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Liu C, Wang D, Huang X, Song Z, Ye L, Zhou G. The expression and clinical significance of cytokines Th1, Th2, and Th17 in ovarian cancer. Am J Med Sci 2025; 369:346-353. [PMID: 39332523 DOI: 10.1016/j.amjms.2024.08.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 08/15/2024] [Accepted: 08/20/2024] [Indexed: 09/29/2024]
Abstract
BACKGROUND This study was to analyze the levels of Th1, Th2 and Th17 cytokines in peripheral blood samples from ovarian cancer (OC) patients. METHODS Ninty-five OC patients including 45 OC and 50 benign ovarian disease (BOD) were selected at Zhejiang Cancer Hospital from October 2021 to March 2022; 46 healthy participants were simultaneously selected at Taizhou Municipal Hospital as healthy controls (HC). The expressions of Th1, Th2 and Th17 were compared in all participants. Marker levels were analyzed with age, histological type, tumor size, ovarian number and clinical stage of OC. RESULTS The IL6 and IL8 levels were significantly higher in OC compared to BOD and HC (p < 0.00). The IL-4 expression was significantly higher in OC compared to HC (p < 0.00). The expressions of IL2, IL6 and IL10 were significantly higher in pathological stage III-IV OC compared with pathological stage I-II OC (p < 0.05). Meanwhile, the levels of IL-2 and IL-10 were significantly higher in OC with bilateral ovaries than in OC with single ovary (p < 0.05). AUCs of different markers were to diagnose OC. The findings also implied that the expressions of IL-6, IL-8 and IL-10 were significantly different between OC and control groups (p < 0.05), while the levels of IL-2, IL-4, TNF-α, IFN-γ, IL-12p70, IL-1β and IL-5 between the two groups were not different (p > 0.05). CONCLUSIONS In peripheral blood from OC patients, the immune system was more dysregulated and immune cells produced more cytokines with contrasting actions. These data showed significant clinical implications for the diagnosis of OC.
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Affiliation(s)
- Chibo Liu
- Department of Clinical Laboratory Medicine, Taizhou Municipal Hospital, Taizhou, Zhejiang 318000, China
| | - Dongguo Wang
- Department of Clinical Laboratory Medicine, Taizhou Municipal Hospital, Taizhou, Zhejiang 318000, China
| | - Xingtang Huang
- Meikang Biotechnology Co., Ltd, Ningbo, Zhejiang 315105, China
| | - Zhiwei Song
- Department of Clinical Laboratory Medicine, Taizhou Municipal Hospital, Taizhou, Zhejiang 318000, China
| | - Liuqing Ye
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Guoming Zhou
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China.
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Zhang M, Yang Y, Liu J, Guo L, Guo Q, Liu W. Bone marrow immune cells and drug resistance in acute myeloid leukemia. Exp Biol Med (Maywood) 2025; 250:10235. [PMID: 40008144 PMCID: PMC11851207 DOI: 10.3389/ebm.2025.10235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Accepted: 01/23/2025] [Indexed: 02/27/2025] Open
Abstract
In recent years, the relationship between the immunosuppressive niche of the bone marrow and therapy resistance in acute myeloid leukemia (AML) has become a research focus. The abnormal number and function of immunosuppressive cells, including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), along with the dysfunction and exhaustion of immunological effector cells, including cytotoxic T lymphocytes (CTLs), dendritic cells (DCs) and natural killer cells (NKs), can induce immune escape of leukemia cells and are closely linked to therapy resistance in leukemia. This article reviews the research progress on the relationship between immune cells in the marrow microenvironment and chemoresistance in AML, aiming to provide new ideas for the immunotherapy of AML.
