
| | - Catherine Alix-Panabières
- Laboratory of Rare Circulating Human Cells, University Medical Center of Montpellier, Montpellier, France.
- CREEC/CANECEV, MIVEGEC (CREES), University of Montpellier, CNRS, Montpellier, IRD, France.
- European Liquid Biopsy Society (ELBS), Hamburg, Germany.
- LCCRH, Site Unique de Biologie (SUB), 641, Avenue du Doyen Gaston Giraud, Montpellier, 34093, France.
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3
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He X, Guan XY, Li Y. Clinical significance of the tumor microenvironment on immune tolerance in gastric cancer. Front Immunol 2025; 16:1532605. [PMID: 40028336 PMCID: PMC11868122 DOI: 10.3389/fimmu.2025.1532605] [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: 11/22/2024] [Accepted: 01/30/2025] [Indexed: 03/05/2025] Open
Abstract
In the realm of oncology, the tumor microenvironment (TME)-comprising extracellular matrix components, immune cells, fibroblasts, and endothelial cells-plays a pivotal role in tumorigenesis, progression, and response to therapeutic interventions. Initially, the TME exhibits tumor-suppressive properties that can inhibit malignant transformation. However, as the tumor progresses, various factors induce immune tolerance, resulting in TME behaving in a state that promotes tumor growth and metastasis in later stages. This state of immunosuppression is crucial as it enables TME to change from a role of killing tumor cells to a role of promoting tumor progression. Gastric cancer is a common malignant tumor of the gastrointestinal tract with an alarmingly high mortality rate. While chemotherapy has historically been the cornerstone of treatment, its efficacy in prolonging survival remains limited. The emergence of immunotherapy has opened new therapeutic pathways, yet the challenge of immune tolerance driven by the gastric cancer microenvironment complicates these efforts. This review aims to elucidate the intricate role of the TME in mediating immune tolerance in gastric cancer and to spotlight innovative strategies and clinical trials designed to enhance the efficacy of immunotherapeutic approaches. By providing a comprehensive theoretical framework, this review seeks to advance the understanding and application of immunotherapy in the treatment of gastric cancer, ultimately contributing to improved patient outcomes.
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Affiliation(s)
- Xiangyang He
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xin-Yuan Guan
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Clinical Oncology, The University of Hongkong, Hong Kong, Hong Kong SAR, China
| | - Yan Li
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
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4
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Ochman B, Kot A, Mielcarska S, Kula A, Dawidowicz M, Koszewska D, Hudy D, Szrot M, Piecuch J, Waniczek D, Czuba Z, Świętochowska E. Association of SIGLEC9 Expression with Cytokine Expression, Tumor Grading, KRAS, NRAS, BRAF, PIK3CA, AKT Gene Mutations, and MSI Status in Colorectal Cancer. Curr Issues Mol Biol 2024; 46:13617-13646. [PMID: 39727942 PMCID: PMC11726853 DOI: 10.3390/cimb46120814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 11/26/2024] [Accepted: 11/27/2024] [Indexed: 12/28/2024] Open
Abstract
SIGLEC9 (sialic acid-binding Ig-like lectin 9) is a molecule thought to have a significant influence on the immune properties of the colorectal cancer (CRC) tumor microenvironment (TME). In our study, we assessed the expression of the SIGLEC9 protein in CRC tissue and the surgical margin tissue. Using RT-PCR, we analyzed mutations in the KRAS, NRAS, BRAF, PIK3CA, and AKT genes. We observed a significantly elevated expression of the SIGLEC9 protein in CRC tissue compared to the control group. No significant differences were observed in SIGLEC9 protein expression depending on mutations in the KRAS, NRAS, BRAF, PIK3CA, and AKT genes or microsatellite instability (MSI) status. However, we found a significantly higher expression of the SIGLEC9 protein in high-grade tumors compared to the low-grade tumors group. SIGLEC9 expression was significantly associated with the expression of multiple cytokines, chemokines, and growth factors in the CRC TME. These associations suggest the significant potential of SIGLEC9 as a molecule that plays a crucial role in shaping the immune properties of the CRC TME, as well as its potential therapeutic relevance, particularly in the group of high-grade CRC tumors.
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Affiliation(s)
- Błażej Ochman
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 19 Jordana, 41-808 Zabrze, Poland; (B.O.); (A.K.); (S.M.); (D.K.); (D.H.)
| | - Anna Kot
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 19 Jordana, 41-808 Zabrze, Poland; (B.O.); (A.K.); (S.M.); (D.K.); (D.H.)
| | - Sylwia Mielcarska
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 19 Jordana, 41-808 Zabrze, Poland; (B.O.); (A.K.); (S.M.); (D.K.); (D.H.)
| | - Agnieszka Kula
- Department of Oncological Surgery, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 41-808 Katowice, Poland; (A.K.); (M.D.); (D.W.)
| | - Miriam Dawidowicz
- Department of Oncological Surgery, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 41-808 Katowice, Poland; (A.K.); (M.D.); (D.W.)
| | - Dominika Koszewska
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 19 Jordana, 41-808 Zabrze, Poland; (B.O.); (A.K.); (S.M.); (D.K.); (D.H.)
| | - Dorota Hudy
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 19 Jordana, 41-808 Zabrze, Poland; (B.O.); (A.K.); (S.M.); (D.K.); (D.H.)
| | - Monika Szrot
- Department of General and Bariatric Surgery and Emergency Medicine in Zabrze, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 10 Marii Curie-Skłodowskiej, 41-800 Zabrze, Poland; (M.S.); (J.P.)
| | - Jerzy Piecuch
- Department of General and Bariatric Surgery and Emergency Medicine in Zabrze, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 10 Marii Curie-Skłodowskiej, 41-800 Zabrze, Poland; (M.S.); (J.P.)
| | - Dariusz Waniczek
- Department of Oncological Surgery, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 41-808 Katowice, Poland; (A.K.); (M.D.); (D.W.)
| | - Zenon Czuba
- Department of Microbiology and Immunology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 19 Jordana, 41-808 Zabrze, Poland;
| | - Elżbieta Świętochowska
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 19 Jordana, 41-808 Zabrze, Poland; (B.O.); (A.K.); (S.M.); (D.K.); (D.H.)
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Zhang Y, Li J, Li J, Wang J. Dysregulation of systemic immunity and its clinical application in gastric cancer. Front Immunol 2024; 15:1450128. [PMID: 39301031 PMCID: PMC11410619 DOI: 10.3389/fimmu.2024.1450128] [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: 06/18/2024] [Accepted: 08/22/2024] [Indexed: 09/22/2024] Open
Abstract
Immunotherapy has profoundly changed the treatment of gastric cancer, but only a minority of patients benefit from immunotherapy. Therefore, numerous studies have been devoted to clarifying the mechanisms underlying resistance to immunotherapy or developing biomarkers for patient stratification. However, previous studies have focused mainly on the tumor microenvironment. Systemic immune perturbations have long been observed in patients with gastric cancer, and the involvement of the peripheral immune system in effective anticancer responses has attracted much attention in recent years. Therefore, understanding the distinct types of systemic immune organization in gastric cancer will aid personalized treatment designed to pair with traditional therapies to alleviate their detrimental effects on systemic immunity or to directly activate the anticancer response of systemic immunity. Herein, this review aims to comprehensively summarize systemic immunity in gastric cancer, including perturbations in systemic immunity induced by cancer and traditional therapies, and the potential clinical applications of systemic immunity in the detection, prediction, prognosis and therapy of gastric cancer.
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Affiliation(s)
- Yao Zhang
- Department of General Surgery, The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, Sichuan, China
| | - Junfeng Li
- School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China
- Department of Pharmacy, The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, Sichuan, China
| | - Jian Li
- Department of General Surgery, The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, Sichuan, China
| | - Jisheng Wang
- School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China
- Department of Pharmacy, The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, Sichuan, China
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Mao D, Zhou Z, Chen H, Liu X, Li D, Chen X, He Y, Liu M, Zhang C. Pleckstrin-2 promotes tumour immune escape from NK cells by activating the MT1-MMP-MICA signalling axis in gastric cancer. Cancer Lett 2023; 572:216351. [PMID: 37591356 DOI: 10.1016/j.canlet.2023.216351] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 08/08/2023] [Accepted: 08/13/2023] [Indexed: 08/19/2023]
Abstract
Immune escape is a major challenge in tumour immunotherapy. Pleckstrin-2(PLEK2) plays a critical role in tumour progression, but its role in immune escape in gastric cancer (GC) remains uncharacterized. RNA sequencing was used to explore the differentially expressed genes in a GC cell line that was resistant to the antitumor effect of Natural killer (NK) cells. Apoptosis and the expression of IFN-γ and TNF-α were detected by flow cytometry (FCM). PLEK2 expression was examined by Western blotting and immunohistochemistry (IHC). PLEK2 was upregulated in MGC803R cells that were resistant to the antitumor effect of NK cells. PLEK2 knockout increased the sensitivity of GC cells to NK cell killing. PLEK2 expression was negatively correlated with MICA and positively correlated with MT1-MMP expression both in vitro and in vivo. PLEK2 promoted Sp1 phosphorylation through the PI3K-AKT pathway, thereby upregulating MT1-MMP expression, which ultimately led to MICA shedding. In mouse xenograft models, PLEK2 knockout inhibited intraperitoneal metastasis of GC cells and promoted NK cell infiltration. In summary, PLEK2 suppressed NK cell immune surveillance by promoting MICA shedding, which serves as a potential therapeutic target for GC.
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Affiliation(s)
- Deli Mao
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, China; Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, China
| | - Zhijun Zhou
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, China; Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, China; Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, United States
| | - Hengxing Chen
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, China; Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, China
| | - Xinran Liu
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, China; Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, China
| | - Dongsheng Li
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, China; Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, China
| | - Xiancong Chen
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, China; Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, China
| | - Yulong He
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, China; Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, China; Department of Gastrointestinal Surgery of the First Affiliated Hospital of Sun Yat-sen University, No. 58 Zhongshan 2nd Road, Guangzhou, 510080, Guangdong, China
| | - Mingyang Liu
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, China.
| | - Changhua Zhang
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, China; Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, China.
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Jiang D, Zhang J, Mao Z, Shi J, Ma P. Driving natural killer cell-based cancer immunotherapy for cancer treatment: An arduous journey to promising ground. Biomed Pharmacother 2023; 165:115004. [PMID: 37352703 DOI: 10.1016/j.biopha.2023.115004] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 06/06/2023] [Accepted: 06/08/2023] [Indexed: 06/25/2023] Open
Abstract
Immunotherapy represents one of the most effective strategies for cancer treatment. Recently, progress has been made in using natural killer (NK) cells for cancer therapy. NK cells can directly kill tumor cells without pre-sensitization and thus show promise in clinical applications, distinct from the use of T cells. Whereas, research and development on NK cell-based immunotherapy is still in its infancy, and enhancing the therapeutic effects of NK cells remains a key problem to be solved. An incompletely understanding of the mechanisms of action of NK cells, immune resistance in the tumor microenvironment, and obstacles associated with the delivery of therapeutic agents in vivo, represent three mountains that need to be scaled. Here, we firstly describe the mechanisms underlying the development, activity, and maturation of NK cells, and the formation of NK‑cell immunological synapses. Secondly, we discuss strategies for NK cell-based immunotherapy strategies, including adoptive transfer of NK cell therapy and treatment with cytokines, monoclonal antibodies, and immune checkpoint inhibitors targeting NK cells. Finally, we review the use of nanotechnology to overcome immune resistance, including enhancing the anti-tumor efficiency of chimeric antigen receptor-NK, cytokines and immunosuppressive-pathways inhibitors, promoting NK cell homing and developing NK cell-based nano-engagers.
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Affiliation(s)
- Dandan Jiang
- Department of Pharmacy, Henan Provincial People's Hospital; People's Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450003, China
| | - Jingya Zhang
- Patent Examination Cooperation (Henan) Center of the Patent office, China National Intellectual Property Administration, Henan 450046, China
| | - Zhenkun Mao
- Department of Pharmacy, Henan Provincial People's Hospital; People's Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450003, China
| | - Jinjin Shi
- School of Pharmaceutical Sciences, Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Zhengzhou University, Zhengzhou 450001, China.
| | - Peizhi Ma
- Department of Pharmacy, Henan Provincial People's Hospital; People's Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450003, China.
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Haghshenas MR, Ghaderi H, Daneste H, Ghaderi A. Immunological and biological dissection of normal and tumoral salivary glands. Int Rev Immunol 2023; 42:139-155. [PMID: 34378486 DOI: 10.1080/08830185.2021.1958806] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Salivary glands naturally play central roles in oral immunity. The salivary glands microenvironment inevitable may be exposed to exogenous factors consequently triggering the initiation and formation of various malignant and benign tumors. Mesenchymal stem cells are recruited into salivary gland microenvironment, interact with tumor cells, and induce inhibitory cytokines as well as cells with immunosuppressive phenotypes such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). The immune components and tumor immune responses in malignant and benign SGTs are still under investigation. Immune responses may directly play a limiting role in tumor growth and expansion, or may participate in formation of a rich milieu for tumor growth in cooperation with other cellular and regulatory molecules. Immune checkpoint molecules (e.g. PDLs, HLA-G and LAG3) are frequently expressed on tumor cells and/or tumor-infiltrating lymphocytes (TILs) in salivary gland microenvironment, and an increase in their expression is associated with T cell exhaustion, immune tolerance and tumor immune escape. Chemokines and chemokine receptors have influential roles on aggressive behaviors of SGTs, and thereby they could be candidate targets for cancer immunotherapy. To present a broad knowledge on salivary glands, this review first provides a brief description on immunological functions of normal salivary glands, and then describe the SGT's tumor microenvironment, by focusing on mesenchymal stem cells, immune cell subsets, immune checkpoint molecules, chemokines and chemokine receptors, and finally introduces immune checkpoint inhibitors as well as potential targets for cancer therapy.
