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Liu S, Wang M, Xu L, Deng D, Lu L, Tian J, Zhou D, Rui K. New insight into the role of SOCS family in immune regulation and autoimmune pathogenesis. J Adv Res 2025:S2090-1232(25)00313-3. [PMID: 40349956 DOI: 10.1016/j.jare.2025.05.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 04/07/2025] [Accepted: 05/08/2025] [Indexed: 05/14/2025] Open
Abstract
BACKGROUND Suppressor of cytokine signaling (SOCS) proteins regulate signal transduction by interacting with cytokine receptors and signaling proteins and targeting associated proteins for degradation. Recent studies have demonstrated that the SOCS proteins serve as crucial inhibitors in cytokine signaling networks and play a pivotal role in both innate and adaptive immune responses. AIM OF REVIEW In this review, we aim to discuss recent advancements in understanding the complex functions of SOCS proteins in various immune cells, as well as the effects of SOCS proteins in human health and diseases. Increasing evidence indicates that SOCS proteins are frequently dysregulated in developing autoimmune diseases, suggesting that therapeutic targeting of SOCS proteins could provide clinical benefit. KEY SCIENTIFIC CONCEPTS OF REVIEW This review provides a comprehensive understanding of SOCS proteins in immune regulation and autoimmune pathogenesis, it also highlights the role of SOCS-related mimetic peptides in immunotherapy.
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Affiliation(s)
- Shiyi Liu
- Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China; Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Mingwei Wang
- Department of Emergency, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Liangjie Xu
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Daihua Deng
- Department of Rheumatology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Liwei Lu
- Department of Pathology and Shenzhen Institute of Research and Innovation, The University of Hong Kong, Chongqing International Institute for Immunology, China
| | - Jie Tian
- Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China.
| | - Dongmei Zhou
- Department of Rheumatology and Immunology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
| | - Ke Rui
- Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China.
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2
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Ramadan YN, Kamel AM, Medhat MA, Hetta HF. MicroRNA signatures in the pathogenesis and therapy of inflammatory bowel disease. Clin Exp Med 2024; 24:217. [PMID: 39259390 PMCID: PMC11390904 DOI: 10.1007/s10238-024-01476-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 08/20/2024] [Indexed: 09/13/2024]
Abstract
Inflammatory bowel disease (IBD) is a persistent inflammatory illness of the gastrointestinal tract (GIT) triggered by an inappropriate immune response to environmental stimuli in genetically predisposed persons. Unfortunately, IBD patients' quality of life is negatively impacted by the symptoms associated with the disease. The exact etiology of IBD pathogenesis is not fully understood, but the emerging research indicated that the microRNA (miRNA) plays an important role. miRNAs have been documented to possess a significant role in regulating pro- and anti-inflammatory pathways, in addition to their roles in several physiological processes, including cell growth, proliferation, and apoptosis. Variations in the miRNA profiles might be a helpful prognostic indicator and a valuable tool in the differential diagnosis of IBD. Most interestingly, these miRNAs have a promising therapeutic target in several pre-clinical animal studies and phase 2 clinical studies to alleviate inflammation and improve patient's quality of life. This comprehensive review discusses the current knowledge about the significant physiological role of different miRNAs in the health of the intestinal immune system and addresses the role of the most relevant differentially expressed miRNAs in IBD, identify their potential targets, and emphasize their diagnostic and therapeutic potential for future research.
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Affiliation(s)
- Yasmin N Ramadan
- Department of Microbiology and Immunology, Faculty of Pharmacy, Assiut University, Assiut, 71515, Egypt.
| | - Ayat M Kamel
- Department of Microbiology and Immunology, Faculty of Pharmacy, Assiut University, Assiut, 71515, Egypt
| | - Mohammed A Medhat
- Tropical Medicine and Gastroenterology Department, Faculty of Medicine, Assiut University, Assiut, 71515, Egypt
| | - Helal F Hetta
- Division of Microbiology, Immunology and Biotechnology, Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, University of Tabuk, 71491, Tabuk, Saudi Arabia
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3
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Bidgood GM, Keating N, Doggett K, Nicholson SE. SOCS1 is a critical checkpoint in immune homeostasis, inflammation and tumor immunity. Front Immunol 2024; 15:1419951. [PMID: 38947335 PMCID: PMC11211259 DOI: 10.3389/fimmu.2024.1419951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 05/28/2024] [Indexed: 07/02/2024] Open
Abstract
The Suppressor of Cytokine Signaling (SOCS) family proteins are important negative regulators of cytokine signaling. SOCS1 is the prototypical member of the SOCS family and functions in a classic negative-feedback loop to inhibit signaling in response to interferon, interleukin-12 and interleukin-2 family cytokines. These cytokines have a critical role in orchestrating our immune defence against viral pathogens and cancer. The ability of SOCS1 to limit cytokine signaling positions it as an important immune checkpoint, as evidenced by the detection of detrimental SOCS1 variants in patients with cytokine-driven inflammatory and autoimmune disease. SOCS1 has also emerged as a key checkpoint that restricts anti-tumor immunity, playing both a tumor intrinsic role and impacting the ability of various immune cells to mount an effective anti-tumor response. In this review, we describe the mechanism of SOCS1 action, focusing on the role of SOCS1 in autoimmunity and cancer, and discuss the potential for new SOCS1-directed cancer therapies that could be used to enhance adoptive immunotherapy and immune checkpoint blockade.
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Affiliation(s)
- Grace M. Bidgood
- Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia
| | - Narelle Keating
- Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia
| | - Karen Doggett
- Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia
| | - Sandra E. Nicholson
- Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia
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Poirier A, Tremblay ML. Pharmacological potentiation of monocyte-derived dendritic cell cancer immunotherapy. Cancer Immunol Immunother 2022; 72:1343-1353. [DOI: 10.1007/s00262-022-03333-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 11/16/2022] [Indexed: 11/29/2022]
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Ding J, Zheng Y, Wang G, Zheng J, Chai D. The performance and perspectives of dendritic cell vaccines modified by immune checkpoint inhibitors or stimulants. Biochim Biophys Acta Rev Cancer 2022; 1877:188763. [PMID: 35872287 DOI: 10.1016/j.bbcan.2022.188763] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 07/05/2022] [Accepted: 07/18/2022] [Indexed: 11/30/2022]
Abstract
Therapeutic dendritic cell (DC) vaccines stimulate the elimination of tumor cells by the immune system. However, while antigen-specific T cell responses induced by DC vaccines are commonly observed, the clinical response rate is relatively poor, necessitating vaccine optimization. There is evidence that the suppression of DC function by immune checkpoints hinders the anti-tumor immune responses mediated by DC vaccines, ultimately leading to the immune escape of the tumor cells. The use of immune checkpoint inhibitors (ICIs) and immune checkpoint activators (ICAs) has extended the immunotherapeutic range. It is known that both inhibitory and stimulatory checkpoint molecules are expressed by most DC subsets and can thus be used to manipulate the effectiveness of DC vaccines. Such manipulation has been investigated using strategies such as chemotherapy, agonistic or antagonistic antibodies, siRNA, shRNA, CRISPR-Cas9, soluble antibodies, lentiviruses, and adenoviruses to maximize the efficacy of DC vaccines. Thus, a deeper understanding of immune checkpoints may assist in the development of improved DC vaccines. Here, we review the actions of various ICIs or ICAs shown by preclinical studies, as well as their potential application in DC vaccines. New therapeutic interventional strategies for blocking and stimulating immune checkpoint molecules in DCs are also described in detail.
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Affiliation(s)
- Jiage Ding
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China; Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China
| | - Yanyan Zheng
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China; Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China
| | - Gang Wang
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China; Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China.
| | - Junnian Zheng
- Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China.
| | - Dafei Chai
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China; Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China.
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Yarani R, Shojaeian A, Palasca O, Doncheva NT, Jensen LJ, Gorodkin J, Pociot F. Differentially Expressed miRNAs in Ulcerative Colitis and Crohn’s Disease. Front Immunol 2022; 13:865777. [PMID: 35734163 PMCID: PMC9208551 DOI: 10.3389/fimmu.2022.865777] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 04/13/2022] [Indexed: 12/14/2022] Open
Abstract
Differential microRNA (miRNA or miR) regulation is linked to the development and progress of many diseases, including inflammatory bowel disease (IBD). It is well-established that miRNAs are involved in the differentiation, maturation, and functional control of immune cells. miRNAs modulate inflammatory cascades and affect the extracellular matrix, tight junctions, cellular hemostasis, and microbiota. This review summarizes current knowledge of differentially expressed miRNAs in mucosal tissues and peripheral blood of patients with ulcerative colitis and Crohn’s disease. We combined comprehensive literature curation with computational meta-analysis of publicly available high-throughput datasets to obtain a consensus set of miRNAs consistently differentially expressed in mucosal tissues. We further describe the role of the most relevant differentially expressed miRNAs in IBD, extract their potential targets involved in IBD, and highlight their diagnostic and therapeutic potential for future investigations.
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Affiliation(s)
- Reza Yarani
- Translational Type 1 Diabetes Research, Department of Clinical Research, Steno Diabetes Center Copenhagen, Gentofte, Denmark
- Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University School of Medicine, Palo Alto, CA, United States
- *Correspondence: Reza Yarani, ; Flemming Pociot,
| | - Ali Shojaeian
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Oana Palasca
- Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
- Center for Non-Coding RNA in Technology and Health, University of Copenhagen, Copenhagen, Denmark
- Department of Veterinary and Animal Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Nadezhda T. Doncheva
- Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
- Center for Non-Coding RNA in Technology and Health, University of Copenhagen, Copenhagen, Denmark
- Department of Veterinary and Animal Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Lars Juhl Jensen
- Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
- Center for Non-Coding RNA in Technology and Health, University of Copenhagen, Copenhagen, Denmark
| | - Jan Gorodkin
- Center for Non-Coding RNA in Technology and Health, University of Copenhagen, Copenhagen, Denmark
- Department of Veterinary and Animal Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Flemming Pociot
- Translational Type 1 Diabetes Research, Department of Clinical Research, Steno Diabetes Center Copenhagen, Gentofte, Denmark
- Center for Non-Coding RNA in Technology and Health, University of Copenhagen, Copenhagen, Denmark
- Copenhagen Diabetes Research Center, Department of Pediatrics, Herlev University Hospital, Herlev, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- *Correspondence: Reza Yarani, ; Flemming Pociot,
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Ma H, Tan Y, Wen D, Qu N, Kong Q, Li K, Ma S, Zhang J. DC-CTL targeting carbonic anhydrase IX gene combined with iAPA therapy in the treatment of renal cell carcinoma. Hum Vaccin Immunother 2021; 17:4363-4373. [PMID: 34851805 DOI: 10.1080/21645515.2021.1955610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
Abstract
INTRODUCTION To deliver specific antigens in tumor immunotherapy, tumor cell lysates are commonly used to sensitize dendritic cells (DCs). However, the lysates possess low immunogenicity and contain many types of non-tumor-related antigens, which may induce autoimmune diseases. Tumor antigen peptides can provide high specificity but are expensive and their short half-lives limit their clinical application. METHODS In this study, we used adenovirus to transfer the carbonic anhydrase IX (CA9) gene into DCs to generate specificity to renal cell carcinoma (RCC) which is the most common space-occupying lesion in humans. Inhibition of antigen presentation attenuators (iAPA) technology was also used to enhance the DC delivery capacity. Finally, DCs were co-cultured with cytotoxic T-lymphocytes (CTLs) and the anti-tumor effects were evaluated. RESULTS The results showed that the CA9-DC-CTLs possessed a high specificity to CA9-positive cells and showed stronger anti-tumor activity than GFP-DC-CTLs both in vitro and in vivo. DISCUSSION These findings may suggest a novel treatment option for RCC.