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Affiliation(s)
- Miao Zhang
- Department of Pediatrics (Hematological Oncology), Children Hematological Oncology and Birth Defects Laboratory, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
- Sichuan Clinical Research Center for Birth Defects, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - You Yang
- Department of Pediatrics (Hematological Oncology), Children Hematological Oncology and Birth Defects Laboratory, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
- Sichuan Clinical Research Center for Birth Defects, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Jing Liu
- Department of Pediatrics (Hematological Oncology), Children Hematological Oncology and Birth Defects Laboratory, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
- Sichuan Clinical Research Center for Birth Defects, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Ling Guo
- Department of Pediatrics (Hematological Oncology), Children Hematological Oncology and Birth Defects Laboratory, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
- Sichuan Clinical Research Center for Birth Defects, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Qulian Guo
- Department of Pediatrics (Hematological Oncology), Children Hematological Oncology and Birth Defects Laboratory, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
- Sichuan Clinical Research Center for Birth Defects, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Wenjun Liu
- Department of Pediatrics (Hematological Oncology), Children Hematological Oncology and Birth Defects Laboratory, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
- Sichuan Clinical Research Center for Birth Defects, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
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Zhou F, Wang W, Xu R, Liu L, Lin T, He L, Tang L, Wang X, He Y. Unraveling the mechanism of Yiqi Jiedu formula against nasopharyngeal carcinoma: An investigation integrating network pharmacology, serum pharmacochemistry, and metabolomics. JOURNAL OF ETHNOPHARMACOLOGY 2024; 319:117343. [PMID: 37879509 DOI: 10.1016/j.jep.2023.117343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 10/13/2023] [Accepted: 10/22/2023] [Indexed: 10/27/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Yiqi Jiedu formula (YQJDF), rooted in the traditional Chinese medicinal principle of "tonifying qi and detoxifying", is remarkably efficacious in the clinical treatment of nasopharyngeal carcinoma (NPC). Previous studies have shed light on some of its anti-NPC effects and mechanisms, but the responsible pharmacological substances and their precise mechanisms of action remain unclear. AIM OF THE STUDY The purpose of this study was to identify components of YQJDF that entered the bloodstream and to investigate their mechanisms of action against NPC through network pharmacology and serum metabolomics. MATERIAL AND METHODS Components of YQJDF in serum were identified using liquid chromatography-tandem mass spectrometry. With these serum species as the focus of our research, network pharmacology analysis was used to identify active compounds and target genes that might mediate the efficacy of YQJDF in the treatment of NPC. Following establishment of an NPC xenograft model in nude mice, a non-targeted metabolomics approach was adopted to identify significant serum metabolites and metabolic pathways influenced by YQJDF. RESULTS Thirty-six components of YQJDF were identified, primarily consisting of alkaloids, phenylpropanoids, and flavonoids. Notably, pathways such as PI3K/AKT, factors associated with Epstein-Barr virus infection, IL-17 signaling, and lipid metabolism, were highlighted as potential therapeutic targets of YQJDF during NPC treatment. Additionally, our findings suggested that YQJDF modified the metabolism of arginine and proline in the serum of mice bearing nasopharyngeal tumor grafts. CONCLUSIONS This study identified the primary active components of YQJDF, highlighting its holistic role in the treatment of NPC through multiple targets and pathways. Furthermore, our findings provided a roadmap for future research into the mechanism of YQJDF in the therapy of NPC, setting the stage for its clinical application.
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Affiliation(s)
- Fangliang Zhou
- Hunan University of Chinese Medicine, Changsha, 410208, China; Hunan Provincial Engineering and Technological Research Center for Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Chinese Medicine and Protecting Visual Function, Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Wen Wang
- Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Runshi Xu
- Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Liu Liu
- Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Ting Lin
- Hunan University of Chinese Medicine, Changsha, 410208, China; Hunan Provincial Key Lab for the Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Lan He
- Hunan Provincial Engineering and Technological Research Center for Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Chinese Medicine and Protecting Visual Function, Hunan University of Chinese Medicine, Changsha, 410208, China; The First Affiliated Hospital, Hunan University of Chinese Medicine, Changsha, 410007, China
| | - Le Tang
- Hunan University of Chinese Medicine, Changsha, 410208, China; Hunan Provincial Engineering and Technological Research Center for Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Chinese Medicine and Protecting Visual Function, Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Xianwen Wang
- Hunan Provincial Engineering and Technological Research Center for Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Chinese Medicine and Protecting Visual Function, Hunan University of Chinese Medicine, Changsha, 410208, China; The First Affiliated Hospital, Hunan University of Chinese Medicine, Changsha, 410007, China.
| | - Yingchun He
- Hunan University of Chinese Medicine, Changsha, 410208, China; Hunan Provincial Engineering and Technological Research Center for Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Chinese Medicine and Protecting Visual Function, Hunan University of Chinese Medicine, Changsha, 410208, China.