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Affiliation(s)
- Mohammad Reza Haghshenas
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hamid Ghaderi
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hossein Daneste
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Abbas Ghaderi
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
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9
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Zafarani A, Razizadeh MH, Pashangzadeh S, Amirzargar MR, Taghavi-Farahabadi M, Mahmoudi M. Natural killer cells in COVID-19: from infection, to vaccination and therapy. Future Virol 2023:10.2217/fvl-2022-0040. [PMID: 36936055 PMCID: PMC10013930 DOI: 10.2217/fvl-2022-0040] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Accepted: 01/31/2023] [Indexed: 03/15/2023]
Abstract
Natural killer (NK) cells are among the most important innate immunity members, which are the first cells that fight against infected cells. The function of these cells is impaired in patients with COVID-19 and they are not able to prevent the spread of the disease or destroy the infected cells. Few studies have evaluated the effects of COVID-19 vaccines on NK cells, though it has been demonstrated that DNA vaccines and BNT162b2 can affect NK cell response. In the present paper, the effects of SARS-CoV-2 on the NK cells during infection, the effect of vaccination on NK cells, and the NK cell-based therapies were reviewed.
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Affiliation(s)
- Alireza Zafarani
- 1Department of Hematology & Blood Banking, School of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | | | - Salar Pashangzadeh
- 3Iranian Research Center for HIV/AIDS, Iranian Institute for Reduction of High-Risk Behaviors, Tehran University of Medical Sciences, Tehran, Iran
- 4Immunology Today, Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | - Mohammad Reza Amirzargar
- 1Department of Hematology & Blood Banking, School of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mahsa Taghavi-Farahabadi
- 5Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Mahmoudi
- 6Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, 1449614535, Iran
- Author for correspondence: Tel.: +98 936 002 0731;
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10
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Lu C, Liu Y, Ali NM, Zhang B, Cui X. The role of innate immune cells in the tumor microenvironment and research progress in anti-tumor therapy. Front Immunol 2023; 13:1039260. [PMID: 36741415 PMCID: PMC9893925 DOI: 10.3389/fimmu.2022.1039260] [Citation(s) in RCA: 59] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Accepted: 12/14/2022] [Indexed: 01/20/2023] Open
Abstract
Innate immune cells in the tumor microenvironment (TME) mainly include macrophages, neutrophils, natural killer cells, dendritic cells and bone marrow derived suppressor cells. They play an anti-tumor or pro-tumor role by secreting various cytokines, chemokines and other factors, and determine the occurrence and development of tumors. Comprehending the role of innate immune cells in tumorigenesis and progression can help improve therapeutic approaches targeting innate immune cells in the TME, increasing the likelihood of favorable prognosis. In this review, we discussed the cell biology of innate immune cells, their role in tumorigenesis and development, and the current status of innate immune cell-based immunotherapy, in order to provide an overview for future research lines and clinical trials.
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Affiliation(s)
- Chenglin Lu
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Ying Liu
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, China,Department of Oncology, Affiliated Zhongshan Hospital of Dalian University, Dalian, China
| | - Nasra Mohamoud Ali
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Bin Zhang
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, China,*Correspondence: Xiaonan Cui, ; Bin Zhang,
| | - Xiaonan Cui
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, China,*Correspondence: Xiaonan Cui, ; Bin Zhang,
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Keshavjee SH, Moy RH, Reiner SL, Ryeom SW, Yoon SS. Gastric Cancer and the Immune System: The Key to Improving Outcomes? Cancers (Basel) 2022; 14:cancers14235940. [PMID: 36497422 PMCID: PMC9739366 DOI: 10.3390/cancers14235940] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 11/21/2022] [Accepted: 11/29/2022] [Indexed: 12/04/2022] Open
Abstract
Gastric adenocarcinoma is by far the most common form of gastric cancer (GC) and is a highly lethal form of cancer arising from the gastric epithelium. GC is an important area of focus of the medical community, given its often late-stage of diagnosis and associated high mortality rate. While surgery and chemotherapy remain the primary treatments, attention has been drawn to the use of immunologic therapies, which have shown promise in the treatment of other malignancies. The role for immune-based therapies has become clearer as we obtain a greater understanding of the role of the immune system in gastric cancer formation and growth. A variety treatment to augment the immune system are under evaluation in clinical trials, and these include immune checkpoint inhibitors, antibody-drug conjugates, and immune cell-based therapies. Here, we review the immune landscape and immune-based therapies for GC.
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Affiliation(s)
- Sara H. Keshavjee
- Division of Surgical Oncology, Department of Surgery, Columbia University Irving Medical Center, New York, NY 10032, USA
- Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Ryan H. Moy
- Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
- Division of Hematology/Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Steven L. Reiner
- Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
- Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Sandra W. Ryeom
- Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
- Division of Surgical Sciences, Department of Surgery, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Sam S. Yoon
- Division of Surgical Oncology, Department of Surgery, Columbia University Irving Medical Center, New York, NY 10032, USA
- Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
- Correspondence:
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12
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Dizaji Asl K, Mazloumi Z, Majidi G, Kalarestaghi H, Sabetkam S, Rafat A. NK cell dysfunction is linked with disease severity in SARS-CoV-2 patients. Cell Biochem Funct 2022; 40:559-568. [PMID: 35833321 PMCID: PMC9350078 DOI: 10.1002/cbf.3725] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 05/16/2022] [Accepted: 06/02/2022] [Indexed: 12/13/2022]
Abstract
SARS-CoV-2 first raised from Wuhan City, Hubei Province in November 2019. The respiratory disorder, cough, weakness, fever are the main clinical symptoms of coronavirus disease 2019 (COVID-19) patients. Natural Killer (NK) cells as a first defense barrier of innate immune system have an essential role in early defense against pulmonary virus. They kill the infected cells by inducing apoptosis or the degranulation of perforin and granzymes. Collectively, NK cells function are coordinated by the transmitted signals from activating and inhibitory receptors. It is clear that the cytotoxic function of NK cells is disrupted in COVID-19 patients due to the dysregulation of activating and inhibitory receptors. Therefore, better understanding of the activating and inhibitory receptors mechanism could facilitate the treatment strategy in clinic. To improve the efficacy of immunotherapy in COVID-19 patients, the functional detail of NK cell and manipulation of their key checkpoints are gathered in current review.
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Affiliation(s)
- Khadijeh Dizaji Asl
- Clinical Research Development Unit of Tabriz Valiasr HospitalTabriz University of Medical SciencesTabrizIran
- Department of Histopathology and Anatomy, Faculty of Medicine, Tabriz BranchIslamic Azad UniversityTabrizIran
| | - Zeinab Mazloumi
- Department of Medical Applied Cell Sciences, Faculty of Advanced Medical SciencesTabriz University of Medical SciencesTabrizIran
| | - Ghazal Majidi
- Faculty of MedicineTabriz University of Medical SciencesTabrizIran
| | - Hossein Kalarestaghi
- Research Laboratory for Embryology and Stem Cell, Department of Anatomical Sciences, School of MedicineArdabil University of Medical SciencesArdabilIran
| | - Shahnaz Sabetkam
- Department of Histopathology and Anatomy, Faculty of Medicine, Tabriz BranchIslamic Azad UniversityTabrizIran
| | - Ali Rafat
- Department of Anatomical SciencesTabriz University of Medical SciencesTabrizIran
- Anatomical Sciences Research CenterKashan University of Medical SciencesKashanIran
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13
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Old and New Aspects of H. pylori-Associated Inflammation and Gastric Cancer. CHILDREN 2022; 9:children9071083. [PMID: 35884067 PMCID: PMC9322908 DOI: 10.3390/children9071083] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Revised: 07/17/2022] [Accepted: 07/18/2022] [Indexed: 12/16/2022]
Abstract
H. pylori is involved in the development of 80% of gastric cancers and 5.5% of all malignant conditions worldwide. Its persistence within the host’s stomach causes chronic inflammation, which is a well-known hallmark of carcinogenesis. A wide range of cytokines was reported to be involved in the initiation and long-term persistence of this local and systemic inflammation. IL-8 was among the first cytokines described to be increased in patients with H. pylori infection. Although, this cytokine was initially identified to exert a chemoattracting effect that represents a trigger for the activation of inflammatory cells within H.-pylori-infected mucosa, more recent studies failed in encountering any association between IL-8 and H. pylori infection. IL-6 is a multifunctional, pleiotropic and multipotent cytokine involved in mediating the interaction between innate and adaptive immunity with a dichotomous role acting as both a proinflammatory and an anti-inflammatory cytokine depending on the signaling pathway. IL-1α functions as a promoter of angiogenesis and vascular endothelial cell proliferation in gastric carcinoma since it is closely related to H.-pylori-induced inflammation in children. IL-1β is an essential trigger and enhancer of inflammation. The association between a low IL-1β level and an increased TNF-α level might be considered a risk factor for peptic ulcer disease in the setting of H. pylori infection. IL-10 downregulates both cytotoxic inflammatory responses and cell-mediated immune responses. H. pylori uses the immunosuppressive role of IL-10 to favor its escape from the host’s immune system. TGFβ is a continuous inflammatory mediator that promotes the adherence of H. pylori to the host’s cells and their subsequent colonization. The role of H.-pylori-induced inflammatory responses in the onset of gastric carcinogenesis seems to represent the missing puzzle piece for designing effective preventive and therapeutic strategies in patients with H.-pylori-associated gastric cancer.
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14
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He J, Hu W, Ouyang Q, Zhang S, He L, Chen W, Li X, Hu C. Helicobacter pylori infection induces stem cell-like properties in Correa cascade of gastric cancer. Cancer Lett 2022; 542:215764. [PMID: 35654291 DOI: 10.1016/j.canlet.2022.215764] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 05/16/2022] [Accepted: 05/26/2022] [Indexed: 02/09/2023]
Abstract
Gastric cancer (GC) is the fourth leading cause of cancer-related death. Its poor prognosis is attributed to unclear pathogenesis. Currently, the most widely accepted model for elucidating the mechanism of GC is the Correa cascade, which covers several histological lesions of the gastric mucosa. GC stem cells (CSCs) are crucial for oncogenesis in the Correa cascade and GC progression. As Helicobacter pylori (H. pylori) is the etiological factor in the Correa cascade, growing evidence suggests that enhancement of gastric stem cell-like properties and increase in CSCs correlate with H. pylori infection. In this paper, we review recent studies that present pathogenic mechanisms by which H. pylori induces gastric stem cell-like properties and CSCs, which may supplement the existing Correa model of GC. First, the dysfunction of developmental signaling pathways associated with H. pylori infection leads to the enhancement of gastric stemness. Second, H. pylori infection promotes alteration of the gastric mucosal microenvironment. In addition, epithelial-mesenchymal transition (EMT) may contribute to H. pylori-induced gastric stemness. Taken together, understanding these pathogeneses will provide potential therapeutic targets for the treatment of CSCs and malignant GC in H. pylori induced-Correa cascade of GC.
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Affiliation(s)
- JunJian He
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - WeiChao Hu
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - Qin Ouyang
- Department of Medicinal Chemistry, College of Pharmacy, Army Medical University, Chongqing, 400038, China
| | - ShengWei Zhang
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - LiJiao He
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - WeiYan Chen
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - XinZhe Li
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China.
| | - ChangJiang Hu
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China.
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15
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La Sala L, Gandini S, Bruno A, Allevi R, Gallazzi M, Senesi P, Palano MT, Meregalli P, Longhi E, Sommese C, Luzi L, Trabucchi E. SARS-CoV-2 Immunization Orchestrates the Amplification of IFNγ-Producing T Cell and NK Cell Persistence. Front Immunol 2022; 13:798813. [PMID: 35237261 PMCID: PMC8882867 DOI: 10.3389/fimmu.2022.798813] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 01/21/2022] [Indexed: 12/13/2022] Open
Abstract
A successful vaccination would represent the most efficient means to control the pandemic of Coronavirus Disease-19 (COVID-19) that led to millions of deaths worldwide. Novel mRNA-based vaccines confer protective immunity against SARS-CoV-2, but whether immunity is immediately effective and how long it will remain in recipients are uncertain. We sought to assess the effectiveness of a two-dose regimen since the boosts are often delayed concerning the recommended intervals.MethodsA longitudinal cohort of healthcare workers (HCW, N = 46; 30.4% men; 69.6% women; mean age 36.05 ± 2.2 years) with no SARS-CoV-2 infection as documented by negative polymerase chain reaction was immunophenotyped in PBMC once a week for 4 weeks from the prime immunization (Pfizer mRNA BNT162b2) and had received 2 doses, to study the kinetic response.ResultsWe identified three risk groups to develop SARS-CoV-2 infection IgG+-based (late responders, R-; early responders, R+; pauci responders, PR). In all receipts, amplification of B cells and NK cells, including IL4-producing B cells and IL4-producing CD8+ T cells, is early stimulated by the vaccine. After the boost, we observed a growing increase of NK cells but a resistance of T cells, IFNγ-producing CD4+T cells, and IFNγ-producing NK cells. Also, hematologic parameters decline until the boost. The positive association of IFNγ-producing NK with IFNγ-producing CD4+T cells by the multiple mixed-effect model, adjusted for confounders (p = 0.036) as well as the correlation matrix (r = 0.6, p < 0.01), suggests a relationship between these two subsets of lymphocytes.ConclusionsThese findings introduce several concerns about policy delay in vaccination: based on immunological protection, B cells and the persistent increase of NK cells during 2 doses of the mRNA-based vaccine could provide further immune protection against the virus, while CD8+ T cells increased slightly only in the R+ and PR groups.
