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1
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Lei W, Zhou K, Lei Y, Li Q, Zhu H. Pathogenesis and Systemic Treatment of Hepatocellular Carcinoma: Current Status and Prospects. Mol Cancer Ther 2025; 24:692-708. [PMID: 39417575 DOI: 10.1158/1535-7163.mct-24-0403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 08/14/2024] [Accepted: 10/08/2024] [Indexed: 10/19/2024]
Abstract
Hepatocellular carcinoma (HCC) remains one of the major threats to human health worldwide. The emergence of systemic therapeutic options has greatly improved the prognosis of patients with HCC, particularly those with advanced stages of the disease. In this review, we discussed the pathogenesis of HCC, genetic alterations associated with the development of HCC, and alterations in the tumor immune microenvironment. Then, important indicators and emerging technologies related to the diagnosis of HCC are summarized. Also, we reviewed the major advances in treatments for HCC, offering insights into future prospects for next-generation managements.
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Affiliation(s)
- Wanting Lei
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Kexun Zhou
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Ye Lei
- College of Liberal Arts, Neijiang Normal University, Neijiang, China
| | - Qiu Li
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Hong Zhu
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
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2
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Keskitalo S, Seppänen MRJ, Del Sol A, Varjosalo M. From rare to more common: The emerging role of omics in improving understanding and treatment of severe inflammatory and hyperinflammatory conditions. J Allergy Clin Immunol 2025; 155:1435-1450. [PMID: 39978687 DOI: 10.1016/j.jaci.2025.02.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 01/31/2025] [Accepted: 02/11/2025] [Indexed: 02/22/2025]
Abstract
Inflammation is a pathogenic driver of many diseases, including atherosclerosis and rheumatoid arthritis. Hyperinflammation can be seen as any inflammatory response that is deleterious to the host, regardless of cause. In medicine, hyperinflammation is defined as severe, deleterious, and fluctuating systemic or local inflammation with presence of a cytokine storm. It has been associated with rare autoinflammatory disorders. However, advances in omics technologies, including genomics, proteomics, and metabolomics, have revealed it to be more common, occurring in sepsis and severe coronavirus disease 2019. With a focus on proteomics, this review highlights the key role of omics in this shift. Through an exploration of research, we present how omics technologies have contributed to improved diagnostics, prognostics, and targeted therapeutics in the field of hyperinflammation. We also discuss the integration of advanced technologies, multiomics approaches, and artificial intelligence in analyzing complex datasets to develop targeted therapies, and we address their potential for revolutionizing the clinical aspects of hyperinflammation. We emphasize personalized medicine approaches for effective treatments and outline challenges, including the need for standardized methodologies, robust bioinformatics tools, and ethical considerations regarding data privacy. This review aims to provide a comprehensive overview of the molecular mechanisms underpinning hyperinflammation and underscores the potential of omics technologies in enabling successful clinical management.
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Affiliation(s)
- Salla Keskitalo
- Institute of Biotechnology, Helsinki Institute of Life Science HiLIFE, University of Helsinki, Helsinki, Finland.
| | - Mikko R J Seppänen
- Pediatric Research Center, New Children's Hospital, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland; Translational Immunology Research Program, University of Helsinki, Helsinki, Finland; European Reference Network Rare Immunodeficiency Autoinflammatory and Autoimmune Diseases Network (ERN RITA) Core Center, Helsinki, The Netherlands
| | - Antonio Del Sol
- Computational Biology Group, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg; Computational Biology Group, Basque Research and Technology Alliance (CIC bioGUNE-BRTA), Derio, Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Spain
| | - Markku Varjosalo
- Institute of Biotechnology, Helsinki Institute of Life Science HiLIFE, University of Helsinki, Helsinki, Finland; Department of Biochemistry and Developmental Biology and Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
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3
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Zhu Y, Zhou L, Mo L, Hong C, Pan L, Lin J, Qi Y, Tan S, Qian M, Hu T, Zhao Y, Qiu H, Lin P, Ma X, Yang Q. Plasmodium yoelii Infection Enhances the Expansion of Myeloid-Derived Suppressor Cells via JAK/STAT3 Pathway. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 213:170-186. [PMID: 38819229 DOI: 10.4049/jimmunol.2300541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Accepted: 05/07/2024] [Indexed: 06/01/2024]
Abstract
Myeloid-derived suppressor cells (MDSCs), the negative immune regulators, have been demonstrated to be involved in immune responses to a variety of pathological conditions, such as tumors, chronic inflammation, and infectious diseases. However, the roles and mechanisms underlying the expansion of MDSCs in malaria remain unclear. In this study, the phenotypic and functional characteristics of splenic MDSCs during Plasmodium yoelii NSM infection are described. Furthermore, we provide compelling evidence that the sera from P. yoelii-infected C57BL/6 mice containing excess IL-6 and granulocyte-macrophage colony-stimulating factor promote the accumulation of MDSCs by inducing Bcl2 expression. Serum-induced MDSCs exert more potent suppressive effects on T cell responses than control MDSCs within both in vivo P. yoelii infection and in vitro serum-treated bone marrow cells experiments. Serum treatment increases the MDSC inhibitory effect, which is dependent on Arg1 expression. Moreover, mechanistic studies reveal that the serum effects are mediated by JAK/STAT3 signaling. By inhibiting STAT3 phosphorylation with the JAK inhibitor JSI-124, effects of serum on MDSCs are almost eliminated. In vivo depletion of MDSCs with anti-Gr-1 or 5-fluorouracil significantly reduces the parasitemia and promotes Th1 immune response in P. yoelii-infected C57BL/6 mice by upregulating IFN-γ expression. In summary, this study indicates that P. yoelii infection facilitates the accumulation and function of MDSCs by upregulating the expression of Bcl2 and Arg1 via JAK/STAT3 signaling pathway in vivo and in vitro. Manipulating the JAK/STAT3 signaling pathway or depleting MDSCs could be promising therapeutic interventions to treat malaria.
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Affiliation(s)
- Yiqiang Zhu
- Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
- Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou, China
| | - Lu Zhou
- Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Lengshan Mo
- Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Cansheng Hong
- Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Lingxia Pan
- Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Jie Lin
- Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Yanwei Qi
- Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Simin Tan
- Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Manhongtian Qian
- Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Tengfei Hu
- Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Yi Zhao
- Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Huaina Qiu
- Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Peibin Lin
- Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
| | - Xiancai Ma
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou, China
| | - Quan Yang
- Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
- Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
- Second Affiliated Hospital, State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, Guangzhou Medical University, Guangzhou, China
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
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4
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Yang Y, Zhang M, Zhang Y, Liu K, Lu C. 5-Fluorouracil Suppresses Colon Tumor through Activating the p53-Fas Pathway to Sensitize Myeloid-Derived Suppressor Cells to FasL + Cytotoxic T Lymphocyte Cytotoxicity. Cancers (Basel) 2023; 15:1563. [PMID: 36900354 PMCID: PMC10001142 DOI: 10.3390/cancers15051563] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 02/24/2023] [Accepted: 02/27/2023] [Indexed: 03/06/2023] Open
Abstract
Myelosuppression is a major adverse effect of 5-fluorouracil (5-FU) chemotherapy. However, recent findings indicate that 5-FU selectively suppresses myeloid-derived suppressor cells (MDSCs), to enhance antitumor immunity in tumor-bearing mice. 5-FU-mediated myelosuppression may thus have a beneficial effect for cancer patients. The molecular mechanism underlying 5-FU's suppression of MDSCs is currently unknown. We aimed at testing the hypothesis that 5-FU suppresses MDSCs through enhancing MDSC sensitivity to Fas-mediated apoptosis. We observed that, although FasL is highly expressed in T cells, Fas is weakly expressed in myeloid cells in human colon carcinoma, indicating that downregulation of Fas is a mechanism underlying myeloid cell survival and accumulation in human colon cancer. 5-FU treatment upregulated expression of both p53 and Fas, and knocking down p53 diminished 5-FU-induced Fas expression in MDSC-like cells, in vitro. 5-FU treatment also increased MDSC-like cell sensitivity to FasL-induced apoptosis in vitro. Furthermore, we determined that 5-FU therapy increased expression of Fas on MDSCs, suppressed MDSC accumulation, and increased CTL tumor infiltration in colon tumor-bearing mice. In human colorectal cancer patients, 5-FU chemotherapy decreased MDSC accumulation and increased CTL level. Our findings determine that 5-FU chemotherapy activates the p53-Fas pathway, to suppress MDSC accumulation, to increase CTL tumor infiltration.
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Affiliation(s)
- Yingcui Yang
- School of Life Sciences, Tianjin University, Tianjin 300072, China
| | - Mingqing Zhang
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin 300121, China
| | - Yongdan Zhang
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin 300121, China
| | - Kebin Liu
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA
- Georgia Cancer Center, Augusta, GA 30912, USA
| | - Chunwan Lu
- School of Life Sciences, Tianjin University, Tianjin 300072, China
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5
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Abstract
The tumor microenvironment forms a complex pro-tumorigenic milieu constituted by extracellular matrix, surrounding stroma, infiltrating cell populations, and signaling molecules. Proteomic studies have the potential to reveal how individual cell populations within the tumor tissue modulate the microenvironment through protein secretion and consequently alter their protein expression and localization to adapt to this milieu. As a result, proteomic approaches have uncovered how these dynamic components communicate and promote tumor development and progression. The characterization of these mechanisms is relevant for the identification of clinically targetable pathways and for the development of diagnostic tools. Here we describe a method based on the isolation of individual cell compartments and the chromatographic fractionation of intact proteins, followed by enzymatic digestion of individual fractions, and mass-spectrometry analysis, for the profiling of tumor microenvironment cell populations.
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Affiliation(s)
- Michela Capello
- Departments of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hiroyuki Katayama
- Departments of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Samir M Hanash
- Departments of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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6
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Li K, Shi H, Zhang B, Ou X, Ma Q, Chen Y, Shu P, Li D, Wang Y. Myeloid-derived suppressor cells as immunosuppressive regulators and therapeutic targets in cancer. Signal Transduct Target Ther 2021; 6:362. [PMID: 34620838 PMCID: PMC8497485 DOI: 10.1038/s41392-021-00670-9] [Citation(s) in RCA: 443] [Impact Index Per Article: 110.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 02/21/2021] [Accepted: 06/01/2021] [Indexed: 02/05/2023] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogenic population of immature myeloid cells with immunosuppressive effects, which undergo massive expansion during tumor progression. These cells not only support immune escape directly but also promote tumor invasion via various non-immunological activities. Besides, this group of cells are proved to impair the efficiency of current antitumor strategies such as chemotherapy, radiotherapy, and immunotherapy. Therefore, MDSCs are considered as potential therapeutic targets for cancer therapy. Treatment strategies targeting MDSCs have shown promising outcomes in both preclinical studies and clinical trials when administrated alone, or in combination with other anticancer therapies. In this review, we shed new light on recent advances in the biological characteristics and immunosuppressive functions of MDSCs. We also hope to propose an overview of current MDSCs-targeting therapies so as to provide new ideas for cancer treatment.
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Affiliation(s)
- Kai Li
- Department of Thoracic Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, 610041, Chengdu, China
| | - Houhui Shi
- Department of Gynecology and Obstetrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, 610041, Chengdu, China
| | - Benxia Zhang
- Department of Thoracic Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, 610041, Chengdu, China
| | - Xuejin Ou
- Department of Thoracic Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, 610041, Chengdu, China
| | - Qizhi Ma
- Department of Thoracic Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, 610041, Chengdu, China
| | - Yue Chen
- Department of Thoracic Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, 610041, Chengdu, China
| | - Pei Shu
- Department of Thoracic Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, 610041, Chengdu, China
| | - Dan Li
- Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, and Precision Medicine Center, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, 610041, Chengdu, China.
| | - Yongsheng Wang
- Department of Thoracic Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, 610041, Chengdu, China. .,Clinical Trial Center, West China Hospital, Sichuan University, 610041, Chengdu, China.