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Affiliation(s)
- Heran Ma
- Qilu Cell Therapy Technology Co., Ltd, Jinan, China.,Shandong Yinfeng Life Science Research Institute, Jinan, China
| | - Yi Tan
- Qilu Cell Therapy Technology Co., Ltd, Jinan, China.,Shandong Yinfeng Life Science Research Institute, Jinan, China
| | - Dingke Wen
- Qilu Cell Therapy Technology Co., Ltd, Jinan, China
| | - Na Qu
- Qilu Cell Therapy Technology Co., Ltd, Jinan, China
| | - Qunfang Kong
- Qilu Cell Therapy Technology Co., Ltd, Jinan, China
| | - Kun Li
- Department of Digestion, First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Suxia Ma
- Heze Municipal Hospital, Heze, Shandong, China
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Sobah ML, Liongue C, Ward AC. SOCS Proteins in Immunity, Inflammatory Diseases, and Immune-Related Cancer. Front Med (Lausanne) 2021; 8:727987. [PMID: 34604264 PMCID: PMC8481645 DOI: 10.3389/fmed.2021.727987] [Citation(s) in RCA: 87] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Accepted: 08/16/2021] [Indexed: 01/10/2023] Open
Abstract
Cytokine signaling represents one of the cornerstones of the immune system, mediating the complex responses required to facilitate appropriate immune cell development and function that supports robust immunity. It is crucial that these signals be tightly regulated, with dysregulation underpinning immune defects, including excessive inflammation, as well as contributing to various immune-related malignancies. A specialized family of proteins called suppressors of cytokine signaling (SOCS) participate in negative feedback regulation of cytokine signaling, ensuring it is appropriately restrained. The eight SOCS proteins identified regulate cytokine and other signaling pathways in unique ways. SOCS1–3 and CISH are most closely involved in the regulation of immune-related signaling, influencing processes such polarization of lymphocytes and the activation of myeloid cells by controlling signaling downstream of essential cytokines such as IL-4, IL-6, and IFN-γ. SOCS protein perturbation disrupts these processes resulting in the development of inflammatory and autoimmune conditions as well as malignancies. As a consequence, SOCS proteins are garnering increased interest as a unique avenue to treat these disorders.
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Affiliation(s)
| | - Clifford Liongue
- School of Medicine, Deakin University, Geelong, VIC, Australia.,Institue of Mental and Physical Health and Clinical Translation, Deakin University, Geelong, VIC, Australia
| | - Alister C Ward
- School of Medicine, Deakin University, Geelong, VIC, Australia.,Institue of Mental and Physical Health and Clinical Translation, Deakin University, Geelong, VIC, Australia
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Hua L, Yang Z, Li W, Zhang Q, Ren Z, Ye C, Zheng X, Li D, Long Q, Bai H, Sun W, Yang X, Zheng P, He J, Chen Y, Huang W, Ma Y. A Novel Immunomodulator Delivery Platform Based on Bacterial Biomimetic Vesicles for Enhanced Antitumor Immunity. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2021; 33:e2103923. [PMID: 34510598 DOI: 10.1002/adma.202103923] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 07/06/2021] [Indexed: 06/13/2023]
Abstract
T cell activation-induced cell death (AICD) during tumor pathogenesis is a tumor immune escape process dependent on dendritic cells (DCs). Proper immune-modulatory therapies effectively inhibit tumor-specific CD8+ T cell exhaustion and enhance antitumor immune responses. Here, high-pressure homogenization is utilized to drive immunomodulator IL10-modified bacteria to extrude through the gap and self-assemble into bacterial biomimetic vesicles exposing IL10 (IL10-BBVs) on the surface with high efficiency. IL10-BBVs efficiently target DCs in tumor-draining lymph nodes and thus increase the interaction between IL10 on BBVs and IL10R on DCs to suppress AICD and mitigate CD8+ T cell exhaustion specific to tumor antigens. Two subcutaneous peripheral injections of IL10-BBVs 1 week apart in tumor-bearing mice effectively increase systemic and intratumoral proportions of CD8+ T cells to suppress tumor growth and metastasis. Tumor-specific antigen E7 is enclosed into the periplasm of IL10-BBVs (IL10-E7-BBVs) to realize concurrent actions of the immunomodulator IL10 and the tumor antigen human papillomavirus (HPV) 16E7 in lymph nodes, further enhancing the antitumor effects mediated by CD8+ T cells. The development of this modified BBV delivery platform will expand the application of bacterial membranes and provide novel immunotherapeutic strategies for tumor treatment.
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Affiliation(s)
- Liangqun Hua
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 935 Jiaoling Road, Kunming, 650118, China
- School of Life Sciences, Yunnan University, 2 Cuihu North Road, Kunming, 650091, China
| | - Zhongqian Yang
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 935 Jiaoling Road, Kunming, 650118, China
| | - Weiran Li
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 935 Jiaoling Road, Kunming, 650118, China
| | - Qishu Zhang
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 935 Jiaoling Road, Kunming, 650118, China
| | - Zhaoling Ren
- The Second Affiliated Hospital of Kunming Medical University, 374 Dian Burma Avenue, Kunming, 650101, China
| | - Chao Ye
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 935 Jiaoling Road, Kunming, 650118, China
| | - Xiao Zheng
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 935 Jiaoling Road, Kunming, 650118, China
- School of Life Sciences, Yunnan University, 2 Cuihu North Road, Kunming, 650091, China
| | - Duo Li
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 935 Jiaoling Road, Kunming, 650118, China
- Department of Acute Infectious Diseases Control and Prevention, Yunnan Provincial Center for Disease Control and Prevention, 158 Dongsi Street, Kunming, 530112, China
| | - Qiong Long
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 935 Jiaoling Road, Kunming, 650118, China
| | - Hongmei Bai
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 935 Jiaoling Road, Kunming, 650118, China
| | - Wenjia Sun
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 935 Jiaoling Road, Kunming, 650118, China
| | - Xu Yang
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 935 Jiaoling Road, Kunming, 650118, China
| | - Peng Zheng
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 935 Jiaoling Road, Kunming, 650118, China
| | - Jinrong He
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 935 Jiaoling Road, Kunming, 650118, China
- Kunming Medical University, 1168 Chunrong West Road, Kunming, 650500, China
| | - Yongjun Chen
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 935 Jiaoling Road, Kunming, 650118, China
| | - Weiwei Huang
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 935 Jiaoling Road, Kunming, 650118, China
| | - Yanbing Ma
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 935 Jiaoling Road, Kunming, 650118, China
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Mattiuz R, Brousse C, Ambrosini M, Cancel J, Bessou G, Mussard J, Sanlaville A, Caux C, Bendriss‐Vermare N, Valladeau‐Guilemond J, Dalod M, Crozat K. Type 1 conventional dendritic cells and interferons are required for spontaneous CD4 + and CD8 + T-cell protective responses to breast cancer. Clin Transl Immunology 2021; 10:e1305. [PMID: 34277006 PMCID: PMC8279130 DOI: 10.1002/cti2.1305] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 04/26/2021] [Accepted: 06/03/2021] [Indexed: 12/30/2022] Open
Abstract
OBJECTIVES To better understand how immune responses may be harnessed against breast cancer, we investigated which immune cell types and signalling pathways are required for spontaneous control of a mouse model of mammary adenocarcinoma. METHODS The NOP23 mammary adenocarcinoma cell line expressing epitopes derived from the ovalbumin model antigen is spontaneously controlled when orthotopically engrafted in syngeneic C57BL/6 mice. We combined this breast cancer model with antibody-mediated depletion of lymphocytes and with mutant mice affected in interferon (IFN) or type 1 conventional dendritic cell (cDC1) responses. We monitored tumor growth and immune infiltration including the activation of cognate ovalbumin-specific T cells. RESULTS Breast cancer immunosurveillance required cDC1, NK/NK T cells, conventional CD4+ T cells and CD8+ cytotoxic T lymphocytes (CTLs). cDC1 were required constitutively, but especially during T-cell priming. In tumors, cDC1 were interacting simultaneously with CD4+ T cells and tumor-specific CTLs. cDC1 expression of the XCR1 chemokine receptor and of the T-cell-attracting or T-cell-activating cytokines CXCL9, IL-12 and IL-15 was dispensable for tumor rejection, whereas IFN responses were necessary, including cDC1-intrinsic signalling by STAT1 and IFN-γ but not type I IFN (IFN-I). cDC1 and IFNs promoted CD4+ and CD8+ T-cell infiltration, terminal differentiation and effector functions. In breast cancer patients, high intratumor expression of genes specific to cDC1, CTLs, CD4+ T cells or IFN responses is associated with a better prognosis. CONCLUSION Interferons and cDC1 are critical for breast cancer immunosurveillance. IFN-γ plays a prominent role over IFN-I in licensing cDC1 for efficient T-cell activation.
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Affiliation(s)
- Raphaël Mattiuz
- Centre d'Immunologie de Marseille‐LuminyTuring Center for Living SystemsCNRSINSERMAix Marseille UnivMarseilleFrance
- Present address:
The Precision Immunology Institute and Tisch Cancer InstituteIcahn School of Medicine at Mount SinaiNew YorkNYUSA
| | - Carine Brousse
- Centre d'Immunologie de Marseille‐LuminyTuring Center for Living SystemsCNRSINSERMAix Marseille UnivMarseilleFrance
| | - Marc Ambrosini
- Centre d'Immunologie de Marseille‐LuminyTuring Center for Living SystemsCNRSINSERMAix Marseille UnivMarseilleFrance
| | - Jean‐Charles Cancel
- Centre d'Immunologie de Marseille‐LuminyTuring Center for Living SystemsCNRSINSERMAix Marseille UnivMarseilleFrance
| | - Gilles Bessou
- Centre d'Immunologie de Marseille‐LuminyTuring Center for Living SystemsCNRSINSERMAix Marseille UnivMarseilleFrance
| | - Julie Mussard
- INSERM 1052CNRS 5286Centre Léon BérardCancer Research Center of LyonUniv LyonUniversité Claude Bernard Lyon 1LyonFrance
| | - Amélien Sanlaville
- INSERM 1052CNRS 5286Centre Léon BérardCancer Research Center of LyonUniv LyonUniversité Claude Bernard Lyon 1LyonFrance
| | - Christophe Caux
- INSERM 1052CNRS 5286Centre Léon BérardCancer Research Center of LyonUniv LyonUniversité Claude Bernard Lyon 1LyonFrance
| | - Nathalie Bendriss‐Vermare
- INSERM 1052CNRS 5286Centre Léon BérardCancer Research Center of LyonUniv LyonUniversité Claude Bernard Lyon 1LyonFrance
| | - Jenny Valladeau‐Guilemond
- INSERM 1052CNRS 5286Centre Léon BérardCancer Research Center of LyonUniv LyonUniversité Claude Bernard Lyon 1LyonFrance
| | - Marc Dalod
- Centre d'Immunologie de Marseille‐LuminyTuring Center for Living SystemsCNRSINSERMAix Marseille UnivMarseilleFrance
| | - Karine Crozat
- Centre d'Immunologie de Marseille‐LuminyTuring Center for Living SystemsCNRSINSERMAix Marseille UnivMarseilleFrance
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Limosilactobacillus fermentum CECT5716: Mechanisms and Therapeutic Insights. Nutrients 2021; 13:nu13031016. [PMID: 33801082 PMCID: PMC8003974 DOI: 10.3390/nu13031016] [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: 01/30/2021] [Revised: 03/09/2021] [Accepted: 03/18/2021] [Indexed: 12/12/2022] Open
Abstract
Probiotics microorganisms exert their health-associated activities through some of the following general actions: competitive exclusion, enhancement of intestinal barrier function, production of bacteriocins, improvement of altered microbiota, and modulation of the immune response. Among them, Limosilactobacillus fermentum CECT5716 has become one of the most promising probiotics and it has been described to possess potential beneficial effects on inflammatory processes and immunological alterations. Different studies, preclinical and clinical trials, have evidenced its anti-inflammatory and immunomodulatory properties and elucidated the precise mechanisms of action involved in its beneficial effects. Therefore, the aim of this review is to provide an updated overview of the effect on host health, mechanisms, and future therapeutic approaches.
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Wang Y, Lu C, Huang H, Yao S, Xu C, Ye Y, Gui S, Li G. A lipid-soluble extract of Pinellia pedatisecta Schott orchestrates intratumoral dendritic cell-driven immune activation through SOCS1 signaling in cervical cancer. JOURNAL OF ETHNOPHARMACOLOGY 2021; 267:112837. [PMID: 32276009 DOI: 10.1016/j.jep.2020.112837] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 03/14/2020] [Accepted: 04/01/2020] [Indexed: 06/11/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Pinellia pedatisecta Schott extract (PE) is generated from Pinellia pedatisecta Schott, a traditional Chinese medicinal plant. PE suppresses cervical tumor growth and exhibits effects on dendritic cells (DCs) that lead to modulation of antitumor CD4+ and CD8+ responses. AIMS To explore the underlying mechanisms by which PE modulates tumor-associated dendritic cell (TADC) activation and function. METHODS DCs and TADCs were generated from murine bone marrow and exposed to PE solutions at different doses, as well as to repeated doses separated at different time intervals. Quantitative PCR, Western blot analysis, flow cytometry, and gene silencing were used to analyze the modulatory effects of PE on the SOCS1/JAK2/STAT pathways. Furthermore, we separated human cervical tumor-infiltrated DCs (TIDCs) and conducted an ex-vivo stimulation model to observe the effect of PE. For phenotypic analysis of cultured DCs and ex vivo human specimens, we used flow cytometry to detect the molecular markers associated with cell function. RESULTS In cultured TADCs and human cervical TIDCs, maturation- and functional markers (MHCII, CD80, CD83, CD86, and IL-12) were downregulated, whereas SOCS1 was upregulated. PE enhanced the expression of CD80, CD86, and IL-12 in cervical TIDCs, which induced increased expression of CD107a, GZMB, and perforin in CTLs, and furthermore induced apoptosis in a larger number of tumor cells. In cultured TADCs, PE downregulated SOCS1 expression and activated the phosphorylation of JAK2, STAT1, STAT4, and STAT5 in both dose- and time-dependent manners. The effects of PE upregulating MHCII, CD80, CD86, IL-12 on TADCs were blocked after SOCS1 silencing. CONCLUSIONS In this study, PE restored the impaired function of cervical TIDCs, thereby eliciting further antitumor CTL responses. The effects of PE on TADCs were mediated through inhibition of SOCS1 and activation of downstream JAK2-STAT1/STAT4/STAT5 pathways. PE may be a potent and effective immunomodulatory drug for antitumor treatment via the blockade of SOCS1 signaling in DCs.