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Peng Z, Dong X, He M, Zhao Y, Liu Y, Li M, Li G, Wang X, Li L, Hu Y. Elevated profiles of peripheral Th22, Th17, Th2 cells, and decreased percentage of Th1 cells in breast cancer patients. Thorac Cancer 2023; 14:3282-3294. [PMID: 37732365 PMCID: PMC10665788 DOI: 10.1111/1759-7714.15119] [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: 07/23/2023] [Revised: 09/10/2023] [Accepted: 09/11/2023] [Indexed: 09/22/2023] Open
Abstract
BACKGROUND Th22 subset is a particular type of CD4+ T helper cells subset. Our study aimed to explore the expression level of circulating Th22, Th17, Th1, and Th2 cells and the possible mechanism of these cells in breast cancer (BC) with different pathological features. METHODS Our study enrolled 43 newly diagnosed BC patients and 30 healthy controls. Frequencies of peripheral Th22, Th17, Th1, and Th2 cells were tested by flow cytometry. Concentrations of IL-22 cytokine in plasma were examined by enzyme-linked immunosorbent assay (ELISA). Real-time PCR was done to test aromatic hydrocarbon receptor (AHR) and RAR-associated orphan receptor C (RORC) gene expression. RESULTS Frequencies of Th22, Th17, Th2 subsets, and the plasma IL-22 level was obviously higher in the BC patients. A positive correlation between Th22 frequency and IL-22 concentration in plasma was detected in BC patients. Furthermore, the percentage of Th22, Th2 subsets in peripheral blood of HER2 positive BC was higher than that in HER2 negative BC patients. A negative correlation between Th1 subset and Ki-67% as well as a positive correlation between Th2 subset and Ki-67% was found in BC patients. The proportion of Th1 cells in BC patients was significantly lower than that of the control group. Expression of AHR and RORC transcription factors were also observed to be upregulated in the BC patients. Furthermore, Th22 cells were positively correlated with BC tumor stage and clinical outcomes. The BC patients with a higher percentage of Th22, Th17, Th1 cells or a lower percentage of Th1 cells showed a decreased trend of survival rate. CONCLUSION Th22, Th17, Th1, and Th2 subsets may play an essential role in BC patients. Th22, Th17, Th1, and Th2 cells may have potential significance to be used as clinical markers in BC patients with different molecular classification. Th22 cells may have potential value in BC patients' outcomes prediction, providing clinical value.
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Affiliation(s)
- Zhiguo Peng
- Department of Organ Transplantation, Qilu Hospital, Cheeloo College of MedicineShandong UniversityJinanChina
| | - Xinyue Dong
- Department of OncologyQilu Hospital of Shandong University Dezhou HospitalDezhouChina
| | - Miao He
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of MedicineShandong UniversityJinanChina
| | - Yajing Zhao
- Department of Hematology, Qilu Hospital, Cheeloo College of MedicineShandong UniversityJinanChina
| | - Yujia Liu
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of MedicineShandong UniversityJinanChina
| | - Mo Li
- Department of OncologyWeifang People's HospitalWeifangChina
| | - Guosheng Li
- Department of Hematology, Qilu Hospital, Cheeloo College of MedicineShandong UniversityJinanChina
| | - Xiuwen Wang
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of MedicineShandong UniversityJinanChina
| | - Li Li
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of MedicineShandong UniversityJinanChina
| | - Yu Hu
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of MedicineShandong UniversityJinanChina
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Matsuyama-Kato A, Shojadoost B, Boodhoo N, Raj S, Alizadeh M, Fazel F, Fletcher C, Zheng J, Gupta B, Abdul-Careem MF, Plattner BL, Behboudi S, Sharif S. Activated Chicken Gamma Delta T Cells Are Involved in Protective Immunity against Marek's Disease. Viruses 2023; 15:v15020285. [PMID: 36851499 PMCID: PMC9962238 DOI: 10.3390/v15020285] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 01/10/2023] [Accepted: 01/17/2023] [Indexed: 01/20/2023] Open
Abstract