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7
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Bondhopadhyay B, Sisodiya S, Alzahrani FA, Bakhrebah MA, Chikara A, Kasherwal V, Khan A, Rani J, Dar SA, Akhter N, Tanwar P, Agrawal U, Hussain S. Exosomes: A Forthcoming Era of Breast Cancer Therapeutics. Cancers (Basel) 2021; 13:4672. [PMID: 34572899 PMCID: PMC8464658 DOI: 10.3390/cancers13184672] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 06/20/2021] [Accepted: 06/29/2021] [Indexed: 12/24/2022] Open
Abstract
Despite the recent advancements in therapeutics and personalized medicine, breast cancer remains one of the most lethal cancers among women. The prognostic and diagnostic aids mainly include assessment of tumor tissues with conventional methods towards better therapeutic strategies. However, current era of gene-based research may influence the treatment outcome particularly as an adjunct to diagnostics by exploring the role of non-invasive liquid biopsies or circulating markers. The characterization of tumor milieu for physiological fluids has been central to identifying the role of exosomes or small extracellular vesicles (sEVs). These exosomes provide necessary communication between tumor cells in the tumor microenvironment (TME). The manipulation of exosomes in TME may provide promising diagnostic/therapeutic strategies, particularly in triple-negative breast cancer patients. This review has described and highlighted the role of exosomes in breast carcinogenesis and how they could be used or targeted by recent immunotherapeutics to achieve promising intervention strategies.
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Affiliation(s)
- Banashree Bondhopadhyay
- ICMR-National Institute of Cancer Prevention and Research, Noida 201301, India; (B.B.); (S.S.); (A.C.); (V.K.); (J.R.)
| | - Sandeep Sisodiya
- ICMR-National Institute of Cancer Prevention and Research, Noida 201301, India; (B.B.); (S.S.); (A.C.); (V.K.); (J.R.)
- Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune 411004, India
| | - Faisal Abdulrahman Alzahrani
- Department of Biochemistry, Faculty of Science, Embryonic Stem Cells Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
| | - Muhammed A. Bakhrebah
- Life Science and Environment Research Institute, King Abdulaziz City for Science and Technology (KACST), Riyadh 11442, Saudi Arabia;
| | - Atul Chikara
- ICMR-National Institute of Cancer Prevention and Research, Noida 201301, India; (B.B.); (S.S.); (A.C.); (V.K.); (J.R.)
- Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune 411004, India
| | - Vishakha Kasherwal
- ICMR-National Institute of Cancer Prevention and Research, Noida 201301, India; (B.B.); (S.S.); (A.C.); (V.K.); (J.R.)
- Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Noida 201313, India
| | - Asiya Khan
- Centre for Medical Biotechnology, Amity Institute of Biotechnology, Amity University, Noida 201313, India;
- Laboratory Oncology Unit, Dr. Bheem Rao Ambedkar Institute Rotary Cancer Hospital (Dr. BRA-IRCH), All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110023, India;
| | - Jyoti Rani
- ICMR-National Institute of Cancer Prevention and Research, Noida 201301, India; (B.B.); (S.S.); (A.C.); (V.K.); (J.R.)
| | - Sajad Ahmad Dar
- Research and Scientific Studies Unit, College of Nursing, Jazan University, Jazan 45142, Saudi Arabia;
| | - Naseem Akhter
- Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Albaha University, Albaha 65411, Saudi Arabia;
| | - Pranay Tanwar
- Laboratory Oncology Unit, Dr. Bheem Rao Ambedkar Institute Rotary Cancer Hospital (Dr. BRA-IRCH), All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110023, India;
| | - Usha Agrawal
- ICMR-National Institute of Pathology, New Delhi 110029, India;
| | - Showket Hussain
- ICMR-National Institute of Cancer Prevention and Research, Noida 201301, India; (B.B.); (S.S.); (A.C.); (V.K.); (J.R.)
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8
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Li X, Li Y, Yu Q, Qian P, Huang H, Lin Y. Metabolic reprogramming of myeloid-derived suppressor cells: An innovative approach confronting challenges. J Leukoc Biol 2021; 110:257-270. [PMID: 34075637 PMCID: PMC8361984 DOI: 10.1002/jlb.1mr0421-597rr] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 04/11/2021] [Accepted: 04/12/2021] [Indexed: 02/06/2023] Open
Abstract
Immune cells such as T cells, macrophages, dendritic cells, and other immunoregulatory cells undergo metabolic reprogramming in cancer and inflammation-derived microenvironment to meet specific physiologic and functional demands. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that are characterized by immunosuppressive activity, which plays a key role in host immune homeostasis. In this review, we have discussed the core metabolic pathways, including glycolysis, lipid and fatty acid biosynthesis, and amino acid metabolism in the MDSCs under various pathologic situations. Metabolic reprogramming is a determinant of the phenotype and functions of MDSCs, and is therefore a novel therapeutic possibility in various diseases.
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Affiliation(s)
- Xiaoqing Li
- Bone Marrow Transplantation Center, the First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouZhejiangChina
- Institute of HematologyZhejiang UniversityHangzhouZhejiangChina
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity TherapyHangzhouZhejiangChina
- Liangzhu LaboratoryZhejiang University Medical CenterHangzhouZhejiangChina
| | - Yixue Li
- Bone Marrow Transplantation Center, the First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouZhejiangChina
- Institute of HematologyZhejiang UniversityHangzhouZhejiangChina
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity TherapyHangzhouZhejiangChina
- Liangzhu LaboratoryZhejiang University Medical CenterHangzhouZhejiangChina
| | - Qinru Yu
- Bone Marrow Transplantation Center, the First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouZhejiangChina
- Institute of HematologyZhejiang UniversityHangzhouZhejiangChina
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity TherapyHangzhouZhejiangChina
- Liangzhu LaboratoryZhejiang University Medical CenterHangzhouZhejiangChina
| | - Pengxu Qian
- Institute of HematologyZhejiang UniversityHangzhouZhejiangChina
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity TherapyHangzhouZhejiangChina
- Liangzhu LaboratoryZhejiang University Medical CenterHangzhouZhejiangChina
| | - He Huang
- Bone Marrow Transplantation Center, the First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouZhejiangChina
- Institute of HematologyZhejiang UniversityHangzhouZhejiangChina
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity TherapyHangzhouZhejiangChina
- Liangzhu LaboratoryZhejiang University Medical CenterHangzhouZhejiangChina
| | - Yu Lin
- Bone Marrow Transplantation Center, the First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouZhejiangChina
- Institute of HematologyZhejiang UniversityHangzhouZhejiangChina
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity TherapyHangzhouZhejiangChina
- Liangzhu LaboratoryZhejiang University Medical CenterHangzhouZhejiangChina
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9
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Cole KE, Ly QP, Hollingsworth MA, Cox JL, Padussis JC, Foster JM, Vargas LM, Talmadge JE. Human splenic myeloid derived suppressor cells: Phenotypic and clustering analysis. Cell Immunol 2021; 363:104317. [PMID: 33714729 DOI: 10.1016/j.cellimm.2021.104317] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 02/11/2021] [Accepted: 02/12/2021] [Indexed: 12/12/2022]
Abstract
Myeloid derived suppressor cells (MDSCs) can be subset into monocytic (M-), granulocytic (G-) or polymorphonuclear (PMN-), and immature (i-) or early MDSCs and have a role in many disease states. In cancer patients, the frequencies of MDSCs can positively correlate with stage, grade, and survival. Most clinical studies into MDSCs have been undertaken with peripheral blood (PB); however, in the present studies, we uniquely examined MDSCs in the spleens and PB from patients with gastrointestinal cancers. In our studies, MDSCs were rigorously subset using the following markers: Lineage (LIN) (CD3, CD19 and CD56), human leukocyte antigen (HLA)-DR, CD11b, CD14, CD15, CD33, CD34, CD45, and CD16. We observed a significantly higher frequency of PMN- and M-MDSCs in the PB of cancer patients as compared to their spleens. Expression of the T-cell suppressive enzymes arginase (ARG1) and inducible nitric oxide synthase (i-NOS) were higher on all MDSC subsets for both cancer patients PB and spleen cells as compared to MDSCs from the PB of normal donors. Similar findings for the activation markers lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), program death ligand 1 (PD-L1) and program cell death protein 1 (PD-1) were observed. Interestingly, the total MDSC cell number exported to clustering analyses was similar between all sample types; however, clustering analyses of these MDSCs, using these markers, uniquely documented novel subsets of PMN-, M- and i-MDSCs. In summary, we report a comparison of splenic MDSC frequency, subtypes, and functionality in cancer patients to their PB by clustering and cytometric analyses.
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Affiliation(s)
- Kathryn E Cole
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Quan P Ly
- Department of Surgery, University of Nebraska Medical Center, Omaha, NE 68198-4990, United States
| | - Michael A Hollingsworth
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-5950, United States
| | - Jesse L Cox
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - James C Padussis
- Department of Surgery, University of Nebraska Medical Center, Omaha, NE 68198-4990, United States
| | - Jason M Foster
- Department of Surgery, University of Nebraska Medical Center, Omaha, NE 68198-4990, United States
| | - Luciano M Vargas
- Department of Surgery, University of Nebraska Medical Center, Omaha, NE 68198-4990, United States
| | - James E Talmadge
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, United States; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, United States.
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10
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Farshidpour M, Ahmed M, Junna S, Merchant JL. Myeloid-derived suppressor cells in gastrointestinal cancers: A systemic review. World J Gastrointest Oncol 2021; 13:1-11. [PMID: 33510845 PMCID: PMC7805271 DOI: 10.4251/wjgo.v13.i1.1] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 12/01/2020] [Accepted: 12/16/2020] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal (GI) cancers are one of the most common malignancies worldwide, with high rates of morbidity and mortality. Myeloid-derived suppressor cells (MDSCs) are major components of the tumor microenvironment (TME). MDSCs facilitate the transformation of premalignant cells and play roles in tumor growth and metastasis. Moreover, in patients with GI malignancies, MDSCs can lead to the suppression of T cells and natural killer cells. Accordingly, a better understanding of the role and mechanism of action of MDSCs in the TME will aid in the development of novel immune-targeted therapies.
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Affiliation(s)
- Maham Farshidpour
- Inpatient Medicine, Banner University of Medical Center, Tucson, AZ 85724, United States
| | - Monjur Ahmed
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Thomas Jefferson University, Philadelphia, PA 19107, United States
| | - Shilpa Junna
- Division of Gastroenterology and Hepatology, Banner University of Medical Center, Tucson, AZ 85724, United States
| | - Juanita L Merchant
- Division of Gastroenterology and Hepatology, Banner University of Medical Center, Tucson, AZ 85724, United States
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11
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Fenselau C, Ostrand-Rosenberg S. Molecular cargo in myeloid-derived suppressor cells and their exosomes. Cell Immunol 2021; 359:104258. [PMID: 33338939 PMCID: PMC7802618 DOI: 10.1016/j.cellimm.2020.104258] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 11/25/2020] [Accepted: 12/03/2020] [Indexed: 12/12/2022]
Abstract
Collaborative research is reviewed in which mass spectrometry-based proteomics and next generation sequencing were used qualitatively and quantitatively to interrogate proteins and RNAs carried in intact myeloid-derived suppressor cells (MDSC) and exosomes shed in vitro by MDSC. In aggregate exosomes more than 4000 proteins were identified, including annexins and immunosuppressive mediators. Bioassays showed that exosomes induce MDSC chemotaxis dependent on S100A8 and S100A9 in their cargo. Surface selective chemistry identified glycoproteins on MDSC and exosome surfaces, including CD47 and thrombospondin 1, which both facilitate exosome-catalyzed chemotaxis. Large numbers of mRNAs and microRNAs were identified in aggregate exosomes, whose potential functions in receptor cells include angiogenesis, and proinflammatory and immunosuppressive activities. Inflammation was found to have asymmetric effects on MDSC and exosomal cargos. Collectively, our findings indicate that the exosomes shed by MDSC provide divergent and complementary functions that support the immunosuppression and tumor promotion activities of MDSC.