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Affiliation(s)
- Lucia La Sala
- Lab of Cardiovascular Diabetology and Dysmetabolic Disease, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy
- *Correspondence: Lucia La Sala,
| | - Sara Gandini
- Department of Experimental Oncology, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy
| | - Antonino Bruno
- Laboratory of Innate Immunity, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy
| | - Raffaele Allevi
- Department of Biomedical and Clinical Sciences “L. Sacco”, University of Milan, Milan, Italy
| | - Matteo Gallazzi
- Laboratory of Immunology and General Pathology, Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
| | - Pamela Senesi
- Lab of Cardiovascular Diabetology and Dysmetabolic Disease, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy
- Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
| | - Maria Teresa Palano
- Laboratory of Innate Immunity, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy
| | - Paola Meregalli
- Lab of Cardiovascular Diabetology and Dysmetabolic Disease, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy
| | - Ermanno Longhi
- Lab of Cardiovascular Diabetology and Dysmetabolic Disease, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy
| | - Carmen Sommese
- Lab of Cardiovascular Diabetology and Dysmetabolic Disease, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy
| | - Livio Luzi
- Lab of Cardiovascular Diabetology and Dysmetabolic Disease, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy
- Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
| | - Emilio Trabucchi
- Lab of Cardiovascular Diabetology and Dysmetabolic Disease, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy
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16
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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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17
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Zhou J, Zhang S, Guo C. Crosstalk between macrophages and natural killer cells in the tumor microenvironment. Int Immunopharmacol 2021; 101:108374. [PMID: 34824036 DOI: 10.1016/j.intimp.2021.108374] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 11/08/2021] [Accepted: 11/10/2021] [Indexed: 12/17/2022]
Abstract
The tumor microenvironment (TME) is jointly constructed by a variety of cell types, including tumor cells, immune cells, fibroblasts, and epithelial cells, among others. The cells within the TME interact with each other and with tumor cells to influence tumor development and progression. As the most abundant immune cells in the TME, macrophages regulate the immune network by not only secreting a large amount of versatile cytokines but also expressing a series of ligands or receptors on the surface to interact with other cells directly. Due to their strong plasticity, they exert both immunostimulatory and immunosuppressive effects in the complex TME. The major effector cells of the immune system that directly target cancer cells include but are not limited to natural killer cells (NKs), dendritic cells (DCs), macrophages, polymorphonuclear leukocytes, mast cells, and cytotoxic T lymphocytes (CTLs). Among them, NK cells are the predominant innate lymphocyte subsets that mediate antitumor and antiviral responses. The activation and inhibition of NK cells are regulated by cytokines and the balance between activating and inhibitory receptors. There is an inextricable regulatory relationship between macrophages and NK cells. Herein, we systematically elaborate on the regulatory network between macrophages and NK cells through soluble mediator crosstalk and cell-to-cell interactions. We believe that a better understanding of the crosstalk between macrophages and NKs in the TME will benefit the development of novel macrophage- or NK cell-focused therapeutic strategies with superior efficacies in cancer therapy.
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Affiliation(s)
- Jingping Zhou
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, PR China
| | - Shaolong Zhang
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, PR China
| | - Changying Guo
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, PR China.
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18
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Lin Q, Rong L, Jia X, Li R, Yu B, Hu J, Luo X, Badea SR, Xu C, Fu G, Lai K, Lee MC, Zhang B, Gong H, Zhou N, Chen XL, Lin SH, Fu G, Huang JD. IFN-γ-dependent NK cell activation is essential to metastasis suppression by engineered Salmonella. Nat Commun 2021; 12:2537. [PMID: 33953170 PMCID: PMC8099885 DOI: 10.1038/s41467-021-22755-3] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Accepted: 03/25/2021] [Indexed: 02/07/2023] Open
Abstract
Metastasis accounts for 90% of cancer-related deaths and, currently, there are no effective clinical therapies to block the metastatic cascade. A need to develop novel therapies specifically targeting fundamental metastasis processes remains urgent. Here, we demonstrate that Salmonella YB1, an engineered oxygen-sensitive strain, potently inhibits metastasis of a broad range of cancers. This process requires both IFN-γ and NK cells, as the absence of IFN-γ greatly reduces, whilst depletion of NK cells in vivo completely abolishes, the anti-metastatic ability of Salmonella. Mechanistically, we find that IFN-γ is mainly produced by NK cells during early Salmonella infection, and in turn, IFN-γ promotes the accumulation, activation, and cytotoxicity of NK cells, which kill the metastatic cancer cells thus achieving an anti-metastatic effect. Our findings highlight the significance of a self-regulatory feedback loop of NK cells in inhibiting metastasis, pointing a possible approach to develop anti-metastatic therapies by harnessing the power of NK cells.
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Affiliation(s)
- Qiubin Lin
- grid.194645.b0000000121742757School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR China ,HKU-Zhejiang Institute of Research and Innovation (HKU-ZIRI), Hangzhou, China
| | - Li Rong
- grid.194645.b0000000121742757School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR China
| | - Xian Jia
- grid.12955.3a0000 0001 2264 7233State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Medicine, Xiamen University, Xiamen, China
| | - Renhao Li
- grid.194645.b0000000121742757School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR China ,grid.194645.b0000000121742757Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR China
| | - Bin Yu
- grid.194645.b0000000121742757School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR China
| | - Jingchu Hu
- grid.9227.e0000000119573309Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Xiao Luo
- grid.9227.e0000000119573309Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - S. R. Badea
- grid.194645.b0000000121742757School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR China
| | - Chen Xu
- grid.194645.b0000000121742757School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR China
| | - Guofeng Fu
- grid.12955.3a0000 0001 2264 7233State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Medicine, Xiamen University, Xiamen, China
| | - Kejiong Lai
- grid.12955.3a0000 0001 2264 7233State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Medicine, Xiamen University, Xiamen, China
| | - Ming-chun Lee
- grid.194645.b0000000121742757School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR China
| | - Baozhong Zhang
- grid.9227.e0000000119573309Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Huarui Gong
- grid.194645.b0000000121742757School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR China
| | - Nan Zhou
- grid.9227.e0000000119573309Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Xiao Lei Chen
- grid.12955.3a0000 0001 2264 7233State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Medicine, Xiamen University, Xiamen, China ,grid.12955.3a0000 0001 2264 7233Cancer Research Center of Xiamen University, Xiamen, China
| | - Shu-hai Lin
- grid.12955.3a0000 0001 2264 7233State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Medicine, Xiamen University, Xiamen, China
| | - Guo Fu
- grid.12955.3a0000 0001 2264 7233State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Medicine, Xiamen University, Xiamen, China ,grid.12955.3a0000 0001 2264 7233Cancer Research Center of Xiamen University, Xiamen, China
| | - Jian-Dong Huang
- grid.194645.b0000000121742757School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR China ,HKU-Zhejiang Institute of Research and Innovation (HKU-ZIRI), Hangzhou, China ,grid.9227.e0000000119573309Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
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19
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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]
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20
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van Eeden C, Khan L, Osman MS, Cohen Tervaert JW. Natural Killer Cell Dysfunction and Its Role in COVID-19. Int J Mol Sci 2020; 21:E6351. [PMID: 32883007 PMCID: PMC7503862 DOI: 10.3390/ijms21176351] [Citation(s) in RCA: 114] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 08/27/2020] [Accepted: 08/27/2020] [Indexed: 12/15/2022] Open
Abstract
When facing an acute viral infection, our immune systems need to function with finite precision to enable the elimination of the pathogen, whilst protecting our bodies from immune-related damage. In many instances however this "perfect balance" is not achieved, factors such as ageing, cancer, autoimmunity and cardiovascular disease all skew the immune response which is then further distorted by viral infection. In SARS-CoV-2, although the vast majority of COVID-19 cases are mild, as of 24 August 2020, over 800,000 people have died, many from the severe inflammatory cytokine release resulting in extreme clinical manifestations such as acute respiratory distress syndrome (ARDS) and hemophagocytic lymphohistiocytosis (HLH). Severe complications are more common in elderly patients and patients with cardiovascular diseases. Natural killer (NK) cells play a critical role in modulating the immune response and in both of these patient groups, NK cell effector functions are blunted. Preliminary studies in COVID-19 patients with severe disease suggests a reduction in NK cell number and function, resulting in decreased clearance of infected and activated cells, and unchecked elevation of tissue-damaging inflammation markers. SARS-CoV-2 infection skews the immune response towards an overwhelmingly inflammatory phenotype. Restoration of NK cell effector functions has the potential to correct the delicate immune balance required to effectively overcome SARS-CoV-2 infection.
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Affiliation(s)
| | | | | | - Jan Willem Cohen Tervaert
- Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada; (C.v.E.); (L.K.); (M.S.O.)
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21
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Ma W, Zhang Y, Yu M, Wang B, Xu S, Zhang J, Li X, Ye X. In-vitro and in-vivo anti-breast cancer activity of synergistic effect of berberine and exercise through promoting the apoptosis and immunomodulatory effects. Int Immunopharmacol 2020; 87:106787. [PMID: 32707493 DOI: 10.1016/j.intimp.2020.106787] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Revised: 06/12/2020] [Accepted: 07/04/2020] [Indexed: 01/02/2023]
Abstract
PURPOSE Breast cancer is the most common reason of cancer death in women. Berberine (BBR), a main alkaloid in Coptis chinensis, exerted anti-cancer activities. Exercise is a new immunotherapy treatment against cancer. However, it is unclear whether exercise has effects on breast cancer and whether exercise has synergistic anti-cancer effect when co-treated with BBR. Thus, it is assumed that exercise might exert an anti-cancer effect through the immune way. METHOD The anti-tumor effect of exercise and BBR in vivo was studied in mice. The MTT method, hoechst staining and cell morphology were performed to determine the synergistic effect of exercise and BBR on breast cancer in vitro. At the same time, Western blotting, intestinal microbial and SCFA detection, Q-PCR and other methods were used to study the anti-cancer molecular mechanism. RESULTS The study found that exercise and BBR co-treatment significantly slowed the progression of breast cancer in 4T1 tumor-bearing mice (p < 0.01). Compared with the TC group, the infiltration of NK cells increased in the combined group of BBR and exercise (p < 0.01), and the expression of immune factors and cytokines was also regulated. At the same time, the synergistic effect significantly increased the level of short chain fatty acids (SCFA). SCFA can promote apoptosis of 4T1 cells and change the inflammatory factors in vitro. The expression of bcl-2 and XIAP was reduced in tumor tissues, and the expression of Fas, Fadd, Bid, Cyto-C, and Caspase-3/8/9 was also increased in vitro experiments (p < 0.05). CONCLUSIONS These results indicate that the synergistic treatment of exercise and BBR can improve the immune system, regulate intestinal microbial metabolite (SCFA), activate the mitochondrial apoptosis pathway and Fas death receptor apoptosis pathway, and thus play an anticancer role. This may provide a new method for the treatment of breast cancer.
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Affiliation(s)
- Wenyu Ma
- Chongqing Key Laboratory of Plant Resource Conservation and Germplasm Innovation, School of Life Sciences, Southwest University, Chongqing 400715, China
| | - Yaru Zhang
- Chongqing Key Laboratory of Plant Resource Conservation and Germplasm Innovation, School of Life Sciences, Southwest University, Chongqing 400715, China
| | - Min Yu
- Chongqing Key Laboratory of Plant Resource Conservation and Germplasm Innovation, School of Life Sciences, Southwest University, Chongqing 400715, China
| | - Bin Wang
- Chongqing Key Laboratory of Plant Resource Conservation and Germplasm Innovation, School of Life Sciences, Southwest University, Chongqing 400715, China
| | - Shiyu Xu
- Chongqing Key Laboratory of Plant Resource Conservation and Germplasm Innovation, School of Life Sciences, Southwest University, Chongqing 400715, China
| | - Jian Zhang
- Chongqing Key Laboratory of Plant Resource Conservation and Germplasm Innovation, School of Life Sciences, Southwest University, Chongqing 400715, China
| | - Xuegang Li
- School of Pharmaceutical Sciences, Southwest University, Chongqing 400716, China.
| | - Xiaoli Ye
- Chongqing Key Laboratory of Plant Resource Conservation and Germplasm Innovation, School of Life Sciences, Southwest University, Chongqing 400715, China.