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Affiliation(s)
- Yumeng Wang
- Department of Integration of Western and Traditional Medicine, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200090, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai, 200011, China
| | - Chong Lu
- Department of Integration of Western and Traditional Medicine, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200090, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai, 200011, China
| | - Haixia Huang
- Department of Integration of Western and Traditional Medicine, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200090, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai, 200011, China
| | - Sheng Yao
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Congjian Xu
- Department of Integration of Western and Traditional Medicine, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200090, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai, 200011, China
| | - Yang Ye
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Suiqi Gui
- Department of Integration of Western and Traditional Medicine, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200090, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai, 200011, China
| | - Guiling Li
- Department of Integration of Western and Traditional Medicine, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200090, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai, 200011, China.
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Chen Q, Mang G, Wu J, Sun P, Li T, Zhang H, Wang N, Tong Z, Wang W, Zheng Y, Tian J, E M, Zhang M, Yu B. Circular RNA circSnx5 Controls Immunogenicity of Dendritic Cells through the miR-544/SOCS1 Axis and PU.1 Activity Regulation. Mol Ther 2020; 28:2503-2518. [PMID: 32681834 DOI: 10.1016/j.ymthe.2020.07.001] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 05/13/2020] [Accepted: 06/28/2020] [Indexed: 12/18/2022] Open
Abstract
Dendritic cells (DCs) can orchestrate either immunogenic or tolerogenic responses to relay information on the functional state. Emerging studies indicate that circular RNAs (circRNAs) are involved in immunity; however, it remains unclear whether they govern DC development and function at the transcriptional level. In this study, we identified a central role for a novel circRNA, circSnx5, in modulating DC-driven immunity and tolerance. Ectopic circSnx5 suppresses DC activation and promotes the development of tolerogenic functions of DCs, while circSnx5 knockdown promotes their activation and inflammatory phenotype. Mechanistically, circSnx5 can act as a miR-544 sponge to attenuate miRNA-mediated target depression on suppressor of cytokine signaling 1 (SOCS1) and inhibit nuclear translocation of PU.1, regulating DC activation and function. Furthermore, the main splicing factors (SFs) were identified in DCs, of which heterogeneous nuclear ribonucleoprotein (hnRNP) C was essential for circSnx5 generation. Moreover, our data demonstrated that vaccination with circSnx5-conditioned DCs prolonged cardiac allograft survival in mice and alleviated experimental autoimmune myocarditis. Taken together, our results revealed circSnx5 as a key modulator to fine-tune DC function, suggesting that circSnx5 may serve as a potential therapeutic avenue for immune-related diseases.
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Affiliation(s)
- Qi Chen
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, No. 246 Xuefu Road, Nangang District, Harbin 150001, China; The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, No. 246 Xuefu Road, Nangang District, Harbin 50001, Heilongjiang Province, China
| | - Ge Mang
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, No. 246 Xuefu Road, Nangang District, Harbin 150001, China; The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, No. 246 Xuefu Road, Nangang District, Harbin 50001, Heilongjiang Province, China
| | - Jian Wu
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, No. 246 Xuefu Road, Nangang District, Harbin 150001, China; The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, No. 246 Xuefu Road, Nangang District, Harbin 50001, Heilongjiang Province, China
| | - Ping Sun
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, No. 246 Xuefu Road, Nangang District, Harbin 150001, China; The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, No. 246 Xuefu Road, Nangang District, Harbin 50001, Heilongjiang Province, China
| | - Tingting Li
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, No. 246 Xuefu Road, Nangang District, Harbin 150001, China; The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, No. 246 Xuefu Road, Nangang District, Harbin 50001, Heilongjiang Province, China
| | - Hanlu Zhang
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, No. 246 Xuefu Road, Nangang District, Harbin 150001, China; The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, No. 246 Xuefu Road, Nangang District, Harbin 50001, Heilongjiang Province, China
| | - Naixin Wang
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, No. 246 Xuefu Road, Nangang District, Harbin 150001, China; The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, No. 246 Xuefu Road, Nangang District, Harbin 50001, Heilongjiang Province, China
| | - Zhonghua Tong
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, No. 246 Xuefu Road, Nangang District, Harbin 150001, China; The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, No. 246 Xuefu Road, Nangang District, Harbin 50001, Heilongjiang Province, China
| | - Weiwei Wang
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, No. 246 Xuefu Road, Nangang District, Harbin 150001, China; The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, No. 246 Xuefu Road, Nangang District, Harbin 50001, Heilongjiang Province, China
| | - Yang Zheng
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, No. 246 Xuefu Road, Nangang District, Harbin 150001, China; The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, No. 246 Xuefu Road, Nangang District, Harbin 50001, Heilongjiang Province, China
| | - Jinwei Tian
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, No. 246 Xuefu Road, Nangang District, Harbin 150001, China; The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, No. 246 Xuefu Road, Nangang District, Harbin 50001, Heilongjiang Province, China
| | - Mingyan E
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Nangang District, Harbin 50001, Heilongjiang Province, China.
| | - Maomao Zhang
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, No. 246 Xuefu Road, Nangang District, Harbin 150001, China; The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, No. 246 Xuefu Road, Nangang District, Harbin 50001, Heilongjiang Province, China.
| | - Bo Yu
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, No. 246 Xuefu Road, Nangang District, Harbin 150001, China; The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, No. 246 Xuefu Road, Nangang District, Harbin 50001, Heilongjiang Province, China
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miR-155 indicates the fate of CD4 + T cells. Immunol Lett 2020; 224:40-49. [PMID: 32485191 DOI: 10.1016/j.imlet.2020.05.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 05/14/2020] [Accepted: 05/24/2020] [Indexed: 12/20/2022]
Abstract
MicroRNAs (miRNAs) are a class of short noncoding RNAs that regulate the translation of target messenger RNA (mRNA) and consequently participate in a variety of biological processes at the posttranscriptional level. miR-155, encoded within a region known as the B cell integration cluster (BIC), plays multifunctional roles in shaping lymphocytes ranging from biological development to adaptive immunity. It has been revealed that miR-155 plays a key role in fine-tuning the regulation of lymphocyte subsets, including dendritic cells (DCs), macrophages, B cells, and CD8+ and CD4+ T cells. Antigen-specific CD4+ T lymphocytes are critical for host defense against pathogens and prevention of damage resulting from excessive inflammation. Over the past years, various studies have shown that miR-155 plays a critical role in CD4+ T cells function. Therefore, we summarize multiple target genes of miR-155 that regulate aspects of CD4+ T cells immunity, particularly CD4+ T cells differentiation, in this review. In addition, we also focus on the role of miR-155 in the regulation of immunological diseases, suggesting it as a potential disease biomarker and therapeutic target.
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Lalor R, O'Neill S. Bovine κ-casein induces a hypo-responsive DC population which exhibit a reduced capacity to elicit T-cell responses. J Funct Foods 2020. [DOI: 10.1016/j.jff.2019.103620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
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A Novel Anti-PD-L1 Vaccine for Cancer Immunotherapy and Immunoprevention. Cancers (Basel) 2019; 11:cancers11121909. [PMID: 31805690 PMCID: PMC6966557 DOI: 10.3390/cancers11121909] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 11/22/2019] [Indexed: 12/22/2022] Open
Abstract
Dendritic cells (DCs) are potent antigen-presenting cells that play a critical role in activating cellular and humoral immune responses. DC-based tumor vaccines targeting tumor-associated antigens (TAAs) have been extensively tested and demonstrated to be safe and potent in inducing anti-TAA immune responses in cancer patients. Sipuleucel-T (Provenge), a cancer vaccine of autologous DCs loaded with TAA, was approved by the United States Food and Drug Administration (FDA) for the treatment of castration-resistant prostate cancer. Sipuleucel-T prolongs patient survival, but has little or no effect on clinical disease progression or biomarker kinetics. Due to the overall limited clinical efficacy of tumor vaccines, there is a need to enhance their potency. PD-L1 is a key immune checkpoint molecule and is frequently overexpressed on tumor cells to evade antitumor immune destruction. Repeated administrations of PD-L1 or PD-1 antibodies have induced sustained tumor regression in a fraction of cancer patients. In this study, we tested whether vaccinations with DCs, loaded with a PD-L1 immunogen (PDL1-Vax), are able to induce anti-PD-L1 immune responses. We found that DCs loaded with PDL1-Vax induced anti-PD-L1 antibody and T cell responses in immunized mice and that PD-L1-specific CTLs had cytolytic activities against PD-L1+ tumor cells. We demonstrated that vaccination with PDL1-Vax DCs potently inhibited the growth of PD-L1+ tumor cells. In summary, this study demonstrates for the first time the principle and feasibility of DC vaccination (PDL1-Vax) to actively induce anti-PD-L1 antibody and T cell responses capable of inhibiting PD-L1+ tumor growth. This novel anti-PD-L1 vaccination strategy could be used for cancer treatment and prevention.
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Wang Y, Huang H, Yao S, Li G, Xu C, Ye Y, Gui S. A lipid-soluble extract of Pinellia pedatisecta Schott enhances antitumor T cell responses by restoring tumor-associated dendritic cell activation and maturation. JOURNAL OF ETHNOPHARMACOLOGY 2019; 241:111980. [PMID: 31146000 DOI: 10.1016/j.jep.2019.111980] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 05/22/2019] [Accepted: 05/26/2019] [Indexed: 06/09/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Pinellia pedatisecta Schott (PPS)is a traditional Chinese medicine functioning as reducing swelling and drying dampness. Pinellia pedatisecta Schott extract (PE) has been confirmed to suppress cervical tumor growth and modulate the antitumor CD4+T helper immunity towards Th1. AIMS To explore the roles of PE in modulating tumor-associated dendritic cell (TADC) activation and function. METHODS For in vivo studies, HPV+TC-1 mouse tumor models were conducted and treated with PE for 3 weeks (10 mg/kg/d or 20 mg/kg/day). The immune profiles of spleen, tumor-draining lymph nodes (TDLNs), tumor and serum were analyzed by flow cytometry and multiplexed bead-based immunoassay. For in vitro studies, TADCs were generated by tumor-conditioned medium and treated with PE solution. The maturation and function of TADCs were evaluated by flow cytometry, ELISA, mixed lymphocyte reaction (MLR) and cytotoxic T lymphocyte (CTL) assay. Furthermore, the effect of PE on SOCS1 pathway was examined by western blotting and real time PCR. RESULTS PE upregulated the expression of major histocompatibility complex class II (MHCII) and costimulatory molecules CD80 and CD86 on TADCs and promoted IL-12 secretion from TADCs. In addition, PE-treated TADCs promoted the proliferation of CD4+ and CD8+ T cells and induced the differentiation of IFN-γ+CD4+ and GZMB+CD8+ T cells. PE-treated TADCs also elicited a more powerful antigen-specific cytotoxic T lymphocyte (CTL) response. Furthermore, PE treatment in vivo enhanced the proliferation, activated the functional ability (increased Ki67, CD137, GZMB or IFN-γ, TNF-α expression) and reversed the exhaustion (impaired CD95 or PD-1 expression) of antitumor T cells. Mechanistically, PE inhibited SOCS1-restrained JAK2 activation in TADCs. CONCLUSIONS PE efficiently restored the immature status of TADCs and enhanced their function as antigen-presenting cells to further elicit antitumor Th1 and CTL responses, suggesting that PE may be a potential immunomodulatory drug for cancer treatment.