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Affiliation(s)
- Catherine Fenselau
- Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, United States.
| | - Suzanne Ostrand-Rosenberg
- Department of Biological Sciences, University of Maryland, Baltimore County, MD 20742, United States; Department of Pathology, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT 84112, United States
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12
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Shabgah AG, Salmaninejad A, Thangavelu L, Alexander M, Yumashev AV, Goleij P, Hedayati-Moghadam M, Mohammadi H, Ahmadi M, Navashenaq JG. The role of non-coding genome in the behavior of infiltrated myeloid-derived suppressor cells in tumor microenvironment; a perspective and state-of-the-art in cancer targeted therapy. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2020; 161:17-26. [PMID: 33259833 DOI: 10.1016/j.pbiomolbio.2020.11.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Revised: 11/20/2020] [Accepted: 11/25/2020] [Indexed: 12/13/2022]
Abstract
Cancer is one of the healthcare problems that affect many communities around the world. Many factors contribute to cancer development. Besides, these factors are counted as the main impediment in cancer immunotherapy. Myeloid-derived suppressor cells (MDSCs) are one of these impediments. MDSCs inhibit the immune responses through various mechanisms such as inhibitory cytokine release and nitric oxide metabolite production. Several factors are involved in forming these cells, including tumor secreted cytokine and chemokines, transcription factors, and non-coding RNA. In the meantime, micro-RNAs (miRNAs) and long non-coding RNAs (lncRNAs) are the vital gene regulatory elements that affect gene expression. In this study, we are going to discuss the role of miRNAs and lncRNAs in MDSCs development in a cancer situation. It is hoped that miRNA and lncRNAs targeting may prevent the growth and development of these inhibitory cells in the cancer environment.
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Affiliation(s)
- Arezoo Gowhari Shabgah
- School of Medicine, Bam University of Medical Sciences, Bam, Iran; Student Research Committee, Bam University of Medical Sciences, Bam, Iran
| | - Arash Salmaninejad
- Department of Medical Genetics, Medical Genetics Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Lakshmi Thangavelu
- Department of Pharmacology, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
| | | | - Alexei Valerievich Yumashev
- Department of Prosthetic Dentistry, Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - Pouya Goleij
- Sana Institute of Higher Education, Faculty of Biology, Department of Genetics, Sari, Iran
| | | | - Hamed Mohammadi
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran; Department of Immunology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
| | - Majid Ahmadi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Jamshid Gholizadeh Navashenaq
- Student Research Committee, Bam University of Medical Sciences, Bam, Iran; Noncommunicable Diseases Research Center, Bam University of Medical Sciences, Bam, Iran.
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13
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Smith AD, Lu C, Payne D, Paschall AV, Klement JD, Redd PS, Ibrahim ML, Yang D, Han Q, Liu Z, Shi H, Hartney TJ, Nayak-Kapoor A, Liu K. Autocrine IL6-Mediated Activation of the STAT3-DNMT Axis Silences the TNFα-RIP1 Necroptosis Pathway to Sustain Survival and Accumulation of Myeloid-Derived Suppressor Cells. Cancer Res 2020; 80:3145-3156. [PMID: 32554751 PMCID: PMC7416440 DOI: 10.1158/0008-5472.can-19-3670] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Revised: 03/10/2020] [Accepted: 06/11/2020] [Indexed: 12/11/2022]
Abstract
Although accumulation of myeloid-derived suppressor cells (MDSC) is a hallmark of cancer, the underlying mechanism of this accumulation within the tumor microenvironment remains incompletely understood. We report here that TNFα-RIP1-mediated necroptosis regulates accumulation of MDSCs. In tumor-bearing mice, pharmacologic inhibition of DNMT with the DNA methyltransferease inhibitor decitabine (DAC) decreased MDSC accumulation and increased activation of antigen-specific cytotoxic T lymphocytes. DAC-induced decreases in MDSC accumulation correlated with increased expression of the myeloid cell lineage-specific transcription factor IRF8 in MDSCs. However, DAC also suppressed MDSC-like cell accumulation in IRF8-deficient mice, indicating that DNA methylation may regulate MDSC survival through an IRF8-independent mechanism. Instead, DAC decreased MDSC accumulation by increasing cell death via disrupting DNA methylation of RIP1-dependent targets of necroptosis. Genome-wide DNA bisulfite sequencing revealed that the Tnf promoter was hypermethylated in tumor-induced MDSCs in vivo. DAC treatment dramatically increased TNFα levels in MDSC in vitro, and neutralizing TNFα significantly increased MDSC accumulation and tumor growth in tumor-bearing mice in vivo. Recombinant TNFα induced MDSC cell death in a dose- and RIP1-dependent manner. IL6 was abundantly expressed in MDSCs in tumor-bearing mice and patients with human colorectal cancer. In vitro, IL6 treatment of MDSC-like cells activated STAT3, increased expression of DNMT1 and DNMT3b, and enhanced survival. Overall, our findings reveal that MDSCs establish a STAT3-DNMT epigenetic axis, regulated by autocrine IL6, to silence TNFα expression. This results in decreased TNFα-induced and RIP1-dependent necroptosis to sustain survival and accumulation. SIGNIFICANCE: These findings demonstrate that targeting IL6 expression or function represent potentially effective approaches to suppress MDSC survival and accumulation in the tumor microenvironment.
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Affiliation(s)
- Alyssa D Smith
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia
- Georgia Cancer Center, Medical College of Georgia, Augusta, Georgia
- Charlie Norwood VA Medical Center, Augusta, Georgia
| | - Chunwan Lu
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia
- Georgia Cancer Center, Medical College of Georgia, Augusta, Georgia
- Charlie Norwood VA Medical Center, Augusta, Georgia
| | - Daniela Payne
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia
- Georgia Cancer Center, Medical College of Georgia, Augusta, Georgia
| | - Amy V Paschall
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia
- Georgia Cancer Center, Medical College of Georgia, Augusta, Georgia
- Charlie Norwood VA Medical Center, Augusta, Georgia
| | - John D Klement
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia
- Georgia Cancer Center, Medical College of Georgia, Augusta, Georgia
- Charlie Norwood VA Medical Center, Augusta, Georgia
| | - Priscilla S Redd
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia
- Georgia Cancer Center, Medical College of Georgia, Augusta, Georgia
- Charlie Norwood VA Medical Center, Augusta, Georgia
| | - Mohammed L Ibrahim
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia
- Georgia Cancer Center, Medical College of Georgia, Augusta, Georgia
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Dafeng Yang
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia
- Georgia Cancer Center, Medical College of Georgia, Augusta, Georgia
- Charlie Norwood VA Medical Center, Augusta, Georgia
| | - Qimei Han
- Georgia Cancer Center, Medical College of Georgia, Augusta, Georgia
| | - Zhuoqi Liu
- Georgia Cancer Center, Medical College of Georgia, Augusta, Georgia
| | - Huidong Shi
- Georgia Cancer Center, Medical College of Georgia, Augusta, Georgia
| | | | - Asha Nayak-Kapoor
- Georgia Cancer Center, Medical College of Georgia, Augusta, Georgia
- Charlie Norwood VA Medical Center, Augusta, Georgia
| | - Kebin Liu
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia.
- Georgia Cancer Center, Medical College of Georgia, Augusta, Georgia
- Charlie Norwood VA Medical Center, Augusta, Georgia
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14
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Li C, Zhang X, Kang X, Chen C, Guo F, Wang Q, Zhao A. Upregulated TRAIL and Reduced DcR2 Mediate Apoptosis of Decidual PMN-MDSC in Unexplained Recurrent Pregnancy Loss. Front Immunol 2020; 11:1345. [PMID: 32695113 PMCID: PMC7338483 DOI: 10.3389/fimmu.2020.01345] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2020] [Accepted: 05/27/2020] [Indexed: 12/29/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSC), especially polymorphonuclear MDSC (PMN-MDSC), accumulate in maternal-fetal interface during pregnancy and are involved in the maintenance of immune tolerance. Decreased PMN-MDSC is associated with pregnancy complications such as unexplained recurrent pregnancy loss (URPL). In the present study we showed decreased PMN-MDSC in the URPL group compared with the normal pregnancy (NP) group, and PMN-MDSC was the major subset of MDSC in human decidua with potent immune suppression activity. We then performed gene expression profile and found that human decidual PMN-MDSC in the NP and URPL groups showed different gene and pathway signature, including apoptosis. Apoptosis of decidual PMN-MDSC was mediated by TNF-related apoptosis–induced ligand (TRAIL) in a Caspase 3 dependent manner. TRAIL was expressed in decidua and upregulated in decidua of the URPL group. Notably, of all the membrane TRAIL receptors, only DcR2 was down-regulated in PMN-MDSC in the URPL group. In vitro experiment demonstrated that DcR2 blockade sensitized PMN-MDSC to TRAIL-mediated apoptosis. Together, these data indicate that increased TRAIL and reduced DcR2 on PMN-MDSC sensitize PMN-MDSC response to TRAIL-induced apoptosis in the URPL group, which is responsible for decreased accumulation of PMN-MDSC in URPL.
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Affiliation(s)
- Congcong Li
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, China
| | - Xiaoxin Zhang
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaomin Kang
- Department of Reproductive Medical Center, The First People's Hospital of Yunnan Province, Kunming, China
| | - Chao Chen
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, China
| | - Feng Guo
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, China
| | - Qiaohong Wang
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, China
| | - Aimin Zhao
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, China
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15
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Kriek M, Monyai K, Magcwebeba TU, Du Plessis N, Stoychev SH, Tabb DL. Interrogating Fractionation and Other Sources of Variability in Shotgun Proteomes Using Quality Metrics. Proteomics 2020; 20:e1900382. [PMID: 32415754 DOI: 10.1002/pmic.201900382] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 04/04/2020] [Indexed: 12/14/2022]
Abstract
The increasing amount of publicly available proteomics data creates opportunities for data scientists to investigate quality metrics in novel ways. QuaMeter IDFree is used to generate quality metrics from 665 RAW files and 97 WIFF files representing publicly available "shotgun" mass spectrometry datasets. These experiments are selected to represent Mycobacterium tuberculosis lysates, mouse MDSCs, and exosomes derived from human cell lines. Machine learning techniques are demonstrated to detect outliers within experiments and it is shown that quality metrics may be used to distinguish sources of variability among these experiments. In particular, the findings demonstrate that according to nested ANOVA performed on an SDS-PAGE shotgun principal component analysis, runs of fractions from the same gel regions cluster together rather than technical replicates, close temporal proximity, or even biological samples. This indicates that the individual fraction may have had a higher impact on the quality metrics than other factors. In addition, sample type, instrument type, mass analyzer, fragmentation technique, and digestion enzyme are identified as sources of variability. From a quality control perspective, the importance of study design and in particular, the run order, is illustrated in seeking ways to limit the impact of technical variability.