Gamma delta (γδ) T cells play a significant role in the prevention of viral infection and tumor surveillance in mammals. Although the involvement of γδ T cells in Marek's disease virus (MDV) infection has been suggested, their detailed contribution to immunity against MDV or the progression of Marek's disease (MD) remains unknown. In the current study, T cell receptor (TCR)γδ-activated peripheral blood mononuclear cells (PBMCs) were infused into recipient chickens and their effects were examined in the context of tumor formation by MDV and immunity against MDV. We demonstrated that the adoptive transfer of TCRγδ-activated PBMCs reduced virus replication in the lungs and tumor incidence in MDV-challenged chickens. Infusion of TCRγδ-activated PBMCs induced IFN-γ-producing γδ T cells at 10 days post-infection (dpi), and degranulation activity in circulating γδ T cell and CD8α+ γδ T cells at 10 and 21 dpi in MDV-challenged chickens. Additionally, the upregulation of IFN-γ and granzyme A gene expression at 10 dpi was significant in the spleen of the TCRγδ-activated PBMCs-infused and MDV-challenged group compared to the control group. Taken together, our results revealed that TCRγδ stimulation promotes the effector function of chicken γδ T cells, and these effector γδ T cells may be involved in protection against MD.
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Affiliation(s)
- Ayumi Matsuyama-Kato
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada
| | - Bahram Shojadoost
- Ceva Animal Health Inc., Research Park Centre, Guelph, ON N1G 4T2, Canada
| | - Nitish Boodhoo
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada
| | - Sugandha Raj
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada
| | - Mohammadali Alizadeh
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada
| | - Fatemeh Fazel
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada
| | - Charlotte Fletcher
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada
| | - Jiayu Zheng
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada
| | - Bhavya Gupta
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada
| | | | - Brandon L. Plattner
- Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA
| | | | - Shayan Sharif
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada
- Correspondence: ; Tel.: +1-519-824-4120 (ext. 54641); Fax: +1-519-824-5930
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Cui C, Zhang D, Sun K, Zhu Y, Xu J, Kang Y, Zhang G, Cai Y, Mao S, Long R, Ma J, Dong S, Sun Y. Propofol maintains Th17/Treg cell balance in elderly patients undergoing lung cancer surgery through GABAA receptor. BMC Immunol 2022; 23:58. [PMID: 36434505 PMCID: PMC9701037 DOI: 10.1186/s12865-022-00490-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Accepted: 03/17/2022] [Indexed: 11/27/2022] Open
Abstract
Propofol is widely used in clinical anesthesia due to its advantages of rapid onset and less adverse reactions. This study focused on the role of propofol in the balance of Th17/Treg in elderly patients with lung cancer during perioperative period. Patients undergoing lung cancer surgery were anesthetized by propofol or sevoflurane. Veinal blood was collected at different time points to evaluate the changes of Th17/Treg cell. Propofol better maintained the balance of Th17/Treg in vivo. The peripheral blood of patients with lung cancer was collected in vitro before surgery. Cluster of differentiation (CD)4+ T cells were obtained and then treated with propofol at different concentrations and γ-aminobutyric acid A (GABAA) receptor antagonists. Propofol affected Th17/Treg cell balance by increasing Th17 cells, decreasing Treg cells, thus elevating Th17/Treg ratio, and inhibited invasion and migration of lung cancer cells through GABAA receptor, which was counteracted by GABAA receptor inhibitors. Subsequently, tumor in situ model of lung cancer in aged mice was established. Propofol anesthetized mice had lower change of Th17/Treg ratio, higher survival rate and less metastasis. In brief, propofol regulated balance of Th17/Treg in elderly patients undergoing lung cancer surgery through GABAA receptor. Additionally, propofol could inhibit metastasis of lung cancer.
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Affiliation(s)
- Can Cui
- grid.413405.70000 0004 1808 0686Department of Anesthesiology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, 96 DongChuan Road, Guangzhou, 510080 China
| | - Dengwen Zhang
- grid.413405.70000 0004 1808 0686Department of Anesthesiology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, 96 DongChuan Road, Guangzhou, 510080 China
| | - Ke Sun
- grid.413405.70000 0004 1808 0686Department of Anesthesiology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, 96 DongChuan Road, Guangzhou, 510080 China
| | - Yi Zhu
- grid.413405.70000 0004 1808 0686Department of Anesthesiology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, 96 DongChuan Road, Guangzhou, 510080 China
| | - Jindong Xu
- grid.413405.70000 0004 1808 0686Department of Anesthesiology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, 96 DongChuan Road, Guangzhou, 510080 China
| | - Yin Kang
- grid.413405.70000 0004 1808 0686Department of Anesthesiology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, 96 DongChuan Road, Guangzhou, 510080 China
| | - Guangyan Zhang
- grid.413405.70000 0004 1808 0686Department of Anesthesiology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, 96 DongChuan Road, Guangzhou, 510080 China
| | - Yujin Cai
- grid.413405.70000 0004 1808 0686Department of Anesthesiology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, 96 DongChuan Road, Guangzhou, 510080 China
| | - Songsong Mao
- grid.413405.70000 0004 1808 0686Department of Anesthesiology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, 96 DongChuan Road, Guangzhou, 510080 China
| | - Ruichun Long
- grid.413405.70000 0004 1808 0686Department of Anesthesiology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, 96 DongChuan Road, Guangzhou, 510080 China
| | - Jue Ma
- grid.413405.70000 0004 1808 0686Department of Anesthesiology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, 96 DongChuan Road, Guangzhou, 510080 China
| | - Song Dong
- grid.413405.70000 0004 1808 0686Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, 96 DongChuan Road, Guangzhou, 510080 China
| | - Yi Sun
- grid.413405.70000 0004 1808 0686Department of Anesthesiology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, 96 DongChuan Road, Guangzhou, 510080 China
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Karaca F, Keskin S, Mentes S, Okten AI, Cavus G, Arslan A, Afsar CU, Koksal F. Evaluation of IL-17A expressions in high-grade glial tumors receiving radiotherapy. Niger J Clin Pract 2022; 25:582-588. [PMID: 35593599 DOI: 10.4103/njcp.njcp_1408_21] [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: 11/04/2022]
Abstract
Aim In this study, we aimed to investigate the interleukin-17A (IL-17A) levels in patients with high-grade glial tumors before receiving radiotherapy, immediately after radiotherapy, and 3 months after radiotherapy. Patients and Methods A total of 33 patients who applied to Adana City Training and Research Hospital, Department of Radiation Oncology between December 2016 and May 2018 was included in this study. A total of three blood samples was taken from each patient to assess IL-17A levels before and after radiotherapy and 3 months after the completion of radiotherapy. Results The differences in IL-17A levels between genders were not statistically significant. IL-17A levels progressively decreased after the radiotherapy and 3 months after the radiotherapy as compared to the levels before radiotherapy. However, this was not statistically significant. IL-17A levels in the non-surviving patients were high before and after radiotherapy as compared to the surviving ones, but this was also not statistically significant. Conclusion As compared to the period before radiotherapy, IL-17A levels tend to decrease in the period of acute and chronic phases of radiotherapy in all patient groups.
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Affiliation(s)
- F Karaca
- Department of Radiation Oncology, Adana City Training and Research Hospital, Adana, Turkey
| | - S Keskin
- Department of Biostatistics, Van Yüzüncü Yıl University Medical Faculty, Van, Turkey
| | - S Mentes
- Department of Radiation Oncology, Adana City Training and Research Hospital, Adana, Turkey
| | - A I Okten
- Department of Neurosurgery, Adana City Training and Research Hospital, Adana, Turkey
| | - G Cavus
- Department of Neurosurgery, Adana City Training and Research Hospital, Adana, Turkey
| | - A Arslan
- Department of Neurosurgery, Adana City Training and Research Hospital, Adana, Turkey
| | - C U