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Affiliation(s)
- Yumeng Wang
- Department of Integration of Western and Traditional Medicine, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200090, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai, 200011, China
| | - Haixia Huang
- Department of Integration of Western and Traditional Medicine, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200090, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai, 200011, China
| | - Sheng Yao
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Guiling Li
- Department of Integration of Western and Traditional Medicine, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200090, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai, 200011, China.
| | - Congjian Xu
- Department of Integration of Western and Traditional Medicine, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200090, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai, 200011, China
| | - Yang Ye
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Suiqi Gui
- Department of Integration of Western and Traditional Medicine, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200090, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai, 200011, China
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Yang F, Li XF, Cheng LN, Li XL. Long non-coding RNA CRNDE promotes cell apoptosis by suppressing miR-495 in inflammatory bowel disease. Exp Cell Res 2019; 382:111484. [PMID: 31251902 DOI: 10.1016/j.yexcr.2019.06.029] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Revised: 06/04/2019] [Accepted: 06/24/2019] [Indexed: 02/09/2023]
Abstract
OBJECTIVE This article aims to investigate the mechanism of microRNA-495 (miR-495) and long non-coding RNA CRNDE on the apoptosis of colonic epithelial cells in inflammatory bowel diseases (IBDs). METHODS The mouse model of IBD was induced by dextran sulfate sodium (DSS), and human colonic epithelial cell lines (HT-29, LOVO, and Caco-2) were treated with DSS, and received cell transfection. RNA interference was used to down-regulate CRNDE expression. RESULTS CRNDE and SOCS1 were highly expressed, but miR-495 was lowly expressed in the DSS-induced colitis tissues and colonic epithelial cell lines. Interference of CRNDE inhibited cell apoptosis of DSS-induced colonic epithelial cells. The interaction between CRNDE and miR-495 was confirmed by RNA immunoprecipitation and RNA pull-down assay. The target relationship between miR-495 and SOCS1 was confirmed by the luciferase reporter assay. CRNDE promoted DSS-induced colonic epithelial cell apoptosis via miR-495/SOCS1. CRNDE interference in DSS-induced colitis mouse model alleviated clinical manifestations of IBD. CONCLUSIONS Our findings demonstrated that CRNDE promoted DSS-induced colonic epithelial cell apoptosis via suppressing miR-495 and increasing SOCS1, indicating CRNDE as a novel target of treating IBD.
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Affiliation(s)
- Fan Yang
- Department of Gastroenterology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, 450003, China
| | - Xiao-Fang Li
- Department of Gastroenterology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, 450003, China
| | - Li-Na Cheng
- Department of Gastroenterology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, 450003, China
| | - Xiu-Ling Li
- Department of Gastroenterology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, 450003, China.
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Guram K, Kim SS, Wu V, Sanders PD, Patel S, Schoenberger SP, Cohen EEW, Chen SY, Sharabi AB. A Threshold Model for T-Cell Activation in the Era of Checkpoint Blockade Immunotherapy. Front Immunol 2019; 10:491. [PMID: 30936880 PMCID: PMC6431643 DOI: 10.3389/fimmu.2019.00491] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Accepted: 02/22/2019] [Indexed: 12/13/2022] Open
Abstract
Continued discoveries of negative regulators of inflammatory signaling provide detailed molecular insights into peripheral tolerance and anti-tumor immunity. Accumulating evidence indicates that peripheral tolerance is maintained at multiple levels of immune responses by negative regulators of proinflammatory signaling, soluble anti-inflammatory factors, inhibitory surface receptors & ligands, and regulatory cell subsets. This review provides a global overview of these regulatory machineries that work in concert to maintain peripheral tolerance at cellular and host levels, focusing on the direct and indirect regulation of T cells. The recent success of checkpoint blockade immunotherapy (CBI) has initiated a dramatic shift in the paradigm of cancer treatment. Unprecedented responses to CBI have highlighted the central role of T cells in both anti-tumor immunity and peripheral tolerance and underscored the importance of T cell exhaustion in cancer. We discuss the therapeutic implications of modulating the negative regulators of T cell function for tumor immunotherapy with an emphasis on inhibitory surface receptors & ligands—central players in T cell exhaustion and targets of checkpoint blockade immunotherapies. We then introduce a Threshold Model for Immune Activation—the concept that these regulatory mechanisms contribute to defining a set threshold of immunogenic (proinflammatory) signaling required to elicit an anti-tumor or autoimmune response. We demonstrate the value of the Threshold Model in understanding clinical responses and immune related adverse events in the context of peripheral tolerance, tumor immunity, and the era of Checkpoint Blockade Immunotherapy.
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Affiliation(s)
- Kripa Guram
- Department of Radiation Medicine and Applied Sciences, San Diego Moores Cancer Center, University of California, San Diego, San Diego, CA, United States
| | - Sangwoo S Kim
- Department of Radiation Medicine and Applied Sciences, San Diego Moores Cancer Center, University of California, San Diego, San Diego, CA, United States
| | - Victoria Wu
- Moores Comprehensive Cancer Center, University of California, San Diego, San Diego, CA, United States
| | - P Dominick Sanders
- Department of Radiation Medicine and Applied Sciences, San Diego Moores Cancer Center, University of California, San Diego, San Diego, CA, United States
| | - Sandip Patel
- Division of Hematology and Oncology, Center for Personalized Cancer Therapy, San Diego Moores Cancer Center, University of California, San Diego, San Diego, CA, United States
| | - Stephen P Schoenberger
- Division of Hematology and Oncology, Center for Personalized Cancer Therapy, San Diego Moores Cancer Center, University of California, San Diego, San Diego, CA, United States.,Laboratory of Cellular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, United States
| | - Ezra E W Cohen
- Moores Comprehensive Cancer Center, University of California, San Diego, San Diego, CA, United States
| | - Si-Yi Chen
- Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, United States
| | - Andrew B Sharabi
- Department of Radiation Medicine and Applied Sciences, San Diego Moores Cancer Center, University of California, San Diego, San Diego, CA, United States.,Moores Comprehensive Cancer Center, University of California, San Diego, San Diego, CA, United States
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SOCS1 and its Potential Clinical Role in Tumor. Pathol Oncol Res 2019; 25:1295-1301. [DOI: 10.1007/s12253-019-00612-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Accepted: 02/04/2019] [Indexed: 10/27/2022]
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Tao Y, Ai R, Hao Y, Jiang L, Dan H, Ji N, Zeng X, Zhou Y, Chen Q. Role of miR-155 in immune regulation and its relevance in oral lichen planus. Exp Ther Med 2018; 17:575-586. [PMID: 30651838 PMCID: PMC6307429 DOI: 10.3892/etm.2018.7019] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Accepted: 10/04/2018] [Indexed: 02/05/2023] Open
Abstract
Oral lichen planus (OLP) is a chronic mucosal inflammatory disease. The World Health Organization has described it as a potentially malignant condition. The pathogenesis of OLP remains to be fully elucidated, but extensive evidence suggests that immunologic and inflammatory factors have important roles. MicroRNAs (miRs), which are small non-coding RNAs, have been reported to be involved in OLP. In particular, miR-155 is significantly upregulated in patients with OLP. miR-155 has numerous functions and is closely linked to inflammation and immune system regulation. However, in-depth studies of the mechanisms via which miR-155 is involved in OLP are currently insufficient. Considering the close association between miR-155 and immune regulation as well as the importance of immune factors in OLP, the role of miR-155 in the immune system was herein summarized with a focus on OLP. The present review provides a basis for further study of the molecular mechanisms underlying the development and progression of OLP.
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Affiliation(s)
- Yan Tao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral Medicine of West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Ruixue Ai
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral Medicine of West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yilong Hao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral Medicine of West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Lu Jiang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral Medicine of West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Hongxia Dan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral Medicine of West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Ning Ji
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral Medicine of West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Xin Zeng
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral Medicine of West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yu Zhou
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral Medicine of West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Qianming Chen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral Medicine of West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China
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MicroRNAs and immunity in periodontal health and disease. Int J Oral Sci 2018; 10:24. [PMID: 30078842 PMCID: PMC6080405 DOI: 10.1038/s41368-018-0025-y] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Revised: 04/08/2018] [Accepted: 04/11/2018] [Indexed: 02/07/2023] Open
Abstract
MicroRNAs (miRNAs) are critical regulators of the host immune and inflammatory response against bacterial pathogens. In the present review, we discuss target genes, target gene functions, the potential regulatory role of miRNAs in periodontal tissues, and the potential role of miRNAs as biomarkers and therapeutics. In periodontal disease, miRNAs exert control over all aspects of innate and adaptive immunity, including the functions of neutrophils, macrophages, dendritic cells and T and B cells. Previous human studies have highlighted some key miRNAs that are dysregulated in periodontitis patients. In the present study, we mapped the major miRNAs that were altered in our reproducible periodontitis mouse model relative to control animals. The miRNAs that were upregulated as a result of periodontal disease in both human and mouse studies included miR-15a, miR-29b, miR-125a, miR-146a, miR-148/148a and miR-223, whereas miR-92 was downregulated. The association of individual miRNAs with unique aspects of periodontal disease and their stability in gingival crevicular fluid underscores their potential as markers for periodontal disease progression or healthy restitution. Moreover, miRNA therapeutics hold great promise for the future of periodontal therapy because of their ability to modulate the immune response to infection when applied in conjunction with synthetic antagomirs and/or relatively straightforward delivery strategies.
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Liu A, Frostegård J. PCSK9 plays a novel immunological role in oxidized LDL-induced dendritic cell maturation and activation of T cells from human blood and atherosclerotic plaque. J Intern Med 2018; 284:193-210. [PMID: 29617044 DOI: 10.1111/joim.12758] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Activated T cells and dendritic cells (DCs) occur in atherosclerotic plaques. Proprotein convertase subtilisin kexin 9 (PCSK9) targets the LDL-receptor (LDLR) and results in increased LDL levels. We here investigate immune effects of PCSK9 on OxLDL induced DC maturation and T-cell activation. METHODS T cells were isolated from carotid specimens of patients undergoing carotid endarterectomy or from peripheral blood of healthy individuals. Human peripheral blood monocytes were differentiated into DCs. Naïve T cells were cocultured with pretreated DCs. The effects of PCSK9 and its inhibition by silencing were studied. RESULTS OxLDL induced PCSK9 in DCs and promoted DC maturation with increased expressions of CD80, CD83, CD86 and HLA-DR and the scavenger receptors LOX-1 and CD36. T cells exposed to OxLDL-treated DCs proliferated and produced IFN-γ and IL-17, thus with polarization to Th1 and/or Th17 subsets. Silencing of PCSK9 reversed the OxLDL effects on DCs and T cells. DC maturation was repressed, and the production of TNF-α, IL-1β and IL-6 was limited, while TGF-β and IL-10 secretion and T regulatory cells were induced. OxLDL induced miRNA let-7c, miR-27a, miR-27b, miR-185. Silencing PCSK9 repressed miR-27a and to a lesser extent let-7c. PCSK9 silencing enhanced SOCS1 expression induced by OxLDL. Experiments on T cells from carotid atherosclerotic plaques or healthy individuals showed similar results. CONCLUSIONS We demonstrate immunological effects of PCSK9 in relation to activation and maturation of DCs and plaque T cells by OxLDL, a central player in atherosclerosis. This may directly influence atherosclerosis and cardiovascular disease, independent of LDL lowering.
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Affiliation(s)
- A Liu
- Institute of Environmental Medicine, Unit of Immunology and Chronic Disease, Karolinska Institutet, Stockholm, Sweden
| | - J Frostegård
- Institute of Environmental Medicine, Unit of Immunology and Chronic Disease, Karolinska Institutet, Stockholm, Sweden
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Wang D, Huang XF, Hong B, Song XT, Hu L, Jiang M, Zhang B, Ning H, Li Y, Xu C, Lou X, Li B, Yu Z, Hu J, Chen J, Yang F, Gao H, Ding G, Liao L, Rollins L, Jones L, Chen SY, Chen H. Efficacy of intracellular immune checkpoint-silenced DC vaccine. JCI Insight 2018; 3:98368. [PMID: 29415891 PMCID: PMC5821183 DOI: 10.1172/jci.insight.98368] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Accepted: 12/28/2017] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND DC-based tumor vaccines have had limited clinical success thus far. SOCS1, a key inhibitor of inflammatory cytokine signaling, is an immune checkpoint regulator that limits DC immunopotency. METHODS We generated a genetically modified DC (gmDC) vaccine to perform immunotherapy. The adenovirus (Ad-siSSF) delivers two tumor-associated antigens (TAAs), survivin and MUC1; secretory bacterial flagellin for DC maturation; and an RNA interference moiety to suppress SOCS1. A 2-stage phase I trial was performed for patients with relapsed acute leukemia after allogenic hematopoietic stem cell transplantation: in stage 1, we compared the safety and efficacy between gmDC treatment (23 patients) and standard donor lymphocyte infusion (25 patients); in stage 2, we tested the efficacy of the gmDC vaccine for 12 acute myeloid leukemia (AML) patients with early molecular relapse. RESULTS gmDCs elicited potent TAA-specific CTL responses in vitro, and the immunostimulatory activity of gmDC vaccination was demonstrated in rhesus monkeys. A stage 1 study established that this combinatory gmDC vaccine is safe in acute leukemia patients and yielded improved survival rate. In stage 2, we observed a complete remission rate of 83% in 12 relapsed AML patients. Overall, no grade 3 or grade 4 graft-versus-host disease incidence was detected in any of the 35 patients enrolled. CONCLUSIONS This study, with combinatory modifications in DCs, demonstrates the safety and efficacy of SOCS1-silenced DCs in treating relapsed acute leukemia. TRIAL REGISTRATION ClinicalTrials.gov NCT01956630. FUNDING National Institute of Health (R01CA90427); the Key New Drug Development and Manufacturing Program of the "Twelfth Five-Year Plan" of China (2011ZX09102-001-29); and Clinical Application Research of Beijing (Z131107002213148).