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Affiliation(s)
- Marina Kriek
- SATBBI (South African Tuberculosis Bioinformatics Initiative), Centre for Bioinformatics and Computational Biology, Stellenbosch University, Cape Town, 7505, South Africa.,DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, Cape Town, 7505, South Africa.,South African Medical Research Council Centre for Tuberculosis Research, Cape Town, 7505, South Africa.,Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, 7505, South Africa
| | - Koena Monyai
- Council for Scientific and Industrial Research, Pretoria, 0001, South Africa
| | - Tandeka U Magcwebeba
- DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, Cape Town, 7505, South Africa.,South African Medical Research Council Centre for Tuberculosis Research, Cape Town, 7505, South Africa.,Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, 7505, South Africa
| | - Nelita Du Plessis
- DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, Cape Town, 7505, South Africa.,South African Medical Research Council Centre for Tuberculosis Research, Cape Town, 7505, South Africa.,Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, 7505, South Africa
| | - Stoyan H Stoychev
- Council for Scientific and Industrial Research, Pretoria, 0001, South Africa
| | - David L Tabb
- SATBBI (South African Tuberculosis Bioinformatics Initiative), Centre for Bioinformatics and Computational Biology, Stellenbosch University, Cape Town, 7505, South Africa.,DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, Cape Town, 7505, South Africa.,South African Medical Research Council Centre for Tuberculosis Research, Cape Town, 7505, South Africa.,Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, 7505, South Africa
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16
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Salminen A, Kauppinen A, Kaarniranta K. AMPK activation inhibits the functions of myeloid-derived suppressor cells (MDSC): impact on cancer and aging. J Mol Med (Berl) 2019; 97:1049-1064. [PMID: 31129755 PMCID: PMC6647228 DOI: 10.1007/s00109-019-01795-9] [Citation(s) in RCA: 91] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 04/10/2019] [Accepted: 05/08/2019] [Indexed: 02/06/2023]
Abstract
AMP-activated protein kinase (AMPK) has a crucial role not only in the regulation of tissue energy metabolism but it can also control immune responses through its cooperation with immune signaling pathways, thus affecting immunometabolism and the functions of immune cells. It is known that AMPK signaling inhibits the activity of the NF-κB system and thus suppresses pro-inflammatory responses. Interestingly, AMPK activation can inhibit several major immune signaling pathways, e.g., the JAK-STAT, NF-κB, C/EBPβ, CHOP, and HIF-1α pathways, which induce the expansion and activation of myeloid-derived suppressor cells (MDSC). MDSCs induce an immunosuppressive microenvironment in tumors and thus allow the escape of tumor cells from immune surveillance. Chronic inflammation has a key role in the expansion and activation of MDSCs in both tumors and inflammatory disorders. The numbers of MDSCs also significantly increase during the aging process concurrently with the immunosenescence associated with chronic low-grade inflammation. Increased fatty acid oxidation and lactate produced by aerobic glycolysis are important immunometabolic enhancers of MDSC functions. However, it seems that AMPK signaling regulates the functions of MDSCs in a context-dependent manner. Currently, the activators of AMPK signaling are promising drug candidates for cancer therapy and possibly for the extension of healthspan and lifespan. We will describe in detail the AMPK-mediated regulation of the signaling pathways controlling the expansion and activation of immunosuppressive MDSCs. We will propose that the beneficial effects mediated by AMPK activation, e.g., in cancers and the aging process, could be induced by the inhibition of MDSC functions.
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Affiliation(s)
- Antero Salminen
- Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland.
| | - Anu Kauppinen
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland
| | - Kai Kaarniranta
- Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland.,Department of Ophthalmology, Kuopio University Hospital, P.O. Box 100, FI-70029, Kuopio, Finland
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17
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Ostrand-Rosenberg S, Fenselau C. Myeloid-Derived Suppressor Cells: Immune-Suppressive Cells That Impair Antitumor Immunity and Are Sculpted by Their Environment. THE JOURNAL OF IMMUNOLOGY 2018; 200:422-431. [PMID: 29311384 DOI: 10.4049/jimmunol.1701019] [Citation(s) in RCA: 386] [Impact Index Per Article: 55.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Accepted: 08/24/2017] [Indexed: 12/19/2022]
Abstract
Myeloid-derived suppressor cells (MDSC) are a diverse population of immature myeloid cells that have potent immune-suppressive activity. Studies in both mice and humans have demonstrated that MDSC accumulate in most individuals with cancer, where they promote tumor progression, inhibit antitumor immunity, and are an obstacle to many cancer immunotherapies. As a result, there has been intense interest in understanding the mechanisms and in situ conditions that regulate and sustain MDSC, and the mechanisms MDSC use to promote tumor progression. This article reviews the characterization of MDSC and how they are distinguished from neutrophils, describes the suppressive mechanisms used by MDSC to mediate their effects, and explains the role of proinflammatory mediators and the tumor microenvironment in driving MDSC accumulation, suppressive potency, and survival.
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Affiliation(s)
- Suzanne Ostrand-Rosenberg
- Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD 21250; and
| | - Catherine Fenselau
- Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742
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18
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IL-17A weakens the antitumor immuity by inhibiting apoptosis of MDSCs in Lewis lung carcinoma bearing mice. Oncotarget 2018; 8:4814-4825. [PMID: 28002798 PMCID: PMC5354873 DOI: 10.18632/oncotarget.13978] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2016] [Accepted: 12/07/2016] [Indexed: 11/25/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) weaken the antitumor immune response through the inhibition of effector T cell activity and the production of immunosuppressive factors in pathological sites. It is well established that interleukin-17A (IL-17A) has a remarkable role on the promotion of inflammation and tumor formation, and IL-17 has been implicated in the enhancement of immunosuppression of MDSCs, which consequently promotes tumor progression. A detailed study of this relationship remains elusive. In our study, we not only confirmed the promotion of IL-17 on Lewis lung carcinoma (LLC) development but also surprisingly showed that IL-17 could extend the fate and enhance the immunosuppressive effect of MDSCs through activating ERK1/2. Additionally, the effect of IL-17 on MDSCs was reversed, even in tumors by blocking ERK1/2. Interdicting the signaling molecule ERK1/2 could increase the apoptosis of MDSCs and weaken the suppressive activity of MDSCs, so that thereafter, the antitumor immunity could be restored partly. Therefore, these findings offer new insights into the importance of IL-17 and the downstream signaling factor ERK1/2 for MDSCs.
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19
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Shao Y, Shen Y, Chen T, Xu F, Chen X, Zheng S. The functions and clinical applications of tumor-derived exosomes. Oncotarget 2018; 7:60736-60751. [PMID: 27517627 PMCID: PMC5312416 DOI: 10.18632/oncotarget.11177] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/1969] [Accepted: 07/13/2016] [Indexed: 02/06/2023] Open
Abstract
Exosomes are extracellular vesicles with diameters ranging from 30 to 150 nm. They can be secreted by all cell types and transfer information in the form of their contents, which include proteins, lipids and nucleic acids, to other cells throughout the body. They have roles in normal physiological processes as well as in disease development. Here, we review recent findings regarding tumor-derived exosomes, including methods for their extraction and preservation. We also describe the actions of exosomes in tumorigenesis. The exosomal antigen-presenting effect during antitumor immune responses and its suppressive function in immune tolerance are discussed. Finally, we describe the potential application of exosomes to cancer therapy and liquid biopsy.
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Affiliation(s)
- Yingkuan Shao
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Yanwei Shen
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Ting Chen
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Fei Xu
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Xuewen Chen
- Department of Biology, University of North Carolina, Chapel Hill, North Carolina, United States of America
| | - Shu Zheng
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
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20
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Biology of Myeloid-Derived Suppressor Cells. Oncoimmunology 2018. [DOI: 10.1007/978-3-319-62431-0_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
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21
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Kumar S, Saini RV, Mahindroo N. Recent advances in cancer immunology and immunology-based anticancer therapies. Biomed Pharmacother 2017; 96:1491-1500. [PMID: 29198747 DOI: 10.1016/j.biopha.2017.11.126] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2017] [Revised: 11/12/2017] [Accepted: 11/27/2017] [Indexed: 12/14/2022] Open
Abstract
Cancer immunotherapies offer promise for cure of cancer with specificity and minimal toxicity. Recent developments in cancer immunology have led to the better understanding of role of immune regulatory mechanisms in cancer. There is rapid progress in this field in the last few years. Several clinical studies report the efficacy of immunotherapies for treating cancer. The immunology-based anticancer therapies have shown better safety profiles in clinic as compared to other chemotherapeutic agents, thus increasing interest in this area. This review summarizes recent advances in cancer immunology and discusses tumor microenvironment and immunology-based anticancer therapies, including vaccines and therapies targeting immune checkpoints.
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Affiliation(s)
- Sunil Kumar
- School of Pharmaceutical Sciences, Shoolini University, Post Box 9, Solan, 173212, Himachal Pradesh, India
| | - Reena Vohra Saini
- School of Biotechnology, Shoolini University, Post Box 9, Solan, 173212, Himachal Pradesh, India; Centre of Research on Himalayan Sustainability and Development, Shoolini University, Post Box 9, Solan, 173212, Himachal Pradesh, India
| | - Neeraj Mahindroo
- School of Pharmaceutical Sciences, Shoolini University, Post Box 9, Solan, 173212, Himachal Pradesh, India; Centre of Research on Himalayan Sustainability and Development, Shoolini University, Post Box 9, Solan, 173212, Himachal Pradesh, India.
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22
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Geis-Asteggiante L, Belew AT, Clements VK, Edwards NJ, Ostrand-Rosenberg S, El-Sayed NM, Fenselau C. Differential Content of Proteins, mRNAs, and miRNAs Suggests that MDSC and Their Exosomes May Mediate Distinct Immune Suppressive Functions. J Proteome Res 2017; 17:486-498. [PMID: 29139296 DOI: 10.1021/acs.jproteome.7b00646] [Citation(s) in RCA: 80] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Myeloid-derived suppressor cells (MDSC) are immature myeloid cells that accumulate in the circulation and the tumor microenvironment of most cancer patients. There, MDSC suppress both adaptive and innate immunity, hindering immunotherapies. The inflammatory milieu often present in cancers facilitates MDSC suppressive activity, causing aggressive tumor progression and metastasis. MDSC from tumor-bearing mice release exosomes, which carry biologically active proteins and mediate some of the immunosuppressive functions characteristic of MDSC. Studies on other cell types have shown that exosomes may also carry RNAs which can be transferred to local and distant cells, yet the mRNA and microRNA cargo of MDSC-derived exosomes has not been studied to date. Here, the cargo of MDSC and their exosomes was interrogated with the goal of identifying and characterizing molecules that may facilitate MDSC suppressive potency. Because inflammation is an established driving force for MDSC suppressive activity, we used the well-established 4T1 mouse mammary carcinoma system, which includes "conventional" as well as "inflammatory" MDSC. We provide evidence that MDSC-derived exosomes carry proteins, mRNAs, and microRNAs with different quantitative profiles than those of their parental cells. Several of these molecules have known or predicted functions consistent with MDSC suppressive activity, suggesting a potential mechanistic redundancy.