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22
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Lopes A, Feola S, Ligot S, Fusciello M, Vandermeulen G, Préat V, Cerullo V. Oncolytic adenovirus drives specific immune response generated by a poly-epitope pDNA vaccine encoding melanoma neoantigens into the tumor site. J Immunother Cancer 2019; 7:174. [PMID: 31291991 PMCID: PMC6621971 DOI: 10.1186/s40425-019-0644-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 06/19/2019] [Indexed: 02/08/2023] Open
Abstract
Background DNA vaccines against cancer held great promises due to the generation of a specific and long-lasting immune response. However, when used as a single therapy, they are not able to drive the generated immune response into the tumor, because of the immunosuppressive microenvironment, thus limiting their use in humans. To enhance DNA vaccine efficacy, we combined a new poly-epitope DNA vaccine encoding melanoma tumor associated antigens and B16F1-specific neoantigens with an oncolytic virus administered intratumorally. Methods Genomic analysis were performed to find specific mutations in B16F1 melanoma cells. The antigen gene sequences were designed according to these mutations prior to the insertion in the plasmid vector. Mice were injected with B16F1 tumor cells (n = 7–9) and therapeutically vaccinated 2, 9 and 16 days after the tumor injection. The virus was administered intratumorally at day 10, 12 and 14. Immune cell infiltration analysis and cytokine production were performed by flow cytometry, PCR and ELISPOT in the tumor site and in the spleen of animals, 17 days after the tumor injection. Results The combination of DNA vaccine and oncolytic virus significantly increased the immune activity into the tumor. In particular, the local intratumoral viral therapy increased the NK infiltration, thus increasing the production of different cytokines, chemokines and enzymes involved in the adaptive immune system recruitment and cytotoxic activity. On the other side, the DNA vaccine generated antigen-specific T cells in the spleen, which migrated into the tumor when recalled by the local viral therapy. The complementarity between these strategies explains the dramatic tumor regression observed only in the combination group compared to all the other control groups. Conclusions This study explores the immunological mechanism of the combination between an oncolytic adenovirus and a DNA vaccine against melanoma. It demonstrates that the use of a rational combination therapy involving DNA vaccination could overcome its poor immunogenicity. In this way, it will be possible to exploit the great potential of DNA vaccination, thus allowing a larger use in the clinic. Electronic supplementary material The online version of this article (10.1186/s40425-019-0644-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Alessandra Lopes
- Université Catholique de Louvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, B-1200, Brussels, Belgium
| | - Sara Feola
- University of Helsinki, Biocenter 2, Viikinkari 5E, Helsinki, Finland
| | - Sophie Ligot
- Université Catholique de Louvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, B-1200, Brussels, Belgium
| | - Manlio Fusciello
- University of Helsinki, Biocenter 2, Viikinkari 5E, Helsinki, Finland
| | - Gaëlle Vandermeulen
- Université Catholique de Louvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, B-1200, Brussels, Belgium
| | - Véronique Préat
- Université Catholique de Louvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, B-1200, Brussels, Belgium.
| | - Vincenzo Cerullo
- University of Helsinki, Biocenter 2, Viikinkari 5E, Helsinki, Finland.
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23
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Du Y, Wei Y. Therapeutic Potential of Natural Killer Cells in Gastric Cancer. Front Immunol 2019; 9:3095. [PMID: 30719024 PMCID: PMC6348255 DOI: 10.3389/fimmu.2018.03095] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2018] [Accepted: 12/13/2018] [Indexed: 12/19/2022] Open
Abstract
Gastric cancer (GC) is one of the most common cancers, with a high incidence of cancer death. Despite various therapeutic approaches, the cures and prognosis of advanced GC remain poor. Natural killer (NK) cells, which are known as important lymphocytes in innate immunity, play vital roles in suppressing GC initiation, progression, and metastases. A wide range of clinical settings shows that increasing the number of NK cells or improving NK cell antitumor activity is promising in GC patients. NK cell adoptive therapy (especially expanded NK cells) is a safe and well-tolerated method, which can enhance NK cell cytotoxicity against GC. Meanwhile, cytokines, immunomodulatory drugs, immune checkpoint blockades, antibodies, vaccines, and gene therapy have been found to directly or indirectly activate NK cells to improve their killing activity toward GC. In this review, we summarize recent advancements in the relationship between NK cells and GC and point out all the innovative strategies that can enhance NK cells' function to inhibit the growth of GC.
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Affiliation(s)
- Yu Du
- Department of Radiation and Medical Oncology, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Yongchang Wei
- Department of Radiation and Medical Oncology, Zhongnan Hospital, Wuhan University, Wuhan, China
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24
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Luna JI, Grossenbacher SK, Sturgill IR, Ames E, Judge SJ, Bouzid LA, Darrow MA, Murphy WJ, Canter RJ. Bortezomib Augments Natural Killer Cell Targeting of Stem-Like Tumor Cells. Cancers (Basel) 2019; 11:cancers11010085. [PMID: 30646520 PMCID: PMC6356940 DOI: 10.3390/cancers11010085] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 01/04/2019] [Accepted: 01/09/2019] [Indexed: 12/13/2022] Open
Abstract
Tumor cells harboring stem-like/cancer stem cell (CSC) properties have been identified and isolated from numerous hematological and solid malignancies. These stem-like tumor cells can persist following conventional cytoreductive therapies, such as chemotherapy and radiotherapy, thereby repopulating the tumor and seeding relapse and/or metastasis. We have previously shown that natural killer (NK) cells preferentially target stem-like tumor cells via non- major histocompatibility complex (MHC) restricted mechanisms. Here, we demonstrated that the proteasome inhibitor, bortezomib, augments NK cell targeting of stem cell-like tumor cells against multiple solid human tumor-derived cancer lines and primary tissue samples. Mechanistically, this was mediated by the upregulation of cell surface NK ligands MHC class I chain-related protein A and B (MICA and MICB) on aldehyde dehydrogenases (ALDH)-positive CSCs. The increased expression of MICA and MICB on CSC targets thereby enhanced NK cell mediated killing in vitro and ex vivo from both human primary tumor and patient-derived xenograft samples. In vivo, the combination of bortezomib and allogeneic NK cell adoptive transfer in immunodeficient mice led to increased elimination of CSCs as well as tumor growth delay of orthotopic glioblastoma tumors. Taken together, our data support the combination bortezomib and NK transfer as a strategy for both CSC targeting and potentially improved outcomes in clinical cancer patients.
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Affiliation(s)
- Jesus I Luna
- Department of Dermatology, University of California Davis Medical Center, Sacramento, CA 95817, USA.
| | - Steven K Grossenbacher
- Department of Dermatology, University of California Davis Medical Center, Sacramento, CA 95817, USA.
| | - Ian R Sturgill
- Department of Dermatology, University of California Davis Medical Center, Sacramento, CA 95817, USA.
| | - Erik Ames
- Department of Dermatology, University of California Davis Medical Center, Sacramento, CA 95817, USA.
| | - Sean J Judge
- Department of Surgery, Division of Surgical Oncology, University of California Davis Medical Center, Sacramento, CA 95817, USA.
| | - Lyes A Bouzid
- Department of Biological Sciences, California State University Sacramento, Sacramento, CA 95817, USA.
| | - Morgan A Darrow
- Department of Pathology and Laboratory Medicine, University of California Davis Medical Center, Sacramento, CA 95817, USA.
| | - William J Murphy
- Department of Dermatology, University of California Davis Medical Center, Sacramento, CA 95817, USA.
- Department of Internal Medicine, University of California Davis Medical Center, Sacramento, CA 95817, USA.
| | - Robert J Canter
- Department of Surgery, Division of Surgical Oncology, University of California Davis Medical Center, Sacramento, CA 95817, USA.
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Kim JY, Bae BN, Kang G, Kim HJ, Park K. Cytokine expression associated with Helicobacter pylori and Epstein-Barr virus infection in gastric carcinogenesis. APMIS 2017; 125:808-815. [PMID: 28736845 DOI: 10.1111/apm.12725] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Accepted: 04/28/2017] [Indexed: 02/06/2023]
Abstract
Helicobacter pylori and Epstein-Barr virus (EBV) infection, and associated cytokines are involved in gastric carcinogenesis. We investigated the expression of these cytokines and their relationship with clinicopathological characteristics. The study included specimens from 207 patients with gastric adenocarcinoma, 56 with chronic gastritis, 32 with metaplasia, and 30 with low-grade epithelial dysplasia. Tissue microarrays were constructed and immunohistochemical staining for IL-1β, IL-6, IL-10, IL-17, p16, p21, TNF-α, and TNFR1 was performed. EBV and H. pylori infection status was determined. IL-1β, IL-6, IL-17, p16, and p21 protein expression was significantly higher in adenocarcinoma cases than in the other cases (p < 0.05). EBV was only noted in adenocarcinoma (13 cases, 6.3%). The H. pylori infection rate in adenocarcinoma was significantly higher than that in the other cases (p < 0.005). IL-6 expression was associated with improved survival (p < 0.05), whereas IL-17 expression was associated with decreased survival (p < 0.05). IL-6 expression was inversely associated with angioinvasion, and disease stage (p < 0.05), whereas IL-17 expression was associated with disease stage (p < 0.05). IL-10 expression was correlated with IL-1β and TNF-α expression, and p16 expression was correlated with IL-17 and EBV status. Our results indicate that IL-6 and IL-17 are associated with gastric carcinogenesis and may be considered prognostic factors.
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Affiliation(s)
- Jung Yeon Kim
- Department of Pathology, Inje University Sanggye Paik Hospital, Seoul, Korea
| | - Byung-Noe Bae
- Department of Surgery, Inje University Sanggye Paik Hospital, Seoul, Korea
| | - Guhyun Kang
- Department of Pathology, Inje University Sanggye Paik Hospital, Seoul, Korea
| | - Hyun-Jung Kim
- Department of Pathology, Inje University Sanggye Paik Hospital, Seoul, Korea
| | - Kyeongmee Park
- Department of Pathology, Inje University Sanggye Paik Hospital, Seoul, Korea
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Sánchez-Zauco N, Torres J, Gómez A, Camorlinga-Ponce M, Muñoz-Pérez L, Herrera-Goepfert R, Medrano-Guzmán R, Giono-Cerezo S, Maldonado-Bernal C. Circulating blood levels of IL-6, IFN-γ, and IL-10 as potential diagnostic biomarkers in gastric cancer: a controlled study. BMC Cancer 2017; 17:384. [PMID: 28558708 PMCID: PMC5450104 DOI: 10.1186/s12885-017-3310-9] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Accepted: 05/01/2017] [Indexed: 12/11/2022] Open
Abstract
Background Gastric adenocarcinoma is the third most common cause of cancer-associated death worldwide. Helicobacter pylori infection activates a signaling cascade that induces production of cytokines and chemokines involved in the chronic inflammatory response that drives carcinogenesis. We evaluated circulating cytokines and chemokines as potential diagnostic biomarkers for gastric cancer. Methods We included 201 healthy controls and 162 patients with distal gastric cancer who underwent primary surgical resection between 2009 and 2012 in Mexico City. The clinical and pathological data of patients were recorded by questionnaire, and the cancer subtype was classified as intestinal or diffuse. Pathological staging of cancer was based on the tumor–node–metastasis staging system of the International Union Against Cancer. Concentrations of IL-1β, IL-6, TNF-α, IL-10, and MCP-1 in serum were measured using multiplex analyte profiling technology and concentrations of IL-8, IFN-γ, and TGF-β in plasma were measured using enzyme-linked immunosorbent assay. Results Levels of IL-1β, IL-6, IFN-γ, and IL-10 were significantly higher and that of MCP-1 was lower in gastric cancer patients compared with controls. No differences in IL-8 or TNF-α levels were observed between gastric cancer and controls. IFN-γ and IL-10 were significantly higher in both intestinal and diffuse gastric cancer, whereas IL-1β and IL-6 were higher and TGF-β lower only in intestinal gastric cancer; MCP-1 was lower only in diffuse gastric cancer. IFN-γ and IL-10 levels were significantly higher in early (I/II) and late stage (III/IV) gastric cancer; IL-1β and IL-8 were higher and MCP-1 was lower only in late stage (IV) patients. Receiver-operating characteristic analysis showed that for diagnosis of GC, IL-6 had high specificity (0.97) and low sensitivity (0.39), IL-10 had moderate specificity (0.82) and low sensitivity (0.48), and IL-1β and IFN-γ showed low specificity (0.43 and 0.53, respectively) and moderate sensitivity (0.76 and 0.71, respectively). Conclusions Increased levels of IL-6, IFN-γ, and IL-10 might be useful as diagnostic biomarkers for GC; however, this needs to be confirmed with larger number of patients and with control groups other than blood donors, properly age paired. IL-1β, IL-6, MCP-1, and TGF-β differentiate intestinal from diffuse GC. IFN-γ and IL-10 might be useful for diagnosis of early stage GC, and IL-1β, IL-8, and MCP-1 for late stages of the disease. Electronic supplementary material The online version of this article (doi:10.1186/s12885-017-3310-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Norma Sánchez-Zauco
- Laboratorio de Investigación en Inmunología y Proteómica, Hospital Infantil de México Federico Gómez, Dr. Márquez 162, Col. Doctores, 06720, Mexico City, Mexico.,División de Auxiliares de Diagnóstico y Tratamiento UMAE Hospital de Especialidades, Centro Médico Nacional-Siglo XXI, IMSSl, Avenida Cuauhtémoc 330, Col Doctores, 06720, Mexico City, Mexico.,Laboratorio de Bacteriología, Escuela Nacional de Ciencias Biológicas-IPN, Prolongación Manuel Carpio y Plan de Ayala, Santo Tomás, 11350, Mexico City, Mexico
| | - Javier Torres
- Unidad de Investigación en Enfermedades Infecciosas, Hospital de Pediatría, Centro Médico Nacional Siglo XXI, IMSS, Avenida Cuauhtémoc 330, Col Doctores, 06720, Mexico City, Mexico
| | - Alejandro Gómez
- Unidad de Investigación en Enfermedades Infecciosas, Hospital de Pediatría, Centro Médico Nacional Siglo XXI, IMSS, Avenida Cuauhtémoc 330, Col Doctores, 06720, Mexico City, Mexico
| | - Margarita Camorlinga-Ponce
- Unidad de Investigación en Enfermedades Infecciosas, Hospital de Pediatría, Centro Médico Nacional Siglo XXI, IMSS, Avenida Cuauhtémoc 330, Col Doctores, 06720, Mexico City, Mexico
| | - Leopoldo Muñoz-Pérez
- Unidad de Investigación en Enfermedades Infecciosas, Hospital de Pediatría, Centro Médico Nacional Siglo XXI, IMSS, Avenida Cuauhtémoc 330, Col Doctores, 06720, Mexico City, Mexico
| | - Roberto Herrera-Goepfert
- Departamento de Patología, Instituto Nacional de Cancerología, Secretaría de Salud, Av. San Fernando 22, Tlalpan, 1408, Mexico City, Mexico
| | - Rafael Medrano-Guzmán
- Departamento de Sarcomas, Tracto Digestivo Bajo, UMAE Oncología, Centro Médico Nacional Siglo XXI, IMSS, Av. Cuauhtémoc 330, Col Doctores, 06720, Mexico City, Mexico
| | - Silvia Giono-Cerezo
- Laboratorio de Bacteriología, Escuela Nacional de Ciencias Biológicas-IPN, Prolongación Manuel Carpio y Plan de Ayala, Santo Tomás, 11350, Mexico City, Mexico
| | - Carmen Maldonado-Bernal
- Laboratorio de Investigación en Inmunología y Proteómica, Hospital Infantil de México Federico Gómez, Dr. Márquez 162, Col. Doctores, 06720, Mexico City, Mexico.