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MESH Headings
- Adenoviridae/genetics
- Adolescent
- Adult
- Antigens, Neoplasm/genetics
- Antigens, Neoplasm/immunology
- Cancer Vaccines/administration & dosage
- Cancer Vaccines/adverse effects
- Cancer Vaccines/genetics
- Cancer Vaccines/immunology
- Cell Engineering/methods
- Child
- Dendritic Cells/immunology
- Dendritic Cells/transplantation
- Female
- Follow-Up Studies
- Genetic Vectors/genetics
- Graft vs Host Disease/epidemiology
- Graft vs Host Disease/immunology
- Hematopoietic Stem Cell Transplantation/adverse effects
- Humans
- Immunotherapy, Adoptive/methods
- Leukemia, Myeloid, Acute/immunology
- Leukemia, Myeloid, Acute/mortality
- Leukemia, Myeloid, Acute/therapy
- Lymphocyte Transfusion
- Male
- Middle Aged
- Neoplasm Recurrence, Local/immunology
- Neoplasm Recurrence, Local/mortality
- Neoplasm Recurrence, Local/therapy
- Precursor Cell Lymphoblastic Leukemia-Lymphoma/immunology
- Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality
- Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy
- Survival Analysis
- Transplantation, Autologous
- Treatment Outcome
- Young Adult
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Affiliation(s)
- Danhong Wang
- Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China
| | - Xue F. Huang
- Department of Molecular Microbiology and Immunology and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA
| | - Bangxing Hong
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA
| | - Xiao-Tong Song
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA
| | - Liangding Hu
- Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China
| | - Min Jiang
- Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China
| | - Bin Zhang
- Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China
| | - Hongmei Ning
- Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China
| | - Yuhang Li
- Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China
| | - Chen Xu
- Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China
| | - Xiao Lou
- Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China
| | - Botao Li
- Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China
| | - Zhiyong Yu
- Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China
| | - Jiangwei Hu
- Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China
| | - Jianlin Chen
- Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China
| | - Fan Yang
- Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China
| | - Haiyan Gao
- Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China
| | - Guoliang Ding
- Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China
| | - Lianming Liao
- Department of Oncology, Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Lisa Rollins
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA
| | - Lindsey Jones
- Department of Molecular Microbiology and Immunology and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA
| | - Si-Yi Chen
- Department of Molecular Microbiology and Immunology and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA
| | - Hu Chen
- Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China
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Ge C, Li R, Song H, Geng T, Yang J, Tan Q, Song L, Wang Y, Xue Y, Li Z, Dong S, Zhang Z, Zhang N, Guo J, Hua L, Chen S, Song X. Phase I clinical trial of a novel autologous modified-DC vaccine in patients with resected NSCLC. BMC Cancer 2017; 17:884. [PMID: 29268708 PMCID: PMC5740508 DOI: 10.1186/s12885-017-3859-3] [Citation(s) in RCA: 30] [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: 07/15/2016] [Accepted: 11/29/2017] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND The primary aim of this study was to evaluate the safety of a novel dendritic cell (DC) vaccine pulsed with survivin and MUC1, silenced with suppressor of cytokine signaling 1 (SOCS1), and immune stimulated with flagellin for patients with stage I to IIIA non-small cell lung cancer (NSCLC) in a phase I open-label, uncontrolled, and dose-escalation trial. Moreover, we evaluate the potential efficacy of this modified DC vaccine as secondary aim. METHODS The patients were treated with the vaccine at 1 × 106, 1 × 107and the maximum dose 8 × 107 at day 7, 14, and 21 after characterization of the vaccine phenotype by flow cytometry. The safety of the vaccine was assessed by adverse events, and the efficacy by the levels of several specific tumor markers and the patient quality of life. RESULTS The vaccine was well tolerated without dose-limiting toxicity even at higher doses. The most common adverse event reported was just grade 1 flu-like symptoms without unanticipated or serious adverse event. A significant decrease in CD3 + CD4 + CD25 + Foxp3+ T regulatory (Treg) cell number and increase in TNF-α and IL-6 were observed in two patients. Two patients showed 15% and 64% decrease in carcino-embryonic antigen and CYFRA21, respectively. The vaccination with the maximum dose significantly improved the patients'quality of life when administered at the highest dose. More importantly, in the long-term follow-up until February 17, 2017, 1 patient had no recurrence, 1 patients had a progressive disease (PD), and 1 patient was died in the low dose group. In the middle dose group, all 3 patients had no recurrence. In the high dose group, 1 patient was died, 1 patient had a PD, and the other 7 patients had no recurrence. CONCLUSIONS We provide preliminary data on the safety and efficacy profile of a novel vaccine against non-small cell lung cancer, which was reasonably well tolerated, induced modest antitumor activity without dose-limiting toxicity, and improved patients' quality of life. Further more, the vaccine maybe a very efficacious treatment for patients with resected NSCLC to prevent recurrence. Our findings on the safety and efficacy of the vaccine in this phase I trial warrant future phase II/III clinical trial.
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Affiliation(s)
- Chunlei Ge
- Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan 650118 China
| | - Ruilei Li
- Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan 650118 China
| | - Haifeng Song
- Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan 650118 China
| | - Tao Geng
- Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan 650118 China
| | - Jinyan Yang
- Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan 650118 China
| | - Qinghua Tan
- Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan 650118 China
| | - Linfeng Song
- Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan 650118 China
| | - Ying Wang
- Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan 650118 China
| | - Yuanbo Xue
- Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan 650118 China
| | - Zhen Li
- Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan 650118 China
| | - Suwei Dong
- Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan 650118 China
| | - Zhiwei Zhang
- Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan 650118 China
| | - Na Zhang
- Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan 650118 China
| | - Jiyin Guo
- Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan 650118 China
| | - Lin Hua
- Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan 650118 China
| | - Siyi Chen
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX USA
- Department of Immunology, Baylor College of Medicine, Houston, TX USA
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX USA
| | - Xin Song
- Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan 650118 China
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Hargadon KM. Strategies to Improve the Efficacy of Dendritic Cell-Based Immunotherapy for Melanoma. Front Immunol 2017; 8:1594. [PMID: 29209327 PMCID: PMC5702020 DOI: 10.3389/fimmu.2017.01594] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2017] [Accepted: 11/06/2017] [Indexed: 12/20/2022] Open
Abstract
Melanoma is a highly aggressive form of skin cancer that frequently metastasizes to vital organs, where it is often difficult to treat with traditional therapies such as surgery and radiation. In such cases of metastatic disease, immunotherapy has emerged in recent years as an exciting treatment option for melanoma patients. Despite unprecedented successes with immune therapy in the clinic, many patients still experience disease relapse, and others fail to respond at all, thus highlighting the need to better understand factors that influence the efficacy of antitumor immune responses. At the heart of antitumor immunity are dendritic cells (DCs), an innate population of cells that function as critical regulators of immune tolerance and activation. As such, DCs have the potential to serve as important targets and delivery agents of cancer immunotherapies. Even immunotherapies that do not directly target or employ DCs, such as checkpoint blockade therapy and adoptive cell transfer therapy, are likely to rely on DCs that shape the quality of therapy-associated antitumor immunity. Therefore, understanding factors that regulate the function of tumor-associated DCs is critical for optimizing both current and future immunotherapeutic strategies for treating melanoma. To this end, this review focuses on advances in our understanding of DC function in the context of melanoma, with particular emphasis on (1) the role of immunogenic cell death in eliciting tumor-associated DC activation, (2) immunosuppression of DC function by melanoma-associated factors in the tumor microenvironment, (3) metabolic constraints on the activation of tumor-associated DCs, and (4) the role of the microbiome in shaping the immunogenicity of DCs and the overall quality of anti-melanoma immune responses they mediate. Additionally, this review highlights novel DC-based immunotherapies for melanoma that are emerging from recent progress in each of these areas of investigation, and it discusses current issues and questions that will need to be addressed in future studies aimed at optimizing the function of melanoma-associated DCs and the antitumor immune responses they direct against this cancer.
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Affiliation(s)
- Kristian M. Hargadon
- Hargadon Laboratory, Department of Biology, Hampden-Sydney College, Hampden-Sydney, VA, United States
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28
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Wang H, Wang J, Xia Y. Defective Suppressor of Cytokine Signaling 1 Signaling Contributes to the Pathogenesis of Systemic Lupus Erythematosus. Front Immunol 2017; 8:1292. [PMID: 29085365 PMCID: PMC5650678 DOI: 10.3389/fimmu.2017.01292] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2017] [Accepted: 09/26/2017] [Indexed: 12/19/2022] Open
Abstract
Systemic lupus erythematosus (SLE) is a complex autoimmune disease involving injuries in multiple organs and systems. Exaggerated inflammatory responses are characterized as end-organ damage in patients with SLE. Although the explicit pathogenesis of SLE remains unclear, increasing evidence suggests that dysregulation of cytokine signals contributes to the progression of SLE through the Janus kinase/signal transducer and activator of transcription (STAT) signaling pathway. Activated STAT proteins translocate to the cell nucleus and induce transcription of target genes, which regulate downstream cytokine production and inflammatory cell infiltration. The suppressor of cytokine signaling 1 (SOCS1) is considered as a classical inhibitor of cytokine signaling. Recent studies have demonstrated that SOCS1 expression is decreased in patients with SLE and in murine lupus models, and this negatively correlates with the magnitude of inflammation. Dysregulation of SOCS1 signals participates in various pathological processes of SLE such as hematologic abnormalities and autoantibody generation. Lupus nephritis is one of the most serious complications of SLE, and it correlates with suppressed SOCS1 signals in renal tissues. Moreover, SOCS1 insufficiency affects the function of several other organs, including skin, central nervous system, liver, and lungs. Therefore, SOCS1 aberrancy contributes to the development of both systemic and local inflammation in SLE patients. In this review, we discuss recent studies regarding the roles of SOCS1 in the pathogenesis of SLE and its therapeutic implications.
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Affiliation(s)
- Huixia Wang
- Department of Dermatology, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China
| | - Jiaxing Wang
- Core Research Laboratory, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China
| | - Yumin Xia
- Department of Dermatology, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China
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29
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Wu Q, Pi L, Le Trinh T, Zuo C, Xia M, Jiao Y, Hou Z, Jo S, Puszyk W, Pham K, Nelson DR, Robertson K, Ostrov D, Rameshwar P, Xia CQ, Liu C. A Novel Vaccine Targeting Glypican-3 as a Treatment for Hepatocellular Carcinoma. Mol Ther 2017; 25:2299-2308. [PMID: 28865999 PMCID: PMC5628867 DOI: 10.1016/j.ymthe.2017.08.005] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2016] [Revised: 08/07/2017] [Accepted: 08/07/2017] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) has a high morbidity and mortality rate worldwide, with limited treatment options. Glypican-3 (GPC3) is a glycosylphosphatidylinositol-anchored glycoprotein that is overexpressed in most HCC tissues but not in normal tissues. GPC3-targeting antibody therapy shows limited response in a clinical trial due to the lack of a tumor-specific cytotoxic T lymphocyte (CTL) response. Here, in C57/B6 mice, we demonstrated that intravenous infusion of GPC3-coupled lymphocytes (LC/GPC3+) elicited robust GPC3-specific antibody and CTL responses, which effectively restricted proliferation and lysed cultured-HCC cells. Treatment with LC/GPC3+ induced durable tumor regression in HCC-bearing C57/B6 mice. Administration of LC/GPC3+ induced elevated levels of the cytotoxic T cell bioactive factors tumor necrosis factor alpha (TNF-α), interferon-γ (IFN-γ), granzyme B, and perforin, and substantially increased the number of infiltrating CD8+ T cells in tumor tissues. Moreover, immune responses elicited by LC/GPC3+ selectively suppressed GPC3+ tumors, but didn't affect the GPC3- tumors in BALB/c mice. Our findings provide the first preclinical evidence that intravenous infusion of the LC/GPC3+ complex can induce a strong anti-HCC effect through regulating systemic and local immune responses. These results indicate that the LC/GPC3+ complex could be developed as precision therapeutics for HCC patients in the future.