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Affiliation(s)
- Lucía Geis-Asteggiante
- Department of Chemistry and Biochemistry, University of Maryland , College Park, Maryland 20742, United States
| | - Ashton T Belew
- Department of Cell Biology and Molecular Genetics and Center for Bioinformatics and Computational Biology, University of Maryland , College Park, Maryland 20742, United States
| | - Virginia K Clements
- Department of Biological Sciences, University of Maryland Baltimore County , Baltimore, Maryland 21250, United States
| | - Nathan J Edwards
- Department of Biochemistry, Molecular and Cellular Biology, Georgetown University Medical Center , Washington, D.C. 20007, United States
| | - Suzanne Ostrand-Rosenberg
- Department of Biological Sciences, University of Maryland Baltimore County , Baltimore, Maryland 21250, United States
| | - Najib M El-Sayed
- Department of Cell Biology and Molecular Genetics and Center for Bioinformatics and Computational Biology, University of Maryland , College Park, Maryland 20742, United States
| | - Catherine Fenselau
- Department of Chemistry and Biochemistry, University of Maryland , College Park, Maryland 20742, United States
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23
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Abstract
Myeloid cells developed evolutionarily as a major mechanism to protect the host. They evolved as a critical barrier against infections and are important contributors to tissue remodeling. However, in cancer, myeloid cells are largely converted to serve a new master-tumor cells. This process is epitomized by myeloid-derived suppressor cells (MDSC). These cells are closely related to neutrophils and monocytes. MDSCs are not present in the steady state of healthy individuals and appear in cancer and in pathologic conditions associated with chronic inflammation or stress. These cells have emerged as an important contributor to tumor progression. Ample evidence supports a key role for MDSCs in immune suppression in cancer, as well as their prominent role in tumor angiogenesis, drug resistance, and promotion of tumor metastases. MDSCs have a fascinating biology and are implicated in limiting the effects of cancer immunotherapy. Therefore, targeting these cells may represent an attractive therapeutic opportunity. Cancer Immunol Res; 5(1); 3-8. ©2016 AACR.
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24
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Li W, Li C, Zhou T, Liu X, Liu X, Li X, Chen D. Role of exosomal proteins in cancer diagnosis. Mol Cancer 2017; 16:145. [PMID: 28851367 PMCID: PMC5576100 DOI: 10.1186/s12943-017-0706-8] [Citation(s) in RCA: 314] [Impact Index Per Article: 39.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Accepted: 08/01/2017] [Indexed: 12/16/2022] Open
Abstract
Exosomes are emerging as a new type of cancer biomarkers. Exosome is a bilayered nano-sized vesicle secreted by various living cells in all body fluids. Based on the expanding albeit incomplete knowledge of their biogenesis, secretion by cells and cancer cell-specific molecular and genetic contents, exosomes are viewed as promising, clinically-relevant surrogates of cancer progression and response to therapy. Preliminary proteomic, genetic and functional profiling of cancer cell-derived or cancer plasma-derived exosomes confirms their unique characteristics. Alterations in protein or nucleic acid profiles of exosomes in plasma correlate with pathological processes of many diseases including cancer. However, previous studies on exosome application in cancer diagnosis and treatment mainly focussed on miRNAs. With the development of rapid large-scale production, purification, extraction and screening of exosomal contents, exosomal protein application can be explored for early stage cancer diagnosis, monitoring and prognosis evaluation. Here, we summarized the recent developments in application of exosomal proteins for cancer diagnosis.
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Affiliation(s)
- Weihua Li
- YouAn Hospital, Capital Medical University, Beijing, China.,Beijing Institute of Hepatology, Beijing, China.,, NO.8, xitoutiao,Youan men wai, Fengtai District, Beijing, China
| | - Chuanyun Li
- YouAn Hospital, Capital Medical University, Beijing, China
| | - Tong Zhou
- Xinjiang Medical University, Wulumuqi, China
| | - Xiuhong Liu
- Beijing Institute of Hepatology, Beijing, China
| | - Xiaoni Liu
- Beijing Institute of Hepatology, Beijing, China
| | - Xiuhui Li
- YouAn Hospital, Capital Medical University, Beijing, China.
| | - Dexi Chen
- Beijing Institute of Hepatology, Beijing, China.
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25
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Choksawangkarn W, Graham LM, Burke M, Lee SB, Ostrand-Rosenberg S, Fenselau C, Edwards NJ. Peptide-based systems analysis of inflammation induced myeloid-derived suppressor cells reveals diverse signaling pathways. Proteomics 2017; 16:1881-8. [PMID: 27193397 DOI: 10.1002/pmic.201500102] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Revised: 05/03/2016] [Accepted: 05/16/2016] [Indexed: 12/19/2022]
Abstract
A better understanding of molecular signaling between myeloid-derived suppressor cells (MDSC), tumor cells, T-cells, and inflammatory mediators is expected to contribute to more effective cancer immunotherapies. We focus on plasma membrane associated proteins, which are critical in signaling and intercellular communication, and investigate changes in their abundance in MDSC of tumor-bearing mice subject to heightened versus basal inflammatory conditions. Using spectral counting, we observed statistically significant differential abundances for 35 proteins associated with the plasma membrane, most notably the pro-inflammatory proteins S100A8 and S100A9 which induce MDSC and promote their migration. We also tested whether the peptides associated with canonical pathways showed a statistically significant increase or decrease subject to heightened versus basal inflammatory conditions. Collectively, these studies used bottom-up proteomic analysis to identify plasma membrane associated pro-inflammatory molecules and pathways that drive MDSC accumulation, migration, and suppressive potency.
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Affiliation(s)
- Waeowalee Choksawangkarn
- Department of Chemistry and Biochemistry, University of Maryland, College Park, MD, USA.,Department of Biochemistry, Faculty of Science, Burapha University, Chonburi, Thailand
| | - Lauren M Graham
- Department of Chemistry and Biochemistry, University of Maryland, College Park, MD, USA
| | - Meghan Burke
- Department of Chemistry and Biochemistry, University of Maryland, College Park, MD, USA
| | - Sang Bok Lee
- Department of Chemistry and Biochemistry, University of Maryland, College Park, MD, USA.,Graduate School of Nanoscience and Technology (WCU), Korea Advanced Institute of Science and Technology, Daejeon, Korea
| | | | - Catherine Fenselau
- Department of Chemistry and Biochemistry, University of Maryland, College Park, MD, USA
| | - Nathan J Edwards
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC, USA
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26
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Leiber A, Schwarz J, Köstlin N, Spring B, Fehrenbach B, Katava N, Poets CF, Gille C. Neonatal myeloid derived suppressor cells show reduced apoptosis and immunosuppressive activity upon infection with Escherichia coli. Eur J Immunol 2017; 47:1009-1021. [PMID: 28493377 DOI: 10.1002/eji.201646621] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Revised: 02/28/2017] [Accepted: 05/05/2017] [Indexed: 11/08/2022]
Abstract
Susceptibility to infection during the neonatal period and reduced control of inflammation in neonates are attributed to immunosuppression persisting from fetal life. Myeloid-derived suppressor cells (MDSCs) are immature myeloid progenitors with suppressive activity and increased numbers in cord blood. We hypothesized that MDSCs contribute to innate host defence in neonates, paralleled by anti-inflammatory signalling.Phagocytic activity, infection induced apoptosis, expression of B-cell lymphoma (Bcl)-2 family proteins, production of reactive oxygen species (ROS), cytokine production and T-cell suppression of neonatal granulocytic-MDSCs (G-MDSCs) after infection with Escherichia coli (E. coli) were compared to neonatal autologous mature polymorphonuclear leukocytes (PMNs). Phagocytic activity of G-MDSCs upon infection with E. coli was equal to that of mature PMNs, however, apoptosis of G-MDSCs was decreased. G-MDSCs showed enhanced Bcl-2-expression and lower ROS production compared to PMNs. Inhibition of Bcl-2 reduced apoptosis rates of G-MDSCs to that of mature PMNs. Induction of anti-inflammatory transforming growth factor beta (TGF-β) was enhanced, while pro-inflammatory IL-8 decreased in G-MDSCs compared to PMNs. Infected G-MDSCs strongly suppressed proliferation of T cells. We show a direct role of G-MDSCs for anti-bacterial host defence. Prolonged survival and anti-inflammatory capacity suggest that G-MDSCs are important for immune-regulation after bacterial infection.
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Affiliation(s)
- Anja Leiber
- Department of Neonatology, University of Tuebingen, Tuebingen, Germany
| | - Julian Schwarz
- Department of Neonatology, University of Tuebingen, Tuebingen, Germany
| | - Natascha Köstlin
- Department of Neonatology, University of Tuebingen, Tuebingen, Germany
| | - Bärbel Spring
- Department of Neonatology, University of Tuebingen, Tuebingen, Germany
| | - Birgit Fehrenbach
- Department of Dermatology, University of Tuebingen, Tuebingen, Germany
| | - Nenad Katava
- Department of Medical Microbiology, University of Tuebingen, Tuebingen, Germany
| | - Christian F Poets
- Department of Neonatology, University of Tuebingen, Tuebingen, Germany
| | - Christian Gille
- Department of Neonatology, University of Tuebingen, Tuebingen, Germany
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27
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Chauhan S, Danielson S, Clements V, Edwards N, Ostrand-Rosenberg S, Fenselau C. Surface Glycoproteins of Exosomes Shed by Myeloid-Derived Suppressor Cells Contribute to Function. J Proteome Res 2017; 16:238-246. [PMID: 27728760 PMCID: PMC6127855 DOI: 10.1021/acs.jproteome.6b00811] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
In this report, we use a proteomic strategy to identify glycoproteins on the surface of exosomes derived from myeloid-derived suppressor cells (MDSCs), and then test if selected glycoproteins contribute to exosome-mediated chemotaxis and migration of MDSCs. We report successful modification of a surface chemistry method for use with exosomes and identify 21 surface N-glycoproteins on exosomes released by mouse mammary carcinoma-induced MDSCs. These glycoprotein identities and functionalities are compared with 93 N-linked glycoproteins identified on the surface of the parental cells. As with the lysate proteomes examined previously, the exosome surface N-glycoproteins are primarily a subset of the glycoproteins on the surface of the suppressor cells that released them, with related functions and related potential as therapeutic targets. The "don't eat me" molecule CD47 and its binding partners thrombospondin-1 (TSP1) and signal regulatory protein α (SIRPα) were among the surface N-glycoproteins detected. Functional bioassays using antibodies to these three molecules demonstrated that CD47, TSP1, and to a lesser extent SIRPα facilitate exosome-mediated MDSC chemotaxis and migration.
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Affiliation(s)
- Sitara Chauhan
- Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, Maryland 21250, United States
| | - Steven Danielson
- Thermo Fisher Scientific, 355 River Oaks Parkway, San Jose, California 95134, United States
| | - Virginia Clements
- Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, Maryland 21250, United States
| | - Nathan Edwards
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, D.C. 20057, United States
| | - Suzanne Ostrand-Rosenberg
- Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, Maryland 21250, United States
| | - Catherine Fenselau
- Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, Maryland 21250, United States
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28
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Abstract
Myeloid cells developed evolutionarily as a major mechanism to protect the host. They evolved as a critical barrier against infections and are important contributors to tissue remodeling. However, in cancer, myeloid cells are largely converted to serve a new master-tumor cells. This process is epitomized by myeloid-derived suppressor cells (MDSC). These cells are closely related to neutrophils and monocytes. MDSCs are not present in the steady state of healthy individuals and appear in cancer and in pathologic conditions associated with chronic inflammation or stress. These cells have emerged as an important contributor to tumor progression. Ample evidence supports a key role for MDSCs in immune suppression in cancer, as well as their prominent role in tumor angiogenesis, drug resistance, and promotion of tumor metastases. MDSCs have a fascinating biology and are implicated in limiting the effects of cancer immunotherapy. Therefore, targeting these cells may represent an attractive therapeutic opportunity. Cancer Immunol Res; 5(1); 3-8. ©2016 AACR.