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Diaz Orea MA, Muñoz Perez V, Gómez Conde E, Castellanos Sánchez VO, Gonzalez Lopez R, Flores Alonso JC, Cárdenas ME, Galicia AL, Mendoza A. Expression of Cytokines Interleukin-2, Interleukin-4, Interleukin-10 and Transforming Growth Factor β in Gastric Adenocarcinoma Biopsies Obtained from Mexican Patients. Asian Pac J Cancer Prev 2017; 18:577-582. [PMID: 28350427 PMCID: PMC5454761 DOI: 10.22034/apjcp.2017.18.2.577] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Objective: In this study, expression of Interleukin-2, Interleukin-4, Interleukin-10 and transforming growth factor beta in diffuse and intestinal type gastric cancers from Mexican patients was assessed for use as markers of malignancy. Methods: A total of 30 biopsies from gastric adenocarcinomas, 60% diffuse, 20% intestinal and 20% mixed in type, were studied by immunohistochemistry. Results: Regarding expression of cytokines, 23% were positive for IL-2, 26.7% for IL-4, 16.6% for IL-10 and none for TGF-β. There were found Significant statistically stage differences were noted.For example, for stages I-II 100% were IL-2 positive (p = 0.009), 87.5% were IL-4 positive (p = 0.005) and 100.0% IL-10 positive (p = 0.009). Young women were more likely to suffer gastric adenocarcinoma. In biopsies of male patients with gastric cancer, there was an increased expression of IL-2 and in biopsies from female patients in IL4. There was significantly greater detection of IL-4 and IL-10 expression in stages I and II than in stages III and IV. It was also found that IL-4, IL-10 had a higher positive expression in patients biopsies with low-level differentiations than patients with well differentiated gastric cancer in which cases were undetected. Conclusions: These results suggest that positive expression of IL-4 and IL-10 may be useful as a molecular marker to distinguish stage I and II diffuse gastric cancers which can be more readily controlled.
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Affiliation(s)
- Maria Alicia Diaz Orea
- Inmunología Experimental, Facultad de Medicina, Benemerita Universidad Autonoma de Puebla, Puebla, Mexico.
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Cui X, Huang Q, Li X, Liu F, Wang D, Yan D, Wang B, Yang C, Mi J, Tian G. Relationship Between Interleukin-10 Gene C-819T Polymorphism and Gastric Cancer Risk: Insights From a Meta-Analysis. MEDICAL SCIENCE MONITOR : INTERNATIONAL MEDICAL JOURNAL OF EXPERIMENTAL AND CLINICAL RESEARCH 2016; 22:2839-45. [PMID: 27516059 PMCID: PMC4993219 DOI: 10.12659/msm.895333] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
BACKGROUND As a pleiotropic cytokine, interleukin-10 (IL-10) plays a regulatory role in carcinogenesis and tumor growth. The aim of this meta-analysis was to assess the susceptibility of the IL-10 gene C-819T polymorphism to gastric cancer. MATERIAL AND METHODS Study identification and data extraction were independently completed by 2 authors. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated and summarized. RESULTS In total, 11 articles including 1960 gastric cancer patients and 3705 controls were qualified. Overall analyses revealed a 13% reduced risk of gastric cancer conferred by the -819T allele relative to the -819C allele (OR=0.87; 95% CI: 0.77-0.97; P=0.016), without heterogeneity (I2=35.1%). In subgroup analyses, a significant difference was identified in East Asian populations (OR=0.85; 95% CI: 0.73-0.98; P=0.029, I2=43.6%), for gastric adenocarcinoma (OR=0.80; 95% CI: 0.66-0.96; P=0.017, I2=0.0%), and in population-based studies (OR=0.81; 95% CI: 0.70-0.93; P=0.003, I2=0.0%). The visual funnel plots and Egger's tests suggested no evidence of publication bias. CONCLUSIONS Extending previous findings, we demonstrate a protective role of the IL-10 gene -819T allele in susceptibility to gastric cancer, and this role was more evident for gastric adenocarcinoma.
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Affiliation(s)
- Xigang Cui
- Department of Gastric and Intestine, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong, China (mainland)
| | - Qingxian Huang
- Department of Gastric and Intestine, Yantai Yuhuangding Hospital, Yantai, Shandong, China (mainland)
| | | | - Fang Liu
- Medicine and Pharmacy Research Center, Binzhou Medical University, Yantai, Shandong, China (mainland)
| | - Dan Wang
- Medicine and Pharmacy Research Center, Binzhou Medical University, Yantai, Shandong, China (mainland)
| | - Dong Yan
- Medicine and Pharmacy Research Center, Binzhou Medical University, Yantai, Shandong, China (mainland)
| | - Bin Wang
- Institute of Molecular Imaging, Binzhou Medical University, Yantai, Shandong, China (mainland)
| | - Chunhua Yang
- Medicine and Pharmacy Research Center, Binzhou Medical University, Yantai, Shandong, China (mainland)
| | - Jia Mi
- Medicine and Pharmacy Research Center, Binzhou Medical University, Yantai, Shandong, China (mainland)
| | - Geng Tian
- Medicine and Pharmacy Research Center, Binzhou Medical University, Yantai, Shandong, China (mainland)
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Protein Profiling Gastric Cancer and Neighboring Control Tissues Using High-Content Antibody Microarrays. MICROARRAYS 2016; 5:microarrays5030019. [PMID: 27600085 PMCID: PMC5040966 DOI: 10.3390/microarrays5030019] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/18/2016] [Revised: 05/25/2016] [Accepted: 06/13/2016] [Indexed: 12/26/2022]
Abstract
In this study, protein profiling was performed on gastric cancer tissue samples in order to identify proteins that could be utilized for an effective diagnosis of this highly heterogeneous disease and as targets for therapeutic approaches. To this end, 16 pairs of postoperative gastric adenocarcinomas and adjacent non-cancerous control tissues were analyzed on microarrays that contain 813 antibodies targeting 724 proteins. Only 17 proteins were found to be differentially regulated, with much fewer molecules than the numbers usually identified in studies comparing tumor to healthy control tissues. Insulin-like growth factor-binding protein 7 (IGFBP7), S100 calcium binding protein A9 (S100A9), interleukin-10 (IL‐10) and mucin 6 (MUC6) exhibited the most profound variations. For an evaluation of the proteins’ capacity for discriminating gastric cancer, a Receiver Operating Characteristic curve analysis was performed, yielding an accuracy (area under the curve) value of 89.2% for distinguishing tumor from non-tumorous tissue. For confirmation, immunohistological analyses were done on tissue slices prepared from another cohort of patients with gastric cancer. The utility of the 17 marker proteins, and particularly the four molecules with the highest specificity for gastric adenocarcinoma, is discussed for them to act as candidates for diagnosis, even in serum, and targets for therapeutic approaches.
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Bücklein V, Adunka T, Mendler AN, Issels R, Subklewe M, Schmollinger JC, Noessner E. Progressive natural killer cell dysfunction associated with alterations in subset proportions and receptor expression in soft-tissue sarcoma patients. Oncoimmunology 2016; 5:e1178421. [PMID: 27622032 PMCID: PMC5006893 DOI: 10.1080/2162402x.2016.1178421] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Revised: 04/05/2016] [Accepted: 04/10/2016] [Indexed: 12/30/2022] Open
Abstract
Immunotherapy is currently investigated as treatment option in many types of cancer. So far, results from clinical trials have demonstrated that significant benefit from immunomodulatory therapies is restricted to patients with select histologies. To broaden the potential use of these therapies, a deeper understanding for mechanisms of immunosuppression in patients with cancer is needed. Soft-tissue sarcoma (STS) presents a medical challenge with significant mortality even after multimodal treatment. We investigated function and immunophenotype of peripheral natural killer (NK) cells from chemotherapy-naive STS patients (1st line) and STS patients with progression or relapse after previous chemotherapeutic treatment (2nd line). We found NK cells from peripheral blood of both STS patient cohorts to be dysfunctional, being unable to lyse K562 target cells while NK cells from renal cell cancer (RCC) patients did not display attenuated lytic activity. Ex vivo stimulation of NK cells from STS patients with interleukin-2 plus TKD restored cytotoxic function. Furthermore, altered NK cell subset composition with reduced proportions of CD56(dim) cells could be demonstrated, increasing from 1st- to 2nd-line patients. 2nd-line patients additionally displayed significantly reduced expression of receptors (NKG2D), mediators (CD3ζ), and effectors (perforin) of NK cell activation. In these patients, we also detected fewer NK cells with CD57 expression, a marker for terminally differentiated cytotoxic NK cells. Our results elucidate mechanisms of NK cell dysfunction in STS patients with advanced disease. Markers like NKG2D, CD3ζ, and perforin are candidates to characterize NK cells with effective antitumor function for immunotherapeutic interventions.
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Affiliation(s)
- Veit Bücklein
- Clinical Cooperation Group Immunotherapy, HelmholtzZentrum München, Munich, Germany; Department of Internal Medicine III, Klinikum der Universität München, Munich, Germany
| | - Tina Adunka
- Division of Clinical Pharmacology, Department of Internal Medicine IV, Klinikum der Universität München , Munich, Germany
| | - Anna N Mendler
- Institute of Molecular Immunology, HelmholtzZentrum München , Munich, Germany
| | - Rolf Issels
- Department of Internal Medicine III, Klinikum der Universität München , Munich, Germany
| | - Marion Subklewe
- Clinical Cooperation Group Immunotherapy, HelmholtzZentrum München, Munich, Germany; Department of Internal Medicine III, Klinikum der Universität München, Munich, Germany
| | - Jan C Schmollinger
- Institute of Molecular Immunology, HelmholtzZentrum München , Munich, Germany
| | - Elfriede Noessner
- Institute of Molecular Immunology, HelmholtzZentrum München , Munich, Germany
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Abstract
OPINION STATEMENT A comprehensive analysis of the interactions that can occur amongst three complex systems-the tumor cell, tissue microenvironment, and the immune response, is required if we are to realize the potential of immunotherapeutics in gastroesophageal cancer. For many years, epithelial cancers were believed to originate due to the transformation of tissue stem cells. Recently however, it has suggested that bone marrow-derived cells (BMDCs), which are frequently recruited to sites of tissue injury and inflammation, might also represent a potential source of malignancy. The link between infection, chronic inflammation, and cancer has long been recognized in gastric cancer with its close association with Helicobacter pylori as a class I carcinogen. The long-term consequences of recruiting pluripotent cells to areas of chronic inflammation which can result in altered cell signaling and differentiation needs to be defined, but this work provides a fascinating insight into the pivotal role played by the immune system in the development of upper GI tumors. Here, we discuss many of the immunotherapeutic strategies that have been assessed in gastroesophageal cancer in the last two decades. At the time of writing, the use of checkpoint inhibitors represents the most exciting approach and displays the greatest potential for widespread adoption in the clinic. Preliminary data suggest that programmed death ligand-1 (PD-L1) expression ranges from approximately 18 to 42% in gastroesophageal cancer. Phase II and phase III clinical trials involving either single agent PD-1/PD-L1 inhibition or combined with CTLA-4 inhibitors are currently enrolling, and it is expected that checkpoint inhibition will become a new standard of care in the management of advanced disease in the near future.
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Li N, Xie C, Lu NH. Transforming growth factor-β: an important mediator in Helicobacter pylori-associated pathogenesis. Front Cell Infect Microbiol 2015; 5:77. [PMID: 26583078 PMCID: PMC4632021 DOI: 10.3389/fcimb.2015.00077] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Accepted: 10/20/2015] [Indexed: 12/14/2022] Open
Abstract
Helicobacter pylori (H.pylori) is a Gram-negative, microaerophilic, helical bacillus that specifically colonizes the gastric mucosa. The interaction of virulence factors, host genetic factors, and environmental factors contributes to the pathogenesis of H. pylori-associated conditions, such as atrophic gastritis and intestinal metaplasia. Infection with H. pylori has recently been recognized as the strongest risk factor for gastric cancer. As a pleiotropic cytokine, transforming growth factor (TGF)-β regulates various biological processes, including cell cycle, proliferation, apoptosis, and metastasis. Recent studies have shed new light on the involvement of TGF-β signaling in the pathogenesis of H. pylori infection. This review focuses on the potential etiological roles of TGF-β in H. pylori-mediated gastric pathogenesis.
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Affiliation(s)
- Nianshuang Li
- Department of Gastroenterology, Institute of Digestive Disease, The First Affiliated Hospital of Nanchang University Nanchang, China
| | - Chuan Xie
- Department of Gastroenterology, Institute of Digestive Disease, The First Affiliated Hospital of Nanchang University Nanchang, China
| | - Nong-Hua Lu
- Department of Gastroenterology, Institute of Digestive Disease, The First Affiliated Hospital of Nanchang University Nanchang, China
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Zhang J, Yao H, Song G, Liao X, Xian Y, Li W. Regulation of epithelial-mesenchymal transition by tumor-associated macrophages in cancer. Am J Transl Res 2015; 7:1699-1711. [PMID: 26692918 PMCID: PMC4656751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Accepted: 10/11/2015] [Indexed: 06/05/2023]
Abstract
It should be urgently better understood of the mechanism that contributes cancer aggressiveness. Epithelial-mesenchymal transition (EMT) plays a fundamental role in tumor progression and metastasis formation by invasion, resistance to cell death and senescence, resistance to chemotherapy and immunotherapy, immune surveillance, immunosuppression and inflammation, confers stem cell properties. Tumor-associated macrophages (TAMs) are key orchestrators and a set of macrophages in tumor microenvironment. They are major players in the connection between inflammation and cancer. TAMs could promote proliferation, invasion and metastasis of tumor cells, stimulate tumor angiogenesis, and inhibit anti-tumor immune response mediated by T cell followed by promoting tumor progression. Recently, studies showed that TAMs played critical role in the regulation of EMT in cancer, although the underlying mechanism of TAMs-mediated acquisition of EMT has been largely unclear. This review will discuss recent advances in our understanding of the role of TAMs in the regulation of EMT during tumorigenesis and summarize the recent ongoing experimental and pre-clinical TAMs targeted studies.
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Affiliation(s)
- Jia Zhang
- Second Department of Thoracic Surgery, The First Affiliated Hospital of Xi’an Jiaotong University277# West Yanta Road, Xi’an, Shaanxi 710061, China
| | - Hongmei Yao
- Department of Nutrition, The First Affiliated Hospital of Xi’an Jiaotong University277# West Yanta Road, Xi’an, Shaanxi 710061, China
| | - Ge Song
- Department of Nutrition, The First Affiliated Hospital of Xi’an Jiaotong University277# West Yanta Road, Xi’an, Shaanxi 710061, China
| | - Xia Liao
- Department of Nutrition, The First Affiliated Hospital of Xi’an Jiaotong University277# West Yanta Road, Xi’an, Shaanxi 710061, China
| | - Yao Xian
- Department of Nutrition, The First Affiliated Hospital of Xi’an Jiaotong University277# West Yanta Road, Xi’an, Shaanxi 710061, China
| | - Weimin Li
- Department of Nutrition, The First Affiliated Hospital of Xi’an Jiaotong University277# West Yanta Road, Xi’an, Shaanxi 710061, China
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Liu K, Yang K, Wu B, Chen H, Chen X, Chen X, Jiang L, Ye F, He D, Lu Z, Xue L, Zhang W, Li Q, Zhou Z, Mo X, Hu J. Tumor-Infiltrating Immune Cells Are Associated With Prognosis of Gastric Cancer. Medicine (Baltimore) 2015; 94:e1631. [PMID: 26426650 PMCID: PMC4616881 DOI: 10.1097/md.0000000000001631] [Citation(s) in RCA: 92] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2015] [Revised: 08/20/2015] [Accepted: 08/26/2015] [Indexed: 02/07/2023] Open
Abstract
Immune cells contribute to determining the prognosis of gastric cancer. However, their exact role is less clear. We determined the prognostic significance of different immune cells in intratumoral tissue (T), stromal tissue (S), and adjacent normal tissue (N) of 166 gastric cancer cases and their interactions, including CD3+, CD4+, CD8, CD57+, CD68+, CD66b+, and Foxp3+ cells, and established an effective prognostic nomogram based on the immune reactions. We found high densities of TCD3+, TCD4+, TCD8+, SCD3+, SCD4+, SCD57+, SCD66b+, and NFoxp3+ cells, as well as high TCD8+/SCD8+ ratio, TCD68+/SCD68+ ratio, TCD3+/TFoxp3+ ratio, TCD4+/TFoxp3+ ratio, TCD8+/TFoxp3+ ratio, SCD3+/SFoxp3+ ratio, and SCD4+/SCD8+ ratio were associated with better survival, whereas high densities of TCD66b+, TFoxp3+, SFoxp3+ and NCD66b+ cells as well as high TCD57+/SCD57+ ratio, TCD66b+/SCD66b+ ratio, SCD8+/SFoxp3+ ratio, and TFoxp3+/NFoxp3+ ratio were associated with significantly worse outcome. Multivariate analysis indicated that tumor size, longitudinal tumor location, N stage, TCD68+/SCD68+ ratio, TCD8+/TFoxp3+ ratio, density of TFoxp3+ cells, and TCD66b+/SCD66b+ ratio were independent prognostic factors, which were all selected into the nomogram. The calibration curve for likelihood of survival demonstrated favorable consistency between predictive value of the nomogram and actual observation. The C-index (0.83, 95% CI: 0.78 to 0.87) of our nomogram for predicting prognosis was significantly higher than that of TNM staging system (0.70). Collectively, high TCD68+/SCD68+ ratio and TCD8+/TFoxp3+ ratio were associated with improved overall survival, whereas high density of TFoxp3+ cells and TCD66b+/SCD66b+ ratio demonstrated poor overall survival, which are promising independent predictors for overall survival in gastric cancer.
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Affiliation(s)
- Kai Liu
- From the Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, China (KL,KY, BW,HC, XC, XC, LX, WZ, ZZ, JH); Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, China (KL,KY, BW,HC, XC, XC, LX, WZ, JH); Department of Pathology, West China Hospital, Sichuan University, China (LJ, DH); Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (FY); Department of Oncology, West China Hospital, Sichuan University, China (QL); and Laboratory of Stem Cell Biology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, China (XM)
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Exercise as a Polypill for Chronic Diseases. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2015; 135:497-526. [PMID: 26477928 DOI: 10.1016/bs.pmbts.2015.07.019] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Exercise may be described as a polypill to prevent and/or treat almost every chronic disease, with obvious benefits such as its low cost and practical lack of adverse effects. Implementing physical activity interventions in public health is therefore a goal at the medical, social, and economic levels. This chapter describes the importance of health promotion through physical activity and discusses the impacts of exercise on the most prevalent chronic diseases, namely metabolic syndrome-related disorders, cardiovascular diseases, cancer, and Alzheimer's disease. For each of these chronic conditions, we discuss the epidemiological evidence supporting a beneficial role of exercise, provide guidelines for exercise prescription, and describe the biological mechanisms whereby exercise exerts its modulatory effects.
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36
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Pellicciotta I, Marciscano AE, Hardee ME, Francis D, Formenti S, Barcellos-Hoff MH. Development of a novel multiplexed assay for quantification of transforming growth factor-β (TGF-β). Growth Factors 2015; 33:79-91. [PMID: 25586866 DOI: 10.3109/08977194.2014.999367] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Changes in activity or levels of transforming growth factor-β (TGF-β) are associated with a variety of diseases; however, measurement of TGF-β in biological fluids is highly variable. TGF-β is biologically inert when associated with its latency-associated peptide (LAP). Most available immunoassays require exogenous activation by acid/heat to release TGF-β from the latent complex. We developed a novel electrochemiluminescence-based multiplexed assay on the MesoScale Discovery® platform that eliminates artificial activation, simultaneously measures both active TGF-β1 and LAP1 and includes an internal control for platelet-derived TGF-β contamination in blood specimens. We optimized this assay to evaluate plasma levels as a function of activation type and clinical specimen preparation. We determined that breast cancer patients' plasma have higher levels of circulating latent TGF-β (LTGF-β) as measured by LAP1 than healthy volunteers (p < 0.0001). This assay provides a robust tool for correlative studies of LTGF-β levels with disease, treatment outcomes and toxicity with a broad clinical applicability.
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MATYSZEWSKI ARTUR, CZARNECKA ANNAM, SOLAREK WOJCIECH, KORZEŃ PIOTR, SAFIR ILANJ, KUKWA WOJCIECH, SZCZYLIK CEZARY. Molecular basis of carcinogenesis in diabetic patients (Review). Int J Oncol 2015; 46:1435-43. [DOI: 10.3892/ijo.2015.2865] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Accepted: 12/10/2014] [Indexed: 11/05/2022] Open
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Rudnicka K, Miszczyk E, Matusiak A, Walencka M, Moran AP, Rudnicka W, Chmiela M. Helicobacter pylori-driven modulation of NK cell expansion, intracellular cytokine expression and cytotoxic activity. Innate Immun 2014; 21:127-39. [PMID: 24448078 DOI: 10.1177/1753425913518225] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
During Helicobacter pylori (Hp) infections, innate immune cells may be positively or negatively modulated by Hp compounds or by Hp-induced cytokines. We have shown previously that the natural cytotoxic activity of PBMC was lower in Hp-infected [Hp(+)] than Hp-uninfected individuals [Hp(-)]. Here, we asked whether the Hp-modulated cytotoxic amplitude is associated with changes in the number of NK cells, their activation or intracellular cytokine expression. Flow cytometry immunophenotyping of PBMC was performed with regard to the surface receptors CD3, CD56 and CD25, and intracellular cytokine expression of IL-2, IFN-γ and IL-10 after in vitro stimulation with Hp glycine acid extract (GE), Hp LPS or standard Escherichia coli LPS. Hp GE-driven enhancement of lymphocyte cytotoxic activity was associated with the expansion of CD3(-)CD56(+)CD25(+) NK cells and the up-regulation of IFN-γ and/or IL-2 synthesis, up to the higher level in Hp(-) than in Hp(+), while Hp LPS-mediated decrease in lymphocyte cytotoxicity was accompanied by the lack of CD3(-)CD56(+)CD25(+) NK propagation, the inhibition of pro-inflammatory cytokine expression and intense expansion of IL-10-producing NK cells. Thus, the cytotoxic and cytokine activities of NK cells were dependent on the type of antigenic challenge and the Hp status, that is, NK cells could be modulated positively by Hp GE Ags and negatively by Hp LPS.
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Affiliation(s)
- Karolina Rudnicka
- Department of Immunology and Infectious Biology, Faculty of Biology and Environmental Protection, University of Łódź, Łódź, Poland
| | - Eliza Miszczyk
- Department of Immunology and Infectious Biology, Faculty of Biology and Environmental Protection, University of Łódź, Łódź, Poland
| | - Agnieszka Matusiak
- Department of Immunology and Infectious Biology, Faculty of Biology and Environmental Protection, University of Łódź, Łódź, Poland
| | - Maria Walencka
- Department of Immunology and Infectious Biology, Faculty of Biology and Environmental Protection, University of Łódź, Łódź, Poland
| | - Anthony P Moran
- Department of Microbiology, National University of Ireland, University Road, Galway, Ireland
| | - Wiesława Rudnicka
- Department of Immunology and Infectious Biology, Faculty of Biology and Environmental Protection, University of Łódź, Łódź, Poland
| | - Magdalena Chmiela
- Department of Immunology and Infectious Biology, Faculty of Biology and Environmental Protection, University of Łódź, Łódź, Poland
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Lin R, Ma H, Ding Z, Shi W, Qian W, Song J, Hou X. Bone marrow-derived mesenchymal stem cells favor the immunosuppressive T cells skewing in a Helicobacter pylori model of gastric cancer. Stem Cells Dev 2013; 22:2836-2848. [PMID: 23777268 DOI: 10.1089/scd.2013.0166] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Bone marrow-derived mesenchymal stem cells (BM-MSCs) play an important role in Helicobacter pylori-induced gastric carcinogenesis. While the mechanism is not well understood, BM-MSCs have been shown to contribute to the immunosuppressive response found in a number of diseases. Here, BM-MSCs were transplanted into the stomach of mice with a 44-week mouse-adapted H. pylori infection. At day 28 post-transplantation, BM-MSCs migrated from the subserosal to the mucosal layer of the stomach. The grafted BM-MSCs significantly stimulated systemic and local interleukin-10 (IL-10)-secreting T cell and regulatory T cell (Treg) functions. This observation was correlated with an increased percentage of CD4⁺IL-10⁺ cells and CD4⁺CD25⁺FoxP3⁺ cells in splenic mononuclear cells compared with H. pylori-infected mice not receiving BM-MSCs. Moreover, inhibitory cytokines IL-10 and transforming growth factor-β1 increased in the gastric tissue, while there was a decrease in inflammatory interferon-γ (IFN-γ). BM-MSC-transplanted mice also developed elevated IL-10/IFN-γ secreting and Treg/Th17 ratios. A coculture system in the presence or absence of BM-MSCs was also established to evaluate the immune responses in vitro. An increase in IL-10-secreting T cells and Tregs, associated with increased expression of Gata-3 and FoxP3, generation of IL-10 in the supernatant, and proliferation of gastric epithelial cells (GECs) was observed. These findings demonstrate that transplantation of BM-MSCs into a chronic H. pylori-infected mouse model results in the generation of an immunosuppressive environment. The local and systemic immunosuppression mediated by BM-MSCs likely contributed to an environment that is compatible with the development of H. pylori-induced gastric cancer.