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Affiliation(s)
- Qunfeng Wu
- Department of Pathology and Laboratory Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA; Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32611, USA
| | - Liya Pi
- Department of Pediatrics, University of Florida, Gainesville, FL 32611, USA
| | - Thu Le Trinh
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32611, USA; Department of Immunology, Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Chaohui Zuo
- Department of Pathology and Laboratory Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA; Department of Gastroduodenal and Pancreatic Surgery, Translational Medicine Research Center of Liver Cancer, Hunan Province Cancer Hospital and Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan Province 410013, P.R. China
| | - Man Xia
- Department of Pathology and Laboratory Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA; Laboratory of Digestive Oncology, Hunan Province Cancer Institute, Changsha, Hunan Province 410013, P.R. China
| | - Yu Jiao
- Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32611, USA
| | - Zhouhua Hou
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, Hunan Province 410008, P.R. China
| | - Sung Jo
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32611, USA
| | - William Puszyk
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32611, USA
| | - Kien Pham
- Department of Pathology and Laboratory Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA; Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32611, USA
| | - David R Nelson
- Department of Medicine, University of Florida, Gainesville, FL 32611, USA
| | - Keith Robertson
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Rochester, MN 85259, USA
| | - David Ostrov
- Department of Pathology and Laboratory Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA
| | - Pranela Rameshwar
- Department of Medicine, Hematology/Oncology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA
| | - Chang Qing Xia
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32611, USA.
| | - Chen Liu
- Department of Pathology and Laboratory Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA; Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32611, USA.
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Constantino J, Gomes C, Falcão A, Neves BM, Cruz MT. Dendritic cell-based immunotherapy: a basic review and recent advances. Immunol Res 2017; 65:798-810. [DOI: 10.1007/s12026-017-8931-1] [Citation(s) in RCA: 100] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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31
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Zhao HM, Han F, Xu R, Huang XY, Cheng SM, Huang MF, Yue HY, Wang X, Zou Y, Xu HL, Liu DY. Therapeutic effect of curcumin on experimental colitis mediated by inhibiting CD8 +CD11c + cells. World J Gastroenterol 2017; 23:1804-1815. [PMID: 28348486 PMCID: PMC5352921 DOI: 10.3748/wjg.v23.i10.1804] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2016] [Revised: 12/25/2016] [Accepted: 01/17/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To verify whether curcumin (Cur) can treat inflammatory bowel disease by regulating CD8+CD11c+ cells.
METHODS We evaluated the suppressive effect of Cur on CD8+CD11c+ cells in spleen and Peyer’s patches (PPs) in colitis induced by trinitrobenzene sulfonic acid. Mice with colitis were treated by 200 mg/kg Cur for 7 d. On day 8, the therapeutic effect of Cur was evaluated by visual assessment and histological examination, while co-stimulatory molecules of CD8+CD11c+ cells in the spleen and PPs were measured by flow cytometry. The levels of interleukin (IL)-10, interferon (IFN)-γ and transforming growth factor (TGF)-β1 in spleen and colonic mucosa were determined by ELISA.
RESULTS The disease activity index, colon weight, weight index of colon and histological score of experimental colitis were obviously decreased after Cur treatment, while the body weight and colon length recovered. After treatment with Cur, CD8+CD11c+ cells were decreased in the spleen and PPs, and the expression of major histocompatibility complex II, CD205, CD40, CD40L and intercellular adhesion molecule-1 was inhibited. IL-10, IFN-γ and TGF-β1 levels were increased compared with those in mice with untreated colitis.
CONCLUSION Cur can effectively treat experimental colitis, which is realized by inhibiting CD8+CD11c+ cells.
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Jiang M, Zhang WW, Liu P, Yu W, Liu T, Yu J. Dysregulation of SOCS-Mediated Negative Feedback of Cytokine Signaling in Carcinogenesis and Its Significance in Cancer Treatment. Front Immunol 2017; 8:70. [PMID: 28228755 PMCID: PMC5296614 DOI: 10.3389/fimmu.2017.00070] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Accepted: 01/16/2017] [Indexed: 01/30/2023] Open
Abstract
Suppressor of cytokine signaling (SOCS) proteins are major negative feedback regulators of cytokine signaling mediated by the Janus kinase (JAK)-signal transducer and activator of transcription signaling pathway. In particular, SOCS1 and SOCS3 are strong inhibitors of JAKs and can play pivotal roles in the development and progression of cancers. The abnormal expression of SOCS1 and SOCS3 in cancer cells is associated with the dysregulation of cell growth, migration, and death induced by multiple cytokines and hormones in human carcinomas. In addition, the mechanisms involved in SOCS1- and SOCS3-regulated abnormal development and activation of immune cells in carcinogenesis, including T cells, macrophages, dendritic cells, and myeloid-derived suppressor cells, are still unclear. Therefore, this study aims to further discuss the molecules and signal pathways regulating the expression and function of SOCS1 and SOCS3 in various types of cancers and elucidate the feasibility and efficiency of SOCS-based target therapeutic strategy in anticancer treatment.
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Affiliation(s)
- Mengmeng Jiang
- Department of Immunology, Key Laboratory of Cancer Immunology and Biotherapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Key Laboratory of Cancer Prevention and Therapy, Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Wen-Wen Zhang
- Department of Immunology, Key Laboratory of Cancer Immunology and Biotherapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Key Laboratory of Cancer Prevention and Therapy, Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Pengpeng Liu
- Cancer Molecular Diagnostic Center, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital , Tianjin , China
| | - Wenwen Yu
- Department of Immunology, Key Laboratory of Cancer Immunology and Biotherapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Key Laboratory of Cancer Prevention and Therapy, Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Ting Liu
- Department of Immunology, Key Laboratory of Cancer Immunology and Biotherapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Key Laboratory of Cancer Prevention and Therapy, Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Jinpu Yu
- Department of Immunology, Key Laboratory of Cancer Immunology and Biotherapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Key Laboratory of Cancer Prevention and Therapy, Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Cancer Molecular Diagnostic Center, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
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Ilangumaran S, Bobbala D, Ramanathan S. SOCS1: Regulator of T Cells in Autoimmunity and Cancer. Curr Top Microbiol Immunol 2017; 410:159-189. [PMID: 28900678 DOI: 10.1007/82_2017_63] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
SOCS1 is a negative feedback regulator of cytokine and growth factor receptor signaling, and plays an indispensable role in attenuating interferon gamma signaling. Studies on SOCS1-deficient mice have established a crucial role for SOCS1 in regulating CD8+ T cell homeostasis. In the thymus, SOCS1 prevents thymocytes that had failed positive selection from surviving and expanding, ensures negative selection and prevents inappropriate developmental skewing toward the CD8 lineage. In the periphery, SOCS1 not only controls production of T cell stimulatory cytokines but also attenuates the sensitivity of CD8+ T cells to synergistic cytokine stimulation and antigen non-specific activation. As cytokine stimulation of CD8+ T lymphocytes increases their sensitivity to low affinity TCR ligands, SOCS1 likely contributes to peripheral T cell tolerance by putting brakes on aberrant T cell activation driven by inflammatory cytokines. In addition, SOCS1 is critical to maintain the stability of T regulatory cells and control their plasticity to become pathogenic Th17 and Th1 cells under the harmful influence of inflammatory cytokines. SOCS1 also regulates T cell activation by dendritic cells via modulating their generation, maturation, antigen presentation, costimulatory signaling, and cytokine production. The above control mechanisms of SOCS1 on T cells, T regulatory cells and dendritic cells collectively contribute to immunological tolerance and prevent autoimmune manifestation. On other hand, silencing SOCS1 in dendritic cells or CD8+ T cells stimulates efficient antitumor immunity. Thus, even though SOCS1 is not a cell surface checkpoint inhibitor, its regulatory functions on T cell responses qualify SOCS1as a "non-classical" checkpoint blocker. SOCS1 also functions as a tumor suppressor in cancer cells by regulating oncogenic signal transduction pathways. The loss of SOCS1 expression observed in many tumors may have an impact on classical checkpoint pathways. The potential to exploit SOCS1 to treat inflammatory/autoimmune diseases and elicit antitumor immunity is discussed.
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Affiliation(s)
- Subburaj Ilangumaran
- Immunology Division, Faculty of Medicine and Health Sciences, Department of Pediatrics, Université de Sherbrooke, 3001 North 12th avenue, Sherbrooke, QC, J1H 5N4, Canada.
| | - Diwakar Bobbala
- Immunology Division, Faculty of Medicine and Health Sciences, Department of Pediatrics, Université de Sherbrooke, 3001 North 12th avenue, Sherbrooke, QC, J1H 5N4, Canada
| | - Sheela Ramanathan
- Immunology Division, Faculty of Medicine and Health Sciences, Department of Pediatrics, Université de Sherbrooke, 3001 North 12th avenue, Sherbrooke, QC, J1H 5N4, Canada
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Nizyaeva NV, Kulikova GV, Shchyogolev AI, Zemskov VM. The role of microRNA in regulation of the body’s immune responses. ACTA ACUST UNITED AC 2016. [DOI: 10.1134/s2079086416060050] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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Zhao HM, Xu R, Huang XY, Cheng SM, Huang MF, Yue HY, Wang X, Zou Y, Lu AP, Liu DY. Curcumin Suppressed Activation of Dendritic Cells via JAK/STAT/SOCS Signal in Mice with Experimental Colitis. Front Pharmacol 2016; 7:455. [PMID: 27932984 PMCID: PMC5122716 DOI: 10.3389/fphar.2016.00455] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2016] [Accepted: 11/14/2016] [Indexed: 12/21/2022] Open
Abstract
Dendritic cells (DCs) play a pivotal role as initiators in the pathogenesis of inflammatory bowel disease and are regulated by the JAK/STAT/SOCS signaling pathway. As a potent anti-inflammatory compound, curcumin represents a viable treatment alternative or adjunctive therapy in the management of chronic inflammatory bowel disease (IBD). The mechanism of curcumin treated IBD on DCs is not completely understood. In the present study, we explored the mechanism of curcumin treated experimental colitis by observing activation of DCs via JAK/STAT/SOCS signaling pathway in colitis mice. Experimental colitis was induced by 2, 4, 6-trinitrobenzene sulfonic acid. After 7 days treatment with curcumin, its therapeutic effect was verified by decreased colonic weight, histological scores, and remitting pathological injury. Meanwhile, the levels of major histocompatibility complex class II and DC costimulatory molecules (CD83, CD28, B7-DC, CD40, CD40 L, and TLR2) were inhibited and followed the up-regulated levels of IL-4, IL-10, and IFN-γ, and down-regulated GM-CSF, IL-12p70, IL-15, IL-23, and TGF-β1. A key finding was that the phosphorylation of the three members (JAK2, STAT3, and STAT6) of the JAK/STAT/SOCS signaling pathway was inhibited, and the three downstream proteins (SOCS1, SOCS3, and PIAS3) from this pathway were highly expressed. In conclusion, curcumin suppressed the activation of DCs by modulating the JAK/STAT/SOCS signaling pathway to restore immunologic balance to effectively treat experimental colitis.
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Affiliation(s)
- Hai-Mei Zhao
- School of Basic Medical Sciences, Jiangxi University of Traditional Chinese Medicine Nanchang, China
| | - Rong Xu
- Department of Postgraduate, Jiangxi University of Traditional Chinese Medicine Nanchang, China
| | - Xiao-Ying Huang
- Key Laboratory of Modern Preparation of TCM, Ministry of Education, Jiangxi University of Traditional Chinese Medicine Nanchang, China
| | - Shao-Min Cheng
- School of Basic Medical Sciences, Jiangxi University of Traditional Chinese Medicine Nanchang, China
| | - Min-Fang Huang
- Department of Postgraduate, Jiangxi University of Traditional Chinese Medicine Nanchang, China
| | - Hai-Yang Yue
- Department of Postgraduate, Jiangxi University of Traditional Chinese Medicine Nanchang, China
| | - Xin Wang
- Department of Postgraduate, Jiangxi University of Traditional Chinese Medicine Nanchang, China
| | - Yong Zou
- Department of Postgraduate, Jiangxi University of Traditional Chinese Medicine Nanchang, China
| | - Ai-Ping Lu
- School of Chinese Medicine, Hong Kong Baptist University Kowloon Tong, China
| | - Duan-Yong Liu
- Science and Technology College, Jiangxi University of Traditional Chinese Medicine Nanchang, China
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Chuang Y, Knickel BK, Leonard JN. Regulation of the IL-10-driven macrophage phenotype under incoherent stimuli. Innate Immun 2016; 22:647-657. [PMID: 27670945 PMCID: PMC5292318 DOI: 10.1177/1753425916668243] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Macrophages are ubiquitous innate immune cells that play a central role in health and disease by adopting distinct phenotypes, which are broadly divided into classical inflammatory responses and alternative responses that promote immune suppression and wound healing. Although macrophages are attractive therapeutic targets, incomplete understanding of this functional choice limits clinical manipulation. While individual stimuli, pathways, and genes involved in macrophage functional responses have been identified, how macrophages evaluate complex in vivo milieus comprising multiple divergent stimuli remains poorly understood. Here, we used combinations of "incoherent" stimuli-those that individually promote distinct macrophage phenotypes-to elucidate how the immunosuppressive, IL-10-driven macrophage phenotype is induced, maintained, and modulated under such combinatorial stimuli. The IL-10-induced immunosuppressive phenotype was largely insensitive to co-administered IL-12, which has been reported to modulate macrophage phenotype, but maintaining the immunosuppressive phenotype required sustained exposure to IL-10. Our data implicate the intracellular protein, BCL3, as a key mediator of the IL-10-driven phenotype. Notably, co-administration of IFN-γ disrupted an IL-10-mediated positive feedback loop that may reinforce the immunosuppressive phenotype. This novel combinatorial perturbation approach thus generated new insights into macrophage decision making and local immune network function.