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29
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Abstract
Myeloid cells developed evolutionarily as a major mechanism to protect the host. They evolved as a critical barrier against infections and are important contributors to tissue remodeling. However, in cancer, myeloid cells are largely converted to serve a new master-tumor cells. This process is epitomized by myeloid-derived suppressor cells (MDSC). These cells are closely related to neutrophils and monocytes. MDSCs are not present in the steady state of healthy individuals and appear in cancer and in pathologic conditions associated with chronic inflammation or stress. These cells have emerged as an important contributor to tumor progression. Ample evidence supports a key role for MDSCs in immune suppression in cancer, as well as their prominent role in tumor angiogenesis, drug resistance, and promotion of tumor metastases. MDSCs have a fascinating biology and are implicated in limiting the effects of cancer immunotherapy. Therefore, targeting these cells may represent an attractive therapeutic opportunity. Cancer Immunol Res; 5(1); 3-8. ©2016 AACR.
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30
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A core of kinase-regulated interactomes defines the neoplastic MDSC lineage. Oncotarget 2016; 6:27160-75. [PMID: 26320174 PMCID: PMC4694980 DOI: 10.18632/oncotarget.4746] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2015] [Accepted: 07/13/2015] [Indexed: 12/17/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) differentiate from bone marrow precursors, expand in cancer-bearing hosts and accelerate tumor progression. MDSCs have become attractive therapeutic targets, as their elimination strongly enhances anti-neoplastic treatments. Here, immature myeloid dendritic cells (DCs), MDSCs modeling tumor-infiltrating subsets or modeling non-cancerous (NC)-MDSCs were compared by in-depth quantitative proteomics. We found that neoplastic MDSCs differentially expressed a core of kinases which controlled lineage-specific (PI3K-AKT and SRC kinases) and cancer-induced (ERK and PKC kinases) protein interaction networks (interactomes). These kinases contributed to some extent to myeloid differentiation. However, only AKT and ERK specifically drove MDSC differentiation from myeloid precursors. Interfering with AKT and ERK with selective small molecule inhibitors or shRNAs selectively hampered MDSC differentiation and viability. Thus, we provide compelling evidence that MDSCs constitute a distinct myeloid lineage distinguished by a “kinase signature” and well-defined interactomes. Our results define new opportunities for the development of anti-cancer treatments targeting these tumor-promoting immune cells.
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31
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Harman MF, Ranocchia RP, Gorlino CV, Sánchez Vallecillo MF, Castell SD, Crespo MI, Maletto BA, Morón G, Pistoresi-Palencia MC. Expansion of myeloid-derived suppressor cells with arginase activity lasts longer in aged than in young mice after CpG-ODN plus IFA treatment. Oncotarget 2016; 6:13448-61. [PMID: 25922914 PMCID: PMC4537026 DOI: 10.18632/oncotarget.3626] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2015] [Accepted: 03/15/2015] [Indexed: 01/19/2023] Open
Abstract
As we age, the homeostatic function of many systems in the body, such as the immune function declines, which in turn contributes to augment susceptibility to disease. Here we describe that challenging aged mice with synthetic oligodeoxynucleotides containing unmethylated cytosine guanine motifs (CpG-ODN) emulsified in incomplete Freund's adjuvant (IFA), (CpG-ODN+IFA) an inflammatory stimulus, led to the expansion of CD11b+Gr1+ myeloid cells with augmented expression of CD124 and CD31. These myeloid cells lasted longer in the spleen of aged mice than in their younger counterparts after CpG-ODN+IFA treatment and were capable of suppressing T cell proliferative response by arginase induction. Myeloid cells from aged CpG-ODN+IFA-treated mice presented increased arginase-1 expression and enzyme activity. In addition, we found a different requirement of cytokines for arginase induction according to mice age. In myeloid cells from young treated mice, arginase-1 expression and activity is induced by the presence of each IL-4 or IL-6 in their extracellular medium, unlike myeloid cells from aged treated mice which need the presence of both IL-4 and IL-6 together for arginase induction and suppressor function.
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Affiliation(s)
- María F Harman
- Centro de Investigación en Bioquímica Clínica e Inmunología, Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Romina P Ranocchia
- Centro de Investigación en Bioquímica Clínica e Inmunología, Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Carolina V Gorlino
- Centro de Investigación en Bioquímica Clínica e Inmunología, Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - María F Sánchez Vallecillo
- Centro de Investigación en Bioquímica Clínica e Inmunología, Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Sofía D Castell
- Centro de Investigación en Bioquímica Clínica e Inmunología, Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - María I Crespo
- Centro de Investigación en Bioquímica Clínica e Inmunología, Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Belkys A Maletto
- Centro de Investigación en Bioquímica Clínica e Inmunología, Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Gabriel Morón
- Centro de Investigación en Bioquímica Clínica e Inmunología, Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - María C Pistoresi-Palencia
- Centro de Investigación en Bioquímica Clínica e Inmunología, Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
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32
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Beury DW, Carter KA, Nelson C, Sinha P, Hanson E, Nyandjo M, Fitzgerald PJ, Majeed A, Wali N, Ostrand-Rosenberg S. Myeloid-Derived Suppressor Cell Survival and Function Are Regulated by the Transcription Factor Nrf2. THE JOURNAL OF IMMUNOLOGY 2016; 196:3470-8. [PMID: 26936880 DOI: 10.4049/jimmunol.1501785] [Citation(s) in RCA: 91] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/06/2015] [Accepted: 02/06/2016] [Indexed: 12/30/2022]
Abstract
Tumor-induced myeloid-derived suppressor cells (MDSC) contribute to immune suppression in tumor-bearing individuals and are a major obstacle to effective immunotherapy. Reactive oxygen species (ROS) are one of the mechanisms used by MDSC to suppress T cell activation. Although ROS are toxic to most cells, MDSC survive despite their elevated content and release of ROS. NF erythroid 2-related factor 2 (Nrf2) is a transcription factor that regulates a battery of genes that attenuate oxidative stress. Therefore, we hypothesized that MDSC resistance to ROS may be regulated by Nrf2. To test this hypothesis, we used Nrf2(+/+)and Nrf2(-/-)BALB/c and C57BL/6 mice bearing 4T1 mammary carcinoma and MC38 colon carcinoma, respectively. Nrf2 enhanced MDSC suppressive activity by increasing MDSC production of H2O2, and it increased the quantity of tumor-infiltrating MDSC by reducing their oxidative stress and rate of apoptosis. Nrf2 did not affect circulating levels of MDSC in tumor-bearing mice because the decreased apoptotic rate of tumor-infiltrating MDSC was balanced by a decreased rate of differentiation from bone marrow progenitor cells. These results demonstrate that Nrf2 regulates the generation, survival, and suppressive potency of MDSC, and that a feedback homeostatic mechanism maintains a steady-state level of circulating MDSC in tumor-bearing individuals.
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Affiliation(s)
- Daniel W Beury
- Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD 21250
| | - Kayla A Carter
- Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD 21250
| | - Cassandra Nelson
- Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD 21250
| | - Pratima Sinha
- Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD 21250
| | - Erica Hanson
- Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD 21250
| | - Maeva Nyandjo
- Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD 21250
| | - Phillip J Fitzgerald
- Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD 21250
| | - Amry Majeed
- Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD 21250
| | - Neha Wali
- Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD 21250
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Parker KH, Horn LA, Ostrand-Rosenberg S. High-mobility group box protein 1 promotes the survival of myeloid-derived suppressor cells by inducing autophagy. J Leukoc Biol 2016; 100:463-70. [PMID: 26864266 DOI: 10.1189/jlb.3hi0715-305r] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2015] [Accepted: 01/18/2016] [Indexed: 12/19/2022] Open
Abstract
Myeloid-derived suppressor cells are immune-suppressive cells that are elevated in most individuals with cancer, where their accumulation and suppressive activity are driven by inflammation. As myeloid-derived suppressor cells inhibit anti-tumor immunity and promote tumor progression, we are determining how their viability is regulated. Previous studies have established that the damage-associated molecular pattern molecule high-mobility group box protein 1 drives myeloid-derived suppressor cell accumulation and suppressive potency and is ubiquitously present in the tumor microenvironment. As high-mobility group box protein 1 also facilitates tumor cell survival by inducing autophagy, we sought to determine if high-mobility group box protein 1 regulates myeloid-derived suppressor cell survival through induction of autophagy. Inhibition of autophagy increased the quantity of apoptotic myeloid-derived suppressor cells, demonstrating that autophagy extends the survival and increases the viability of myeloid-derived suppressor cells. Inhibition of high-mobility group box protein 1 similarly increased the level of apoptotic myeloid-derived suppressor cells and reduced myeloid-derived suppressor cell autophagy, demonstrating that in addition to inducing the accumulation of myeloid-derived suppressor cells, high-mobility group box protein 1 sustains myeloid-derived suppressor cell viability. Circulating myeloid-derived suppressor cells have a default autophagic phenotype, and tumor-infiltrating myeloid-derived suppressor cells are more autophagic, consistent with the concept that inflammatory and hypoxic conditions within the microenvironment of solid tumors contribute to tumor progression by enhancing immune-suppressive myeloid-derived suppressor cells. Overall, these results demonstrate that in addition to previously recognized protumor effects, high-mobility group box protein 1 contributes to tumor progression by increasing myeloid-derived suppressor cell viability by driving them into a proautophagic state.
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Affiliation(s)
- Katherine H Parker
- Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, Maryland, USA
| | - Lucas A Horn
- Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, Maryland, USA
| | - Suzanne Ostrand-Rosenberg
- Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, Maryland, USA
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34
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Gato M, Blanco-Luquin I, Zudaire M, de Morentin XM, Perez-Valderrama E, Zabaleta A, Kochan G, Escors D, Fernandez-Irigoyen J, Santamaría E. Drafting the proteome landscape of myeloid-derived suppressor cells. Proteomics 2015; 16:367-78. [PMID: 26403437 DOI: 10.1002/pmic.201500229] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2015] [Revised: 08/18/2015] [Accepted: 09/21/2015] [Indexed: 01/12/2023]
Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that are defined by their myeloid origin, immature state, and ability to potently suppress T-cell responses. They regulate immune responses and the population significantly increases in the tumor microenvironment of patients with glioma and other malignant tumors. For their study, MDSCs are usually isolated from the spleen or directly of tumors from a large number of tumor-bearing mice although promising ex vivo differentiated MDSC production systems have been recently developed. During the last years, proteomics has emerged as a powerful approach to analyze MDSCs proteomes using shotgun-based mass spectrometry (MS), providing functional information about cellular homeostasis and metabolic state at a global level. Here, we will revise recent proteome profiling studies performed in MDSCs from different origins. Moreover, we will perform an integrative functional analysis of the protein compilation derived from these large-scale proteomic studies in order to obtain a comprehensive view of MDSCs biology. Finally, we will also discuss the potential application of high-throughput proteomic approaches to study global proteome dynamics and post-translational modifications (PTMs) during the differentiation process of MDSCs that will greatly boost the identification of novel MDSC-specific therapeutic targets to apply in cancer immunotherapy.