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Affiliation(s)
- Rong Lin
- Division of Gastroenterology, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China
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Wang Z, Si X, Xu A, Meng X, Gao S, Qi Y, Zhu L, Li T, Li W, Dong L. Activation of STAT3 in human gastric cancer cells via interleukin (IL)-6-type cytokine signaling correlates with clinical implications. PLoS One 2013; 8:e75788. [PMID: 24116074 PMCID: PMC3792128 DOI: 10.1371/journal.pone.0075788] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2012] [Accepted: 08/21/2013] [Indexed: 12/22/2022] Open
Abstract
Background The signal transducers and activators of transcription 3 (STAT3) signaling pathway plays important roles in oncogenesis, angiogenesis, immunity, and tumor cell invasion. In the present study, we investigated the association of interleukin (IL)-6/STAT3 signaling pathway with T lymphocytes and clinical implication in patients with gastric cancer. Methods Seventy one patients who underwent gastrectomy due to gastric adenocarcinoma were studied. Blood samples were collected before and after surgical gastrectomy to quantify the levels of IL-6, IL-10 and VEGF using an enzyme-linked immunosorbent assay, as well as T lymphocyte subsets (CD3+, CD4+, CD8+, CD4+/CD8+) and natural killer (NK) cells by a flow cytometry. Furthermore, the expression of IL-6, survivin, STAT3, STAT3 phosphorylation (p-STAT3), and VEGF were determined in human gastric cancer and adjacent normal mucosa through Western blot and immunohistochemistry. Results Postoperative levels of IL-6, IL-10 and VEGF in serum were significantly lower than preoperative levels. Percentages of T-cell subsets and NK cells in blood were significantly increased after postoperative-week 1 as compared to preoperative group, which was further augmented at 1 month after gastrectomy. In addition, the expression of IL-6, survivin, STAT3, p-STAT3, and VEGF were increased in human gastric cancer tissues as compared to adjacent normal mucosa. Their expression was associated with TNM stage of gastric cancer. The level of STAT3 activation in clinical samples was correlated with IL-6 expression. All gastric tumor samples, which expressed p-STAT3, also expressed IL-6 with weak expression detected in adjacent normal mucosa. Conclusion Increased IL-6-induced activation of STAT3 was observed in neoplastic gastric tissue, which positively correlated with tumor progression. Moreover, IL-6 and STAT3 downstream signals such as IL-10 and VEGF were reduced in patients after removal of gastric cancer as compared to pre-operation. Therefore, inhibition of the IL-6/STAT3 signaling pathway may provide a new therapeutic strategy against gastric cancer.
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Affiliation(s)
- Zhengguang Wang
- Key Laboratory of Antiinflammatory and Immunopharmacology, Department of Pharmacology, Ministry of Education, Key Laboratory of Chinese Medicine Research and Development, State Administration of Traditional Chinese Medicine, Anhui Medical University, Hefei, Anhui, China
- Department of Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Xiulian Si
- Key Laboratory of Antiinflammatory and Immunopharmacology, Department of Pharmacology, Ministry of Education, Key Laboratory of Chinese Medicine Research and Development, State Administration of Traditional Chinese Medicine, Anhui Medical University, Hefei, Anhui, China
| | - Aman Xu
- Department of Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Xiangning Meng
- Department of Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Shile Gao
- Key Laboratory of Antiinflammatory and Immunopharmacology, Department of Pharmacology, Ministry of Education, Key Laboratory of Chinese Medicine Research and Development, State Administration of Traditional Chinese Medicine, Anhui Medical University, Hefei, Anhui, China
| | - Yijun Qi
- Department of Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Liang Zhu
- Department of Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Tuanjie Li
- Department of Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Weiping Li
- Key Laboratory of Antiinflammatory and Immunopharmacology, Department of Pharmacology, Ministry of Education, Key Laboratory of Chinese Medicine Research and Development, State Administration of Traditional Chinese Medicine, Anhui Medical University, Hefei, Anhui, China
- * E-mail: (LD); (WL)
| | - Liuyi Dong
- Key Laboratory of Antiinflammatory and Immunopharmacology, Department of Pharmacology, Ministry of Education, Key Laboratory of Chinese Medicine Research and Development, State Administration of Traditional Chinese Medicine, Anhui Medical University, Hefei, Anhui, China
- * E-mail: (LD); (WL)
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Rudnicka K, Matusiak A, Miszczyk E, Rudnicka W, Tenderenda M, Chmiela M. Immunophenotype of peripheral blood natural killer cells and IL-10 serum levels in relation to Helicobacter pylori status. APMIS 2013; 121:806-13. [PMID: 23758061 DOI: 10.1111/apm.12120] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2013] [Accepted: 04/08/2013] [Indexed: 12/25/2022]
Abstract
Recent findings suggest that NK (Natural Killer) cells may directly modulate the antimicrobial immune responses. In this study, we performed immunophenotypic analysis of peripheral blood NK cells with regard to CD56, CD16, Nkp46, and CD25 markers, as well as IL-10 levels quantification in the sera samples of asymptomatic, H. pylori (Hp)-infected or uninfected individuals, and combined these results with our previous findings on lymphocyte cytotoxic activity. Twenty healthy volunteers [10 Hp(-);10 Hp(+)] were included in the study. The percentages of classic lymphocytes (CD3(+) ) and NK cells (CD3(-) CD56(+) , CD3(-) Nkp46(+) , CD3(-) CD16(+) ) with or without CD25 receptor were evaluated by fluorochrome-conjugated monoclonal antibody staining and flow cytometry analysis. IL-10 quantification was performed by enzyme-linked immunosorbent assay-ELISA. Our study showed elevated levels of IL-10 and higher NK cell numbers of both CD3(-) CD56(+) CD25(+) and CD3(-) Nkp46(+) CD25(+) phenotypes, as well as CD3(+) CD25(+) classic lymphocytes in Hp(+) compared with Hp(-) individuals. No differences between Hp(-) and Hp(+) individuals were found either in total number of classic lymphocytes or NK cell subtypes. Our data suggest that in Hp(+) donors, there is a domination of lymphocytes and NK cells co-expressing CD25 marker, which might be influenced by the regulatory IL-10. This phenomenon may be a result of H. pylori adaptation to a changing environment in vivo leading to a chronic infection and lack of severe gastric pathologies.
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Affiliation(s)
- Karolina Rudnicka
- Laboratory of Gastroimmunology, Department of Immunology and Infectious Biology, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland
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Zhang H, Liu L, Wang Y, Zhao G, Xie R, Liu C, Xiao X, Wu K, Nie Y, Zhang H, Fan D. KLF8 involves in TGF-beta-induced EMT and promotes invasion and migration in gastric cancer cells. J Cancer Res Clin Oncol 2013; 139:1033-42. [PMID: 23504025 DOI: 10.1007/s00432-012-1363-3] [Citation(s) in RCA: 77] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2012] [Accepted: 12/10/2012] [Indexed: 12/30/2022]
Abstract
PURPOSE Krüppel-like factor 8 (KLF8), a downstream transcription factor of transforming growth factor-β1 (TGF-β1), has a role in tumorigenesis, tumor progress and epithelial-to-mesenchymal transition (EMT) induction. Recent studies mainly focused on its role in breast cancer and hepatocellular carcinoma; however, little is studied in gastric cancer. Here, we aim to explore whether KLF8 is involved in TGF-β1-induced EMT in gastric cancer cells. METHODS Western blot and real-time PCR assays were used to detect the expression of KLF8, E-cadherin and vimentin in gastric cancer cell line SGC7901 treated with or without TGF-β1. The lentivirus-mediated RNA interference technique was used to knock down the expression of KLF8 in gastric cancer cell line SGC7901. In vitro, the ability of cell migration and invasion were measured by transwell and wound healing assays; the cell motility was detected by high content screening assay. RESULTS TGF-β1 could induce EMT via down-regulating E-cadherin and up-regulating vimentin expression in gastric cancer cells. Further study found that TGF-β1 could induce KLF8 expression at the protein and mRNA levels in gastric cancer cells (P < 0.05). Western blot and real-time PCR assays found that small interference RNA (siRNA)-mediated KLF8 silence blocked TGF-β1-induced EMT-like transformation and subsequently reversed the loss of E-cadherin and gain of vimentin. In vitro, inhibition of KLF8 decreased TGF-β1-prompted cell migration, invasion and motility. CONCLUSIONS KLF8, a transcription factor, is involved in TGF-β1-induced EMT in gastric cancer cells and may be a novel therapeutic target for the treatment of gastric cancer.
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Affiliation(s)
- Hui Zhang
- State Key Laboratory of Cancer Biology, Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, 15 West Changle Road, Xi'an, 710032, China
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Eljaszewicz A, Wiese M, Helmin-Basa A, Jankowski M, Gackowska L, Kubiszewska I, Kaszewski W, Michalkiewicz J, Zegarski W. Collaborating with the enemy: function of macrophages in the development of neoplastic disease. Mediators Inflamm 2013; 2013:831387. [PMID: 23576856 PMCID: PMC3613099 DOI: 10.1155/2013/831387] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2012] [Revised: 12/26/2012] [Accepted: 01/13/2013] [Indexed: 01/15/2023] Open
Abstract
Due to the profile of released mediators (such as cytokines, chemokines, growth factors, etc.), neoplastic cells modulate the activity of immune system, directly affecting its components both locally and peripherally. This is reflected by the limited antineoplastic activity of the immune system (immunosuppressive effect), induction of tolerance to neoplastic antigens, and the promotion of processes associated with the proliferation of neoplastic tissue. Most of these responses are macrophages dependent, since these cells show proangiogenic properties, attenuate the adaptive response (anergization of naïve T lymphocytes, induction of Treg cell formation, polarization of immune response towards Th2, etc.), and support invasion and metastases formation. Tumor-associated macrophages (TAMs), a predominant component of leukocytic infiltrate, "cooperate" with the neoplastic tissue, leading to the intensified proliferation and the immune escape of the latter. This paper characterizes the function of macrophages in the development of neoplastic disease.
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Affiliation(s)
- Andrzej Eljaszewicz
- Chair of Immunology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University of Torun, Bydgoszcz, Poland.
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Man YG, Stojadinovic A, Mason J, Avital I, Bilchik A, Bruecher B, Protic M, Nissan A, Izadjoo M, Zhang X, Jewett A. Tumor-infiltrating immune cells promoting tumor invasion and metastasis: existing theories. J Cancer 2013; 4:84-95. [PMID: 23386907 PMCID: PMC3564249 DOI: 10.7150/jca.5482] [Citation(s) in RCA: 144] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2012] [Accepted: 12/20/2012] [Indexed: 12/12/2022] Open
Abstract
It is a commonly held belief that infiltration of immune cells into tumor tissues and direct physical contact between tumor cells and infiltrated immune cells is associated with physical destructions of the tumor cells, reduction of the tumor burden, and improved clinical prognosis. An increasing number of studies, however, have suggested that aberrant infiltration of immune cells into tumor or normal tissues may promote tumor progression, invasion, and metastasis. Neither the primary reason for these contradictory observations, nor the mechanism for the reported diverse impact of tumor-infiltrating immune cells has been elucidated, making it difficult to judge the clinical implications of infiltration of immune cells within tumor tissues. This mini-review presents several existing hypotheses and models that favor the promoting impact of tumor-infiltrating immune cells on tumor invasion and metastasis, and also analyzes their strength and weakness.
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Affiliation(s)
- Yan-gao Man
- 1. Diagnostic and Translational Research Center, Henry Jackson Foundation, Gaithersburg, MD, USA
- 2. College of Animal Science and Veterinary Medicine, Jilin University, Changchun, Jilin, China
| | - Alexander Stojadinovic
- 3. Surgical Oncology, Walter Reed National Military Medical Center, and Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - Jeffrey Mason
- 4. Veterans Affair Medical Center, Washington, DC, USA
| | - Itzhak Avital
- 5. Bon Secours National Cancer Institute (BSNCI), Richmond VA, USA
| | - Anton Bilchik
- 6. John Wayne Cancer Institute; California Oncology Research Institute; and, David Geffen School of Medicine, University of California, Los Angeles, USA
| | | | - Mladjan Protic
- 8. Clinic of Abdominal, Endocrine, and Transplantation Surgery, Clinical Center of Vojvodina, University of Novi Sad - Medical Faculty, Novi Sad, Serbia
| | - Aviram Nissan
- 9. The Surgical Oncology Laboratory, Department of Surgery, Hadassah-Hebrew University Medical Center, Mount Scopus, Jerusalem, Israel
| | - Mina Izadjoo
- 1. Diagnostic and Translational Research Center, Henry Jackson Foundation, Gaithersburg, MD, USA
| | - Xichen Zhang
- 2. College of Animal Science and Veterinary Medicine, Jilin University, Changchun, Jilin, China
| | - Anahid Jewett
- 10. Division of Oral Biology and Medicine, Jonsson Comprehensive Cancer Center, UCLA School of Dentistry, Los Angeles, CA, USA
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Tüzün S, Yücel AF, Pergel A, Kemik AS, Kemik O. Lipid Peroxidation and Transforming Growth Factor-β1 Levels in Gastric Cancer at Pathologic Stages. Balkan Med J 2012; 29:273-6. [PMID: 25207013 DOI: 10.5152/balkanmedj.2012.026] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2012] [Accepted: 03/19/2012] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE High levels of TGF-β1 and enhanced TGF-β1 receptor signaling are related to the pathology of gastric cancer. This effect is caused by oxidative stress and lipid peroxidation products. The aim of this study was to investigate the levels of TGF-β1 and lipid peroxidation products in gastric cancer patients and their correlation with pathologic stage. MATERIAL AND METHODS Lipid peroxidation products and TGF-β1 levels were studied in the serum samples of 50 gastric cancer patients and 18 control subjects. RESULTS HNE-protein adducts and TGF-β1 levels were significantly higher in T2, T3 and T4 gastric cancers than in either the T1 stage or controls (p<0.001). Pathologic stage was correlated with TGF-β1 levels (r=0.702, p<0.05). CONCLUSION These markers production may contribute to tumor angiogenesis and aid in the prognosis of the gastric cancer.
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Affiliation(s)
- Sefa Tüzün
- Clinic of 2 Surgery Clinic, Haseki Training and Research Hospital, İstanbul, Turkey
| | - Ahmet Fikret Yücel
- Department of Surgery, Faculty of Medicine, Recep Tayyip Erdoğan University, Rize, Turkey
| | - Ahmet Pergel
- Department of Surgery, Faculty of Medicine, Recep Tayyip Erdoğan University, Rize, Turkey
| | - Ahu Sarbay Kemik
- Department of Biochemistry, Cerrahpaşa Faculty of Medicine, İstanbul University, İstanbul, Turkey
| | - Ozgür Kemik
- Department of Surgery, Faculty of Medicine, Yüzüncü Yıl University, Van, Turkey
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Rudnicka K, Włodarczyk M, Moran AP, Rechciński T, Miszczyk E, Matusiak A, Szczęsna E, Walencka M, Rudnicka W, Chmiela M. Helicobacter pylori antigens as potential modulators of lymphocytes' cytotoxic activity. Microbiol Immunol 2012; 56:62-75. [PMID: 22040089 DOI: 10.1111/j.1348-0421.2011.00399.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Helicobacter pylori (H.p) colonizes human gastric mucosa and causes gastric and duodenal ulcer disease or gastric cancer. Various H.p compounds may modulate the host immune response in regards to tolerance of the infection or disease development. The aim of this study was to determine whether H.p lipopolysaccharide (LPS) and glycine acid extract antigens (GE) or E. coli LPS influence the cytotoxic activity of peripheral blood lymphocytes from H.p infected - H.p (+) or uninfected - H.p (-) individuals, in the presence or absence of exogenous interleukin (IL)12. Individual H.p status was defined by the urea breath test. Lymphocytes, stimulated or not with H.p, and control antigens, with or without IL-12, were used as effector cells and epithelial HeLa cells as targets. The cytotoxicity of lymphocytes was expressed as the percentage of dead target cells unable to reduce tetrazolium salt. The supernatants from HeLa/lymphocyte cultures were used for detection of the cellular cytotoxicity markers granzyme B and caspase 8. The natural cytotoxic activity of lymphocytes from H.p (+) was less than that of H.p (-) donors. This may have been due to fewer natural killer cells of CD3(-) CD56(+) Nkp46(+) phenotype in H.p (+) in comparison to H.p (-) subjects. H.p GE and standard E. coli LPS enhanced the cytotoxicity of lymphocytes towards target cells whereas H.p LPS downregulated this activity. The decrease in lymphocyte cytotoxicity in response to H.p LPS correlated with a lack of IL-2 and IL-12 production, inhibition of interferon-γ production, and low IL-10 secretion by mononuclear leukocytes. IL-12 significantly enhanced the natural as well as H.p LPS and H.p GE driven cytotoxic capacity of lymphocytes. In conclusion, H.p LPS may negatively modulate natural cytotoxic activity and cytokine secretion by immunocompetent cells and thus be involved in the maintenance of infection and development of gastric pathologies.
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Affiliation(s)
- Karolina Rudnicka
- Department of Immunology and Infectious Biology, University of Łódź, Banacha 12/16, 90-237, Łódź, Poland
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Measurement of human latent Transforming Growth Factor-β1 using a latency associated protein-reactive ELISA. J Immunol Methods 2012; 379:23-9. [PMID: 22406166 DOI: 10.1016/j.jim.2012.02.016] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2012] [Revised: 02/23/2012] [Accepted: 02/23/2012] [Indexed: 12/14/2022]
Abstract
Human Transforming Growth Factor (TGF)-β1, one of three TGF-β isoforms, is a pleotropic cytokine critical for many physiological and immunological processes. TGF-β1 is secreted in a latent form, linked to Latency Associated Protein (LAP). Analysis of Latent TGF-β1 by TGF-β1 ELISA requires dissociation of TGF-β1 from LAP, e.g. by acidification of samples. The ELISA then measures total TGF-β1, equivalent to dissociated Latent TGF-β1 plus any free TGF-β1 present prior to acidification. Evolutionary conservation of TGF-β1 across mammals also renders TGF-β1 ELISAs reactive with TGF-β1 in bovine serum often used in human cell cultures. To enable a direct analysis of Latent TGF-β1, monoclonal antibodies were made against LAP from human Latent TGF-β1 and used to develop a LAP ELISA detecting Latent TGF-β1. The ELISA did not react with LAP from human Latent TGF-β2 or 3, respectively, nor with Latent TGF-β in bovine serum. EDTA-containing plasma from healthy subjects (n=20) was analyzed by conventional TGF-β1 ELISA and LAP ELISA. By TGF-β1 ELISA, total TGF-β1 were detected in all samples (median 133 pM, range 34-348 pM); low levels of free TGF-β1 found in 8/20 non-acidified samples showed that >98.5% of the total TGF-β1 derived from Latent TGF-β1. Latent TGF-β1 found in non-acidified samples by LAP ELISA (median 154 pM, range 48-403 pM) was comparable in molar levels to, and correlated with, total TGF-β1 (r(s) 0.96, p<0.0001). A similar agreement between the total TGF-β1 and the LAP ELISA was found with citrate- and heparin-containing plasma. The LAP ELISA facilitates analysis of Latent TGF-β1 without sample acidification and is not compromised by the presence of bovine serum in human cell supernatants.
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Pan F, Tian J, Pan YY, Zhang Y. Association of IL-10-1082 promoter polymorphism with susceptibility to gastric cancer: evidence from 22 case-control studies. Mol Biol Rep 2012; 39:7143-54. [PMID: 22311038 DOI: 10.1007/s11033-012-1546-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2011] [Accepted: 01/24/2012] [Indexed: 12/21/2022]
Abstract
UNLABELLED Evidence suggested that interleukin-10 (IL-10) may be involved in the etiology of gastric cancer (GC). However, epidemiological studies on the association between IL-10-1082 promoter polymorphism and GC risk are still ambiguous. To quantitatively summarize the evidence for such a relationship, we performed a meta-analysis. Systemic searches of the PubMed and Medline databases were performed, with the last report up to July 2011. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association. 22 independent studies including 4,289 cases and 5,965 controls were involved in this meta-analysis. Obvious association was found when all studies were pooled into the meta-analysis (A vs. G: OR = 0.489, 95% CI = 0.335-0.713, P < 0.001). In the subgroup analysis by ethnicity, we observed significant associations in Asians (A vs. G: OR = 0.651, 95% CI = 0.506-0.838, P = 0.001; AA vs. GG: OR = 0.482, 95% CI = 0.328-0.709, P < 0.001; AA/AG vs. GG: OR = 0.711, 95% CI = 0.527-0.959, P = 0.025; AA vs. AG/GG OR = 0.701, 95% CI = 0.520-0.944, P = 0.019) and Caucasians (A vs. G: OR = 0.365, 95% CI = 0.140-0.949, P = 0.039), but not in Latino population. When stratified analysis by control sources, our results indicated that A allele decreased approximately 48% risk among population-based studies (A vs. G: OR = 0.524, 95% CI = 0.374-0.733, P < 0.001). Taken together, this meta-analysis suggests that IL-10-1082 polymorphism is associated with GC risk.
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Affiliation(s)
- Feng Pan
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
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Kim J, Cho YA, Choi IJ, Lee YS, Kim SY, Shin A, Cho SJ, Kook MC, Nam JH, Ryu KW, Lee JH, Kim YW. Effects of interleukin-10 polymorphisms, Helicobacter pylori infection, and smoking on the risk of noncardia gastric cancer. PLoS One 2012; 7:e29643. [PMID: 22235320 PMCID: PMC3250465 DOI: 10.1371/journal.pone.0029643] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2011] [Accepted: 12/02/2011] [Indexed: 12/15/2022] Open
Abstract
Objective Both variations in the interleukin-10 (IL10) gene and environmental factors are thought to influence inflammation and gastric carcinogenesis. Therefore, we investigated the associations between IL10 polymorphisms, Helicobacter pylori (H. pylori) infection, and smoking in noncardia gastric carcinogenesis in Koreans. Methods We genotyped three promoter polymorphisms (-1082A>G, -819T>C, and -592 A>C) of IL10 in a case-control study of 495 noncardia gastric cancer patients and 495 sex- and age-matched healthy controls. Multiple logistic regression models were used to detect the effects of IL10 polymorphisms, H. pylori infection, and smoking on the risk of gastric cancer, which was stratified by the histological type of gastric cancer. Results The IL10-819C and -592C alleles were found to have complete linkage disequilibrium, and all three IL10 polymorphisms were associated with an increased risk of intestinal-type noncardia gastric cancer. These associations were observed only in H. pylori-positive subjects and current smokers. A statistically significant interaction between the IL10-592 genotype and H. pylori infection on the risk of intestinal-type gastric cancer was observed (P for interaction = 0.047). In addition, H. pylori-positive smokers who were carriers of either the IL10-1082G (OR [95% CI] = 17.76 [6.17−51.06]) or the -592C (OR [95% CI] = 8.37 [2.79−25.16]) allele had an increased risk of intestinal-type gastric cancer compared to H. pylori-negative nonsmokers homozygous for IL10-1082A and -592A, respectively. The interaction between the IL10-1082 polymorphism and the combined effects of H. pylori infection and smoking tended towards significance (P for interaction = 0.080). Conclusions Inflammation-related genetic variants may interact with H. pylori infection and smoking to increase the risk of noncardia gastric cancer, particularly the intestinal-type. These findings may be helpful in identifying individuals at an increased risk for developing noncardia gastric cancer.
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Affiliation(s)
- Jeongseon Kim
- Cancer Epidemiology Branch, National Cancer Center, Goyang, Korea
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Brenu EW, van Driel ML, Staines DR, Ashton KJ, Ramos SB, Keane J, Klimas NG, Marshall-Gradisnik SM. Immunological abnormalities as potential biomarkers in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. J Transl Med 2011; 9:81. [PMID: 21619669 PMCID: PMC3120691 DOI: 10.1186/1479-5876-9-81] [Citation(s) in RCA: 181] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2011] [Accepted: 05/28/2011] [Indexed: 12/17/2022] Open
Abstract
Background Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is characterised by severe prolonged fatigue, and decreases in cognition and other physiological functions, resulting in severe loss of quality of life, difficult clinical management and high costs to the health care system. To date there is no proven pathomechanism to satisfactorily explain this disorder. Studies have identified abnormalities in immune function but these data are inconsistent. We investigated the profile of markers of immune function (including novel markers) in CFS/ME patients. Methods We included 95 CFS/ME patients and 50 healthy controls. All participants were assessed on natural killer (NK) and CD8+T cell cytotoxic activities, Th1 and Th2 cytokine profile of CD4+T cells, expression of vasoactive intestinal peptide receptor 2 (VPACR2), levels of NK phenotypes (CD56bright and CD56dim) and regulatory T cells expressing FoxP3 transcription factor. Results Compared to healthy individuals, CFS/ME patients displayed significant increases in IL-10, IFN-γ, TNF-α, CD4+CD25+ T cells, FoxP3 and VPACR2 expression. Cytotoxic activity of NK and CD8+T cells and NK phenotypes, in particular the CD56bright NK cells were significantly decreased in CFS/ME patients. Additionally granzyme A and granzyme K expression were reduced while expression levels of perforin were significantly increased in the CFS/ME population relative to the control population. These data suggest significant dysregulation of the immune system in CFS/ME patients. Conclusions Our study found immunological abnormalities which may serve as biomarkers in CFS/ME patients with potential for an application as a diagnostic tool.
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Affiliation(s)
- Ekua W Brenu
- Population Health and Neuroimmunology Unit, Faculty of Health Science and Medicine, Bond University, Robina, Queensland, Australia
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