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Affiliation(s)
- Yishan Chuang
- Department of Chemical and Biological Engineering, Northwestern University, Evanston, Illinois 60208, United States
| | - Brianne K. Knickel
- Department of Chemical and Biological Engineering, Northwestern University, Evanston, Illinois 60208, United States
| | - Joshua N. Leonard
- Department of Chemical and Biological Engineering, Northwestern University, Evanston, Illinois 60208, United States
- Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois 60208, United States
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Evanston, Illinois 60208, United States
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Boosani CS, Agrawal DK. Epigenetic Regulation of Innate Immunity by microRNAs. Antibodies (Basel) 2016; 5:E8. [PMID: 31557989 PMCID: PMC6698855 DOI: 10.3390/antib5020008] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Revised: 03/16/2016] [Accepted: 03/16/2016] [Indexed: 12/20/2022] Open
Abstract
The innate immune response, which is usually referred to as the first line of defense, protects the hosts against pathogenic micro-organisms. Some of the biomolecules released from the pathogens, such as proteins, lipoproteins and nucleic acids, which are collectively termed as pathogen-associated molecular patterns (PAMPs), elicit signaling mechanisms that trigger immune responses in the hosts. Pathogen recognition receptors (PRRs) on the host cells recognize these PAMPs and initiate intracellular signaling through toll-like receptors (TLRs), RIG-I-like receptors (RLRs), and other pathways which induce production of pro-inflammatory cytokines and type I interferons. Recently, different members of tripartite motif containing proteins (TRIM) family of proteins were identified to intercept and regulate these cellular pathways. Specific targets of TRIM proteins have been identified and their molecular mechanisms were unraveled and identified unique domains involved in protein-protein interactions. Though innate immunity represents a tight and well conserved immune system in the host, gene expression in innate immunity was identified to be influenced by several epigenetic mechanisms including regulation by microRNAs (miRNAs). In this review, we present critical analysis of the findings on the identification of specific miRNAs that modulate expression of target genes involved in the regulation of innate immunity.
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Affiliation(s)
- Chandra S Boosani
- Department of Clinical & Translational Science, Creighton University School of Medicine, Omaha, NE 68178, USA.
| | - Devendra K Agrawal
- Department of Clinical & Translational Science, Creighton University School of Medicine, Omaha, NE 68178, USA.
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Abstract
Being a member of the early growth response (Egr) family of transcription factors, Egr-2 is expressed in a variety of cell types of the immune system. Recent findings imply that Egr-2 is important in the development and function of T helper (Th) 17 cell, regulatory T (Treg) cell, as well as dendritic cell (DC). Although these cells perform significantly in the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus, multiple sclerosis, and systemic sclerosis, the roles of Egr-2 in the pathogenesis of autoimmune diseases can not be neglected. In this article, we will discuss recent findings about the important roles of Egr-2 in immune cells and the possible pathological roles of Egr-2 in autoimmune diseases.
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A novel cyclic helix B peptide inhibits dendritic cell maturation during amelioration of acute kidney graft rejection through Jak-2/STAT3/SOCS1. Cell Death Dis 2015; 6:e1993. [PMID: 26610206 PMCID: PMC4670942 DOI: 10.1038/cddis.2015.338] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2015] [Revised: 09/22/2015] [Accepted: 10/09/2015] [Indexed: 12/23/2022]
Abstract
We recently synthesized a novel proteolysis-resistant cyclic helix B peptide (CHBP) that exhibits promising renoprotective effects. Dendritic cells (DCs) play an activation role in acute rejection (AR). Thus, the present study was designed to investigate the effects of CHBP on DCs in a rat renal transplantation model. The left kidney was harvested from male Lewis rats and then transplanted into male Wistar rats with or without CHBP treatment. Five successive treatment doses of CHBP after transplantation significantly ameliorated AR with lower histological injury, apoptosis and CD4+ and CD8+ T-cell infiltration in renal allografts. CHBP reduced IFN-γ and IL-1β levels but increased IL-4 and IL-10 levels in the serum. The number of mature DCs was significantly decreased in renal allografts treated with CHBP. In addition, incubating DCs with CHBP in vitro led to reduction in TNF-α, IFN-γ, IL-1β and IL-12 levels and increase of IL-10 expression at the protein level in the supernatant. Mechanistically, CHBP inhibited TLR activation-induced DC maturation by increasing SOCS1 expression through Jak-2/STAT3 signaling. In conclusion, CHBP suppresses renal allograft AR by inhibiting the maturation of DCs via Jak-2/STAT3/SOCS1 signaling, suggesting that CHBP may be an potential therapeutic drug for treating renal AR.
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Ma YL, Ma ZJ, Wang M, Liao MY, Yao R, Liao YH. MicroRNA-155 induces differentiation of RAW264.7 cells into dendritic-like cells. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2015; 8:14050-14062. [PMID: 26823719 PMCID: PMC4713505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Accepted: 10/26/2015] [Indexed: 06/05/2023]
Abstract
MicroRNA (miRNA, miR)-155 is the most promising pro-inflammatory miRNA molecule. Lipopolysaccharide (LPS) and oxidized low-density lipoprotein (oxLDL) are the most well-known foreign antigens, initiating immune responses against infection and the development of atherosclerosis (AS), respectively. To explore whether miR-155 is involved in regulating LPS- and oxLDL-initiated inflammations, we investigated the level of miR-155 in both LPS- and oxLDL-treated RAW264.7 cells, assessed whether miR-155 induce morphologic changes of the cells and how did it regulate the production of surface markers and cytokines. The results showed that the level of miR-155 was significantly increased by LPS and was modestly increased by oxLDL. Moreover, RAW264.7 cells displayed morphological transformations from macrophage-like cells into DC-like cells when miR-155 was over-expressed. Furthermore, the gain- and loss-of-function studies demonstrated that miR-155 induced the expression of the surface markers (including MHC-II, MHC-I, CD86, and CD83) and pro-inflammatory cytokines (including interleukin (IL)-12, IL-6, and IL-1b) in both LPS- and oxLDL-treated RAW264.7 cells. Additionally, miR-155 induced the expression of CD36 in oxLDL-treated RAW264.7 cells. In conclusion, up-regulated miR-155 is able to induce morphological and phenotypic changes, and the expression of pro-inflammatory cytokines in both LPS- and oxLDL-treated RAW264.7 cells. Therefore, our study suggests that miR-155 is one important regulator involved in enhancing both LPS- and oxLDL-initiated inflammations, which is critical for the progression of immune responses as well as for the development of AS.
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Affiliation(s)
- Yu-Lan Ma
- Department of Cardiology, General Hospital of Ningxia Medical UniversityYinchuan 750004, China
| | - Zhi-Jun Ma
- Department of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430022, Hubei, China
| | - Min Wang
- Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430022, Hubei, China
| | - Meng-Yang Liao
- Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430022, Hubei, China
| | - Rui Yao
- Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430022, Hubei, China
| | - Yu-Hua Liao
- Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430022, Hubei, China
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McCormick SM, Heller NM. Regulation of Macrophage, Dendritic Cell, and Microglial Phenotype and Function by the SOCS Proteins. Front Immunol 2015; 6:549. [PMID: 26579124 PMCID: PMC4621458 DOI: 10.3389/fimmu.2015.00549] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Accepted: 10/13/2015] [Indexed: 12/11/2022] Open
Abstract
Macrophages are innate immune cells of dynamic phenotype that rapidly respond to external stimuli in the microenvironment by altering their phenotype to respond to and to direct the immune response. The ability to dynamically change phenotype must be carefully regulated to prevent uncontrolled inflammatory responses and subsequently to promote resolution of inflammation. The suppressor of cytokine signaling (SOCS) proteins play a key role in regulating macrophage phenotype. In this review, we summarize research to date from mouse and human studies on the role of the SOCS proteins in determining the phenotype and function of macrophages. We will also touch on the influence of the SOCS on dendritic cell (DC) and microglial phenotype and function. The molecular mechanisms of SOCS function in macrophages and DCs are discussed, along with how dysregulation of SOCS expression or function can lead to alterations in macrophage/DC/microglial phenotype and function and to disease. Regulation of SOCS expression by microRNA is discussed. Novel therapies and unanswered questions with regard to SOCS regulation of monocyte-macrophage phenotype and function are highlighted.
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Affiliation(s)
- Sarah M McCormick
- Anesthesiology and Critical Care Medicine, The Johns Hopkins University , Baltimore, MD , USA
| | - Nicola M Heller
- Anesthesiology and Critical Care Medicine, The Johns Hopkins University , Baltimore, MD , USA ; Anesthesiology and Critical Care Medicine, The Johns Hopkins University , Baltimore, MD , USA
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Lu LF, Gasteiger G, Yu IS, Chaudhry A, Hsin JP, Lu Y, Bos PD, Lin LL, Zawislak CL, Cho S, Sun JC, Leslie CS, Lin SW, Rudensky AY. A Single miRNA-mRNA Interaction Affects the Immune Response in a Context- and Cell-Type-Specific Manner. Immunity 2015; 43:52-64. [PMID: 26163372 DOI: 10.1016/j.immuni.2015.04.022] [Citation(s) in RCA: 140] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2014] [Revised: 04/23/2015] [Accepted: 04/28/2015] [Indexed: 10/23/2022]
Abstract
MicroRNA (miRNA)-dependent regulation of gene expression confers robustness to cellular phenotypes and controls responses to extracellular stimuli. Although a single miRNA can regulate expression of hundreds of target genes, it is unclear whether any of its distinct biological functions can be due to the regulation of a single target. To explore in vivo the function of a single miRNA-mRNA interaction, we mutated the 3' UTR of a major miR-155 target (SOCS1) to specifically disrupt its regulation by miR-155. We found that under physiologic conditions and during autoimmune inflammation or viral infection, some immunological functions of miR-155 were fully or largely attributable to the regulation of SOCS1, whereas others could be accounted only partially or not at all by this interaction. Our data suggest that the role of a single miRNA-mRNA interaction is dependent on cell type and biological context.