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Affiliation(s)
- María Gato
- Immunomodulation Laboratory, Navarrabiomed, Fundación Miguel Servet, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
| | - Idoia Blanco-Luquin
- Immunomodulation Laboratory, Navarrabiomed, Fundación Miguel Servet, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
| | - Maribel Zudaire
- Immunomodulation Laboratory, Navarrabiomed, Fundación Miguel Servet, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
| | - Xabier Martínez de Morentin
- Proteomics Unit, Navarrabiomed, Fundación Miguel Servet, ProteoRed-ISCIII, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
| | - Estela Perez-Valderrama
- Proteomics Unit, Navarrabiomed, Fundación Miguel Servet, ProteoRed-ISCIII, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
| | - Aintzane Zabaleta
- Biofunctional Nanomaterials Laboratory, CIC Biomagune, San Sebastian, Spain
| | - Grazyna Kochan
- Immunomodulation Laboratory, Navarrabiomed, Fundación Miguel Servet, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
| | - David Escors
- Immunomodulation Laboratory, Navarrabiomed, Fundación Miguel Servet, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
| | - Joaquín Fernandez-Irigoyen
- Proteomics Unit, Navarrabiomed, Fundación Miguel Servet, ProteoRed-ISCIII, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
| | - Enrique Santamaría
- Proteomics Unit, Navarrabiomed, Fundación Miguel Servet, ProteoRed-ISCIII, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
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35
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Ostrand-Rosenberg S. Tolerance and immune suppression in the tumor microenvironment. Cell Immunol 2015; 299:23-9. [PMID: 26435343 DOI: 10.1016/j.cellimm.2015.09.011] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2015] [Revised: 09/27/2015] [Accepted: 09/27/2015] [Indexed: 12/27/2022]
Abstract
The concept of immunological tolerance has guided and permeated much of modern immunology. Ray Owen's ground-breaking observations in twin cattle provided the first mechanistic explanation for tolerance to self-molecules and established tolerance as a beneficial process that protects the host against autoreactivity. However, his studies also opened the door to understanding that tolerance may be detrimental, such as occurs when cancer cells induce tolerance/immune suppression resulting in inhibition of anti-tumor immunity. This article briefly traces the early history of the field of tumor immunology with respect to tolerance, and then focuses on a relatively recently identified population of cells called myeloid-derived suppressor cells (MDSCs). MDSC are instrumental in causing tolerance/immune suppression in individuals with cancer. They are present in most individuals with cancer and because of their potent immune suppressive activity are a major deterrent to natural anti-tumor immunity and a significant obstacle to immunotherapy.
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Affiliation(s)
- Suzanne Ostrand-Rosenberg
- Dept. of Biological Sciences, University of Maryland Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, United States.
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36
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Marvel D, Gabrilovich DI. Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected. J Clin Invest 2015; 125:3356-64. [PMID: 26168215 DOI: 10.1172/jci80005] [Citation(s) in RCA: 813] [Impact Index Per Article: 81.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Our understanding of the role of myeloid-derived suppressor cells (MDSCs) in cancer is becoming increasingly complex. In addition to their eponymous role in suppressing immune responses, they directly support tumor growth, differentiation, and metastasis in a number of ways that are only now beginning to be appreciated. It is because of this increasingly complex role that these cells may become an important factor in the treatment of human cancer. In this Review, we discuss the most pertinent and controversial issues of MDSC biology and their role in promoting cancer progression and highlight how these cells may be used in the clinic, both as prognostic factors and as therapeutic targets.
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37
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Parker KH, Beury DW, Ostrand-Rosenberg S. Myeloid-Derived Suppressor Cells: Critical Cells Driving Immune Suppression in the Tumor Microenvironment. Adv Cancer Res 2015. [PMID: 26216631 DOI: 10.1016/bs.acr.2015.04.002] [Citation(s) in RCA: 395] [Impact Index Per Article: 39.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that suppress innate and adaptive immunity. MDSCs are present in many disease settings; however, in cancer, they are a major obstacle for both natural antitumor immunity and immunotherapy. Tumor and host cells in the tumor microenvironment (TME) produce a myriad of pro-inflammatory mediators that activate MDSCs and drive their accumulation and suppressive activity. MDSCs utilize a variety of mechanisms to suppress T cell activation, induce other immune-suppressive cell populations, regulate inflammation in the TME, and promote the switching of the immune system to one that tolerates and enhances tumor growth. Because MDSCs are present in most cancer patients and are potent immune-suppressive cells, MDSCs have been the focus of intense research in recent years. This review describes the history and identification of MDSCs, the role of inflammation and intracellular signaling events governing MDSC accumulation and suppressive activity, immune-suppressive mechanisms utilized by MDSCs, and recent therapeutics that target MDSCs to enhance antitumor immunity.
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Affiliation(s)
- Katherine H Parker
- Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, Maryland, USA
| | - Daniel W Beury
- Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, Maryland, USA
| | - Suzanne Ostrand-Rosenberg
- Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, Maryland, USA.
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Geis-Asteggiante L, Dhabaria A, Edwards N, Ostrand-Rosenberg S, Fenselau C. Top-down analysis of low mass proteins in exosomes shed by murine myeloid-derived suppressor cells. INTERNATIONAL JOURNAL OF MASS SPECTROMETRY 2015; 378:264-269. [PMID: 25937807 PMCID: PMC4413943 DOI: 10.1016/j.ijms.2014.08.035] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
Top-down analysis is reported for a portion of the protein cargo of exosomes shed by myeloid-derived suppressor cells that participate in intracellular signaling in the tumor microenvironment. Instrument mass resolution limited the study to proteins of molecular masses below 30 kDa. A two-step fractionation strategy was used, including open tubular gel electrophoresis and C3 reverse phase high performance liquid chromatography. Twenty-one unique proteins were identified among more than 200 proteoforms, and comprising primarily two functionally important protein families: the S100 proinflammatory mediators and an abundance of histones. Fifty-six percent of the total protein in these exosomes was determined to comprise histones, of which H2B variants contribute 42 %.
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Affiliation(s)
| | | | - Nathan Edwards
- Georgetown University Medical Center, Washington, D.C. 20057. United States
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Novel and enhanced anti-melanoma DNA vaccine targeting the tyrosinase protein inhibits myeloid-derived suppressor cells and tumor growth in a syngeneic prophylactic and therapeutic murine model. Cancer Gene Ther 2014; 21:507-17. [DOI: 10.1038/cgt.2014.56] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2014] [Accepted: 09/30/2014] [Indexed: 12/29/2022]
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Solito S, Marigo I, Pinton L, Damuzzo V, Mandruzzato S, Bronte V. Myeloid-derived suppressor cell heterogeneity in human cancers. Ann N Y Acad Sci 2014; 1319:47-65. [DOI: 10.1111/nyas.12469] [Citation(s) in RCA: 302] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Samantha Solito
- Department of Surgery; Oncology and Gastroenterology; Oncology and Immunology Section; University of Padova; Padova Italy
| | | | - Laura Pinton
- Department of Surgery; Oncology and Gastroenterology; Oncology and Immunology Section; University of Padova; Padova Italy
| | - Vera Damuzzo
- Department of Surgery; Oncology and Gastroenterology; Oncology and Immunology Section; University of Padova; Padova Italy
| | - Susanna Mandruzzato
- Department of Surgery; Oncology and Gastroenterology; Oncology and Immunology Section; University of Padova; Padova Italy
- Istituto Oncologico Veneto; IOV-IRCCS; Padova Italy
| | - Vincenzo Bronte
- Pathology and Diagnostics; Verona University Hospital; Verona Italy
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Weiss JM, Subleski JJ, Back T, Chen X, Watkins SK, Yagita H, Sayers TJ, Murphy WJ, Wiltrout RH. Regulatory T cells and myeloid-derived suppressor cells in the tumor microenvironment undergo Fas-dependent cell death during IL-2/αCD40 therapy. THE JOURNAL OF IMMUNOLOGY 2014; 192:5821-9. [PMID: 24808361 DOI: 10.4049/jimmunol.1400404] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Fas ligand expression in certain tumors has been proposed to contribute to immunosuppression and poor prognosis. However, immunotherapeutic approaches may elicit the Fas-mediated elimination of immunosuppressive regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) within tumors that represent major obstacles for cancer immunotherapy. Previously, we showed that IL-2 and agonistic CD40 Ab (αCD40) elicited synergistic antitumor responses coincident with the efficient removal of Tregs and MDSCs. We demonstrate in this study in two murine tumor models that Treg and MDSC loss within the tumor microenvironment after IL-2/αCD40 occurs through a Fas-dependent cell death pathway. Among tumor-infiltrating leukocytes, CD8(+) T cells, neutrophils, and immature myeloid cells expressed Fas ligand after treatment. Fas was expressed by tumor-associated Tregs and immature myeloid cells, including MDSCs. Tregs and MDSCs in the tumor microenvironment expressed active caspases after IL-2/αCD40 therapy and, in contrast with effector T cells, Tregs significantly downregulated Bcl-2 expression. In contrast, Tregs and MDSCs proliferated and expanded in the spleen after treatment. Adoptive transfer of Fas-deficient Tregs or MDSCs into wild-type, Treg-, or MDSC-depleted hosts resulted in the persistence of Tregs or MDSCs and the loss of antitumor efficacy in response to IL-2/αCD40. These results demonstrate the importance of Fas-mediated Treg/MDSC removal for successful antitumor immunotherapy. Our results suggest that immunotherapeutic strategies that include exploiting Treg and MDSC susceptibility to Fas-mediated apoptosis hold promise for treatment of cancer.
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Affiliation(s)
- Jonathan M Weiss
- Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702
| | - Jeff J Subleski
- Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702
| | - Tim Back
- Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702
| | - Xin Chen
- Basic Science Program, Leidos Biomedical Research, Inc., Frederick, MD 21702
| | | | - Hideo Yagita
- Department of Immunology, Juntendo University School of Medicine, Tokyo 113-8421, Japan; and
| | - Thomas J Sayers
- Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702
| | - William J Murphy
- Department of Dermatology, University of California, Davis, Sacramento, CA 95816
| | - Robert H Wiltrout
- Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702;
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Condamine T, Kumar V, Ramachandran IR, Youn JI, Celis E, Finnberg N, El-Deiry WS, Winograd R, Vonderheide RH, English NR, Knight SC, Yagita H, McCaffrey JC, Antonia S, Hockstein N, Witt R, Masters G, Bauer T, Gabrilovich DI. ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R-mediated apoptosis. J Clin Invest 2014; 124:2626-39. [PMID: 24789911 DOI: 10.1172/jci74056] [Citation(s) in RCA: 303] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) dampen the immune response thorough inhibition of T cell activation and proliferation and often are expanded in pathological conditions. Here, we studied the fate of MDSCs in cancer. Unexpectedly, MDSCs had lower viability and a shorter half-life in tumor-bearing mice compared with neutrophils and monocytes. The reduction of MDSC viability was due to increased apoptosis, which was mediated by increased expression of TNF-related apoptosis-induced ligand receptors (TRAIL-Rs) in these cells. Targeting TRAIL-Rs in naive mice did not affect myeloid cell populations, but it dramatically reduced the presence of MDSCs and improved immune responses in tumor-bearing mice. Treatment of myeloid cells with proinflammatory cytokines did not affect TRAIL-R expression; however, induction of ER stress in myeloid cells recapitulated changes in TRAIL-R expression observed in tumor-bearing hosts. The ER stress response was detected in MDSCs isolated from cancer patients and tumor-bearing mice, but not in control neutrophils or monocytes, and blockade of ER stress abrogated tumor-associated changes in TRAIL-Rs. Together, these data indicate that MDSC pathophysiology is linked to ER stress, which shortens the lifespan of these cells in the periphery and promotes expansion in BM. Furthermore, TRAIL-Rs can be considered as potential targets for selectively inhibiting MDSCs.
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Altevogt P, Bretz NP, Ridinger J, Utikal J, Umansky V. Novel insights into exosome-induced, tumor-associated inflammation and immunomodulation. Semin Cancer Biol 2014; 28:51-7. [PMID: 24769223 DOI: 10.1016/j.semcancer.2014.04.008] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2014] [Accepted: 04/09/2014] [Indexed: 12/13/2022]
Abstract
The immune system of cancer patients is often suppressed. Accumulating evidence suggests that exosomes released from tumor cells may play an essential role in this process but the mechanisms are not fully understood. Here we review recent papers showing that exosomes trigger the release of cytokines/chemokines from immune cells. We suggest that this process will either result in the stimulation of anti-tumor immune reactions or in a systemic immunosuppression. The direction appears to be largely dependent on the duration of interactions between immune cells and exosomes leading to the accumulation of inflammatory factors, i.e. on the length of the exposure to these factors. We propose that a long-term interaction of the immune system with elevated levels of tumor exosomes contributes to the development of immunosuppression in cancer patients.
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Affiliation(s)
- Peter Altevogt
- Translational Immunology, D015, German Cancer Research Center, DKFZ, 69120 Heidelberg, Germany.
| | - Niko P Bretz
- Translational Immunology, D015, German Cancer Research Center, DKFZ, 69120 Heidelberg, Germany
| | - Johannes Ridinger
- Translational Immunology, D015, German Cancer Research Center, DKFZ, 69120 Heidelberg, Germany; Skin Cancer Unit, German Cancer Research Center DKFZ, Heidelberg, Germany; Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, 69120 Heidelberg, Germany
| | - Jochen Utikal
- Skin Cancer Unit, German Cancer Research Center DKFZ, Heidelberg, Germany; Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, 69120 Heidelberg, Germany
| | - Viktor Umansky
- Skin Cancer Unit, German Cancer Research Center DKFZ, Heidelberg, Germany; Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, 69120 Heidelberg, Germany
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Hanash S, Schliekelman M. Proteomic profiling of the tumor microenvironment: recent insights and the search for biomarkers. Genome Med 2014; 6:12. [PMID: 24713112 PMCID: PMC3978437 DOI: 10.1186/gm529] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Although gain of oncogene functions and loss of tumor suppressor functions are driving forces in tumor development, the tumor microenvironment, comprising the extracellular matrix, surrounding stroma, signaling molecules and infiltrating immune and other cell populations, is now also recognized as crucial to tumor development and metastasis. Many interactions at the tumor cell-environment interface occur at the protein level. Proteomic approaches are contributing to the definition of the protein constituents of the microenvironment and their sources, modifications, interactions and turnover, as well as providing information on how these features relate to tumor development and progression. Recently, proteomic studies have revealed how cancer cells modulate the microenvironment through their secreted proteins and how they can alter their protein constituents to adapt to the microenvironment. Moreover, the release of proteins from the microenvironment into the circulatory system has relevance for the development of blood-based cancer diagnostics. Here, we review how proteomic approaches are being applied to studies of the tumor microenvironment to decipher tumor-stroma interactions and to elucidate the role of host cells in the tumor microenvironment.
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Kalantari S, Rutishauser D, Samavat S, Nafar M, Mahmudieh L, Rezaei-Tavirani M, Zubarev RA. Urinary prognostic biomarkers and classification of IgA nephropathy by high resolution mass spectrometry coupled with liquid chromatography. PLoS One 2013; 8:e80830. [PMID: 24339887 PMCID: PMC3855054 DOI: 10.1371/journal.pone.0080830] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2013] [Accepted: 10/16/2013] [Indexed: 12/15/2022] Open
Abstract
IgA nephropathy is the most common cause of primary glomerulonephritis. There are different pathologic biopsy-based scoring systems in use, but there is no consensus among nephrologists yet regarding the best classification method. Our aim was to test urine proteomics as a non-invasive method for classification of IgA nephropathy. This aim was pursued by discovering novel prognostic protein biomarkers in urine, and linking them to pathogenesis of the disease through known signaling and metabolic pathways. 13 urine samples of the patients with biopsy-proven IgA nephropathy were analyzed via two proteomics approaches: nanoflow LC-MS/MS and GeLC-MS/MS. The results of label-free quantification were subjected to multivariate statistical analysis, which could classify patients into two groups, broadly corresponding to the primary and advance stages. The proteome classification correlated well with biopsy-based scoring systems, especially endocapillary hypercellularity score of the Oxford’s classification. Differentially excreted candidate proteins were found as potential prognostic biomarkers: afamin, leucine-rich alpha-2-glycoprotein, ceruloplasmin, alpha-1-microgolbulin, hemopexin, apolipoprotein A-I, complement C3, vitamin D-binding protein, beta-2-microglobulin, and retinol-binding protein 4. Pathway analysis suggested impairment of Extra Cellular Matrix (ECM)-Receptor Interaction pathways as well as activation of complement and coagulation pathway in progression of IgA nephropathy.
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Affiliation(s)
- Shiva Kalantari
- Department of Basic Science, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Dorothea Rutishauser
- Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
- SciLifeLab, Stockholm, Sweden
| | - Shiva Samavat
- Department of Nephrology, Shahid Labbafinejad Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohsen Nafar
- Department of Nephrology, Shahid Labbafinejad Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Leyla Mahmudieh
- Department of Nephrology, Shahid Labbafinejad Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mostafa Rezaei-Tavirani
- Proteomics Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Roman A. Zubarev
- Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
- SciLifeLab, Stockholm, Sweden
- * E-mail:
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Abstract
Tumour-induced granulocytic hyperplasia is associated with tumour vasculogenesis and escape from immunity via T cell suppression. Initially, these myeloid cells were identified as granulocytes or monocytes; however, recent studies have revealed that this hyperplasia is associated with populations of multipotent progenitor cells that have been identified as myeloid-derived suppressor cells (MDSCs). The study of MDSCs has provided a wealth of information regarding tumour pathobiology, has extended our understanding of neoplastic progression and has modified our approaches to immune adjuvant therapy. In this Timeline article, we discuss the history of MDSCs, their influence on tumour progression and metastasis, and the crosstalk between tumour cells, MDSCs and the host macroenvironment.
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Affiliation(s)
- James E Talmadge
- University of Nebraska Medical Center, Department of Pathology and Microbiology, 986495 Nebraska Medical Center, Omaha NE 68198-6495, USA
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Sarkar J, Chaudhary S, Jassim SH, Ozturk O, Chamon W, Ganesh B, Tibrewal S, Gandhi S, Byun YS, Hallak J, Mahmud DL, Mahmud N, Rondelli D, Jain S. CD11b+GR1+ myeloid cells secrete NGF and promote trigeminal ganglion neurite growth: implications for corneal nerve regeneration. Invest Ophthalmol Vis Sci 2013; 54:5920-36. [PMID: 23942970 DOI: 10.1167/iovs.13-12237] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
PURPOSE We characterized fluorescent bone marrow cells (YFP(+) BMCs) in the thy1-YFP mouse and determine if they promote trigeminal ganglion (TG) cell neurite growth. METHODS Excimer laser annular keratectomy was performed in thy1-YFP mice, and corneas were imaged. BMCs were harvested from femur and tibia, and the expression of surface markers on YFP(+) BMCs was analyzed by flow cytometry. The immunosuppressive action of BMCs (YFP(+) and YFP(-)) was evaluated in an allogenic mixed lymphocyte reaction (MLR). Neurotrophic action of BMCs (YFP(+) and YFP(-)) was determined in compartmental and transwell cultures of dissociated TG cells. RESULTS Following annular keratectomy, YFP(+) BMCs infiltrated the cornea. YFP(+) BMCs shared surface markers (CD11b+Gr1+Ly6C+Ly6G-F4/80(low)) with monocytic myeloid-derived suppressor cells (MDSCs), had similar morphology, and suppressed T-cell proliferation in allogenic MLR in a dose-dependent manner. YFP(+) BMCs, but not YFP(-) BMCs, significantly increased growth of TG neurites in vitro. When cultured in a transwell with TG neurites, YFP(+) BMCs expressed neurotrophins and secreted nerve growth factor (NGF) in conditioned medium. YFP(+) BMCs that infiltrated the cornea maintained their phenotype and actions (neuronal and immune). CONCLUSIONS YFP(+) BMCs in thy1-YFP mice have immunophenotypic features of MDSCs. They secrete NGF and promote neuroregeneration. Their immunosuppressive and neurotrophic actions are preserved after corneal infiltration. These findings increase our understanding of the beneficial roles played by leukocyte trafficking in the cornea and may lead to therapeutic strategies that use NGF-secreting myeloid cells to repair diseased or injured neurons.
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Affiliation(s)
- Joy Sarkar
- Corneal Neurobiology Laboratory, Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, College of Medicine, Chicago, Illinois, USA
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Zheng Y, Xu M, Li X, Jia J, Fan K, Lai G. Cimetidine suppresses lung tumor growth in mice through proapoptosis of myeloid-derived suppressor cells. Mol Immunol 2013; 54:74-83. [DOI: 10.1016/j.molimm.2012.10.035] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2012] [Revised: 09/18/2012] [Accepted: 10/12/2012] [Indexed: 11/27/2022]
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Umansky V, Sevko A. Tumor microenvironment and myeloid-derived suppressor cells. CANCER MICROENVIRONMENT 2012; 6:169-77. [PMID: 23242672 DOI: 10.1007/s12307-012-0126-7] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 10/31/2012] [Accepted: 11/14/2012] [Indexed: 01/04/2023]
Abstract
Tumor progression has been demonstrated to be supported by chronic inflammatory conditions developed in the tumor microenvironment and characterized by the long-term secretion of various inflammatory soluble factors (including cytokines, chemokines, growth factors, reactive oxygen and nitrogen species, prostaglandins etc.) and strong leukocyte infiltration. Among leukocytes infiltrating tumors, myeloid-derived suppressor cells (MDSCs) represent one of the most important players mediating immunosuppression. These cells may not only strongly inhibit an anti-tumor immune reactions mediated by T cells but also directly stimulate tumorigenesis, tumor growth and metastasis by enhancing neoangiogenesis and creating a suitable environment for the metastatic formation. This review provides an overview of interactions between MDSCs and tumor cells leading to MDSC generation, activation and migration to the tumor site, where they can strongly enhance tumor progression. Better understanding of the MDSC-tumor interplay is critical for the development of new strategies of tumor immunotherapy.
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Affiliation(s)
- Viktor Umansky
- Skin Cancer Unit, German Cancer Research Center, 69120, Heidelberg, Germany,
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50
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Sevko A, Umansky V. Myeloid-derived suppressor cells interact with tumors in terms of myelopoiesis, tumorigenesis and immunosuppression: thick as thieves. J Cancer 2012; 4:3-11. [PMID: 23386900 PMCID: PMC3564242 DOI: 10.7150/jca.5047] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2012] [Accepted: 11/20/2012] [Indexed: 12/20/2022] Open
Abstract
Tumor progression is often associated with chronic inflammation in the tumor microenvironment, which is mediated by numerous cytokines, chemokines and growth factors produced by cancer and stroma cells. All these mediators support tumor development and immunosuppression in autocrine and/or paracrine ways. Neutralization of chronic inflammatory conditions can lead to the restoration of anti-tumor immune responses. Among stroma cells infiltrating tumors, myeloid-derived suppressor cells (MDSCs) represent one of the most important players mediating immunosuppression. These cells may not only inhibit an anti-tumor immunity but also directly stimulate tumorigenesis as well as tumor growth and expansion. Therefore, understanding the mechanisms of generation, migration to the tumor site and activation of MDSC is necessary for the development of new strategies of tumor immunotherapy.
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Affiliation(s)
- Alexandra Sevko
- Skin Cancer Unit, German Cancer Research Center, Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, 69120 Heidelberg, Germany
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