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Affiliation(s)
- Li-Fan Lu
- Howard Hughes Medical Institute and Immunology Program, and Ludwig Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Division of Biological Sciences and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA
| | - Georg Gasteiger
- Howard Hughes Medical Institute and Immunology Program, and Ludwig Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Institute of Medical Microbiology and Hygiene, University of Mainz Medical Centre, Mainz 55131, Germany
| | - I-Shing Yu
- Laboratory Animal Center, College of Medicine, National Taiwan University, Taipei 100, Taiwan
| | - Ashutosh Chaudhry
- Howard Hughes Medical Institute and Immunology Program, and Ludwig Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
| | - Jing-Ping Hsin
- Howard Hughes Medical Institute and Immunology Program, and Ludwig Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
| | - Yuheng Lu
- Computational Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
| | - Paula D Bos
- Howard Hughes Medical Institute and Immunology Program, and Ludwig Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
| | - Ling-Li Lin
- Howard Hughes Medical Institute and Immunology Program, and Ludwig Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Division of Biological Sciences and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA
| | - Carolyn L Zawislak
- Howard Hughes Medical Institute and Immunology Program, and Ludwig Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
| | - Sunglim Cho
- Division of Biological Sciences and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA
| | - Joseph C Sun
- Howard Hughes Medical Institute and Immunology Program, and Ludwig Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
| | - Christina S Leslie
- Computational Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
| | - Shu-Wha Lin
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei 100, Taiwan; Department of Laboratory Medicine, National Taiwan University Hospital, Taipei 100, Taiwan
| | - Alexander Y Rudensky
- Howard Hughes Medical Institute and Immunology Program, and Ludwig Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
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Ahmed CMI, Larkin J, Johnson HM. SOCS1 Mimetics and Antagonists: A Complementary Approach to Positive and Negative Regulation of Immune Function. Front Immunol 2015; 6:183. [PMID: 25954276 PMCID: PMC4404822 DOI: 10.3389/fimmu.2015.00183] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2015] [Accepted: 04/02/2015] [Indexed: 01/31/2023] Open
Abstract
Suppressors of cytokine signaling (SOCS) are inducible intracellular proteins that play essential regulatory roles in both immune and non-immune function. Of the eight known members, SOCS1 and SOCS3 in conjunction with regulatory T cells play key roles in regulation of the immune system. Molecular tools such as gene transfections and siRNA have played a major role in our functional understanding of the SOCS proteins where a key functional domain of 12-amino acid residues called the kinase inhibitory region (KIR) has been identified on SOCS1 and SOCS3. KIR plays a key role in inhibition of the JAK2 tyrosine kinase, which in turn plays a key role in cytokine signaling. A peptide corresponding to KIR (SOCS1-KIR) bound to the activation loop of JAK2 and inhibited tyrosine phosphorylation of STAT1α transcription factor by JAK2. Cell internalized SOCS1-KIR is a potent therapeutic in the experimental allergic encephalomyelitis (EAE) mouse model of multiple sclerosis and showed promise in a psoriasis model and a model of diabetes-associated cardiovascular disease. By contrast, a peptide, pJAK2(1001-1013), that corresponds to the activation loop of JAK2 is a SOCS1 antagonist. The antagonist enhanced innate and adaptive immune response against a broad range of viruses including herpes simplex virus, vaccinia virus, and an EMC picornavirus. SOCS mimetics and antagonists are thus potential therapeutics for negative and positive regulation of the immune system.
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Affiliation(s)
- Chulbul M I Ahmed
- Department of Microbiology and Cell Science, University of Florida , Gainesville, FL , USA
| | - Joseph Larkin
- Department of Microbiology and Cell Science, University of Florida , Gainesville, FL , USA
| | - Howard M Johnson
- Department of Microbiology and Cell Science, University of Florida , Gainesville, FL , USA
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Zhang JJ, Fan YC, Zhang ZH, Han J, Wang LY, Li T, Zhang F, Yin YP, Hu LH, Yang Y, Sun FK, Wang K. Methylation of suppressor of cytokine signalling 1 gene promoter is associated with acute-on-chronic hepatitis B liver failure. J Viral Hepat 2015; 22:307-317. [PMID: 25045829 DOI: 10.1111/jvh.12286] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2014] [Accepted: 05/14/2014] [Indexed: 12/13/2022]
Abstract
Suppressor of cytokine signalling 1 (SOCS1) was demonstrated to play an important negative role in fulminant hepatitis and might be involved in acute-on-chronic hepatitis B liver failure (ACHBLF). This study was therefore to identify the potential role of SOCS1 and its promoter methylation pattern in ACHBLF patients. Sixty ACHBLF patients, 60 chronic hepatitis B (CHB) patients and 30 healthy controls were investigated in this study. We found that expression of SOCS1 mRNA in CHB and ACHBLF patients was significantly higher than that in healthy controls. The serum level of IL-6, IFN-γ and TNF-α was significantly higher in ACHBLF than CHB. Increased serum level of IL-6, IFN-γ and TNF-α was correlated with total bilirubin, ALT, PTA and MELD scores in ACHBLF. The degree of methylation of the SOCS1 in ACHBLF patients (35.0%, 21/60) was significantly higher than that in CHB patients (16.7%, 10/60). Furthermore, methylated group showed lower level of SOCS1, and higher MELD scores and mortality rate when compared with unmethylated group of ACHBLF. These results suggested that SOCS1 might contribute to immune-related liver damage in ACHBLF, and its aberrant methylation may be a key event for the prognosis of ACHBLF.
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Affiliation(s)
- J-J Zhang
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
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Guerrero AD, Dong MB, Zhao Y, Lau-Kilby A, Tarbell KV. Interleukin-2-mediated inhibition of dendritic cell development correlates with decreased CD135 expression and increased monocyte/macrophage precursors. Immunology 2015; 143:640-50. [PMID: 24954893 DOI: 10.1111/imm.12345] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2014] [Revised: 06/06/2014] [Accepted: 06/18/2014] [Indexed: 11/27/2022] Open
Abstract
We have previously shown that interleukin-2 (IL-2) inhibits dendritic cell (DC) development from mouse bone marrow (BM) precursors stimulated with the ligand for FMS-like tyrosine kinase 3 receptor (Flt3L), and have provided evidence that this inhibition occurs at the monocyte DC precursor stage of DC development. Here, we explored the mechanism of IL-2-mediated inhibition of DC development. First, we showed that these in vitro cultures accurately model DCs that develop in vivo by comparing gene and protein expression of the three main Flt3L-induced DC subsets from the BM, CD11b(+) and CD24(+) conventional DCs (cDCs) and plasmacytoid DCs (pDCs) with their respective ex vivo spleen DC subsets (CD11b(+), CD8(+) and pDCs). Next, gene expression changes were quantified in Flt3L DC subsets that developed in the presence of IL-2. These changes included increased expression of Bcl2l11, which encodes the apoptosis-inducing protein Bim, and decreased expression of Flt3 (CD135), the receptor that initiates DC development. Interleukin-2 also significantly reduced Flt3 protein expression on all three Flt3L DC subsets, and attenuated Flt3L-induced STAT3 phosphorylation in DCs. Based on these data, we hypothesized that decreased Flt3 signalling may divert BM precursors down monocyte and macrophage lineages. Indeed, addition of IL-2 led to increases in Flt3(-) cells, including cKit(+) Ly6C(+) CD11b(-) populations consistent with the recently identified committed monocyte/macrophage progenitor. Therefore, IL-2 can inhibit DC development via decreased signalling through Flt3 and increased monocyte/macrophage development.
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Affiliation(s)
- Alan D Guerrero
- Immune Tolerance Section, Diabetes, Endocrinology and Obesity Branch, National Institute of Diabetes, and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
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Abstract
Inflammatory bowel disease (IBD), comprised of ulcerative colitis and Crohn's disease, is believed to develop as a result of a deregulated inflammatory response to environmental factors in genetically susceptible individuals. Despite advances in understanding the genetic risks of IBD, associated single nucleotide polymorphisms have low penetrance, monozygotic twin studies suggest a low concordance rate, and increasing worldwide IBD incidence leave gaps in our understanding of IBD heritability and highlight the importance of environmental influences. Operating at the interface between environment and heritable molecular and cellular phenotypes, microRNAs (miRNAs) are a class of endogenous, small noncoding RNAs that regulate gene expression. Studies to date have identified unique miRNA expression profile signatures in IBD and preliminary functional analyses associate these deregulated miRNAs to canonical pathways associated with IBD pathogenesis. In this review, we summarize and discuss the miRNA expression signatures associated with IBD in tissue and peripheral blood, highlight miRNAs with potential future clinical applications as diagnostic and therapeutic targets, and provide an outlook on how to develop miRNA based therapies.
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Affiliation(s)
| | - Joel Pekow
- Section of Gastroenterology, Hepatology and Nutrition, University of Chicago, 900 East 57th Street, MB # 9, Chicago, IL 60637, USA
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Batich KA, Swartz AM, Sampson JH. Enhancing dendritic cell-based vaccination for highly aggressive glioblastoma. Expert Opin Biol Ther 2014; 15:79-94. [PMID: 25327832 DOI: 10.1517/14712598.2015.972361] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Patients with primary glioblastoma (GBM) have a dismal prognosis despite standard therapy, which can induce potentially deleterious side effects. Arming the immune system is an alternative therapeutic approach, as its cellular effectors and inherent capacity for memory can be utilized to specifically target invasive tumor cells, while sparing collateral damage to otherwise healthy brain parenchyma. AREAS COVERED Active immunotherapy is aimed at eliciting a specific immune response against tumor antigens. Dendritic cells (DCs) are one of the most potent activators of de novo and recall immune responses and are thus a vehicle for successful immunotherapy. Currently, investigators are optimizing DC vaccines by enhancing maturation status and migratory potential to induce more potent antitumor responses. An update on the most recent DC immunotherapy trials is provided. EXPERT OPINION Targeting of unique antigens restricted to the tumor itself is the most important parameter in advancing DC vaccines. In order to overcome intrinsic mechanisms of immune evasion observed in GBM, the future of DC-based therapy lies in a multi-antigenic vaccine approach. Successful targeting of multiple antigens will require a comprehensive understanding of all immunologically relevant oncological epitopes present in each tumor, thereby permitting a rational vaccine design.
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Affiliation(s)
- Kristen A Batich
- Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of Surgery ; Durham, NC 27710 , USA
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XU YANG, WANG WENLING, GOU AIHONG, LI HAITAO, TIAN YANLI, YAO MEIHUA, YANG RONGYA. Effects of suppressor of cytokine signaling 1 silencing on human melanoma cell proliferation and interferon-γ sensitivity. Mol Med Rep 2014; 11:583-8. [DOI: 10.3892/mmr.2014.2674] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2014] [Accepted: 08/22/2014] [Indexed: 11/05/2022] Open
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49
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Luo Y, Deng Y, Tao Z, Chen S, Xiao B, Ren J, Chen Z, Han J, Kong Y, Xu Y, Deng M. Regulatory effect of microRNA-135a on the Th1/Th2 imbalance in a murine model of allergic rhinitis. Exp Ther Med 2014; 8:1105-1110. [PMID: 25187805 PMCID: PMC4151666 DOI: 10.3892/etm.2014.1855] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2014] [Accepted: 02/10/2014] [Indexed: 12/11/2022] Open
Abstract
Allergic rhinitis (AR) is primarily caused by a T helper cell (Th)1/Th2 imbalance. In a murine AR model of a previous study, the serum ovalbumin (OVA)-sIgE concentration was high, whereas microRNA (miR)-135a was lowly expressed in the nasal mucosa. The abnormal expression pattern of miR-135a coincided with highly expressed endogenous factors, including GATA binding protein (GATA)-3 and interleukin (IL)-4, and lowly expressed factors, including T-box expressed in T cells (T-bet) and interferon (IFN)-γ. We hypothesized that miR-135a may play an important role in immune regulation in AR mice. In the present study, AR was induced by OVA in the mice. Two groups of the AR mice were treated with a miR-135a mimic and a mimic control, respectively. The serum and nasal mucosa were collected for analysis. Following miR-135a application, the serum OVA-sIgE concentration was significantly reduced. In the nasal mucosa, the expression levels of miR-135a were higher, the mRNA and protein expression levels of GATA-3 and IL-4 were lower, and the expression levels of T-bet and IFN-γ were higher. The miR-135a corrected the Th1/Th2 imbalance in the AR mice. Findings of this study may provide a basis for novel genetic treatments in addressing allergic diseases.
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Affiliation(s)
- Yanyun Luo
- Department of Otolaryngology - Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Yuqin Deng
- Department of Otolaryngology - Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Zezhang Tao
- Department of Otolaryngology - Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Shiming Chen
- Department of Otolaryngology - Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Bokui Xiao
- Department of Otolaryngology - Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Jie Ren
- Department of Otolaryngology - Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Zhe Chen
- Department of Otolaryngology - Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Jibo Han
- Department of Otolaryngology - Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Yonggang Kong
- Department of Otolaryngology - Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Yu Xu
- Department of Otolaryngology - Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Minjie Deng
- Department of Otolaryngology - Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
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p38 MAPK-inhibited dendritic cells induce superior antitumour immune responses and overcome regulatory T-cell-mediated immunosuppression. Nat Commun 2014; 5:4229. [PMID: 24957461 DOI: 10.1038/ncomms5229] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2013] [Accepted: 05/27/2014] [Indexed: 01/06/2023] Open
Abstract
Dendritic cell (DC)-based cancer immunotherapy is a promising method, but so far has demonstrated limited clinical benefits. Regulatory T cells (Tregs) represent a major obstacle to cancer immunotherapy approaches. Here we show that inhibiting p38 MAPK during DC differentiation enables DCs to activate tumour-specific effector T cells (Teff), inhibiting the conversion of Treg and compromising Treg inhibitory effects on Teff. Inhibition of p38 MAPK in DCs lowers expression of PPARγ, activating p50 and upregulating OX40L expression in DCs. OX40L/OX40 interactions between DCs and Teff and/or Treg are critical for priming effective and therapeutic antitumour responses. Similarly, p38 MAPK inhibition also augments the T-cell stimulatory capacity of human monocyte-derived DCs in the presence of Treg. These findings contribute to ongoing efforts to improve DC-based immunotherapy in human cancers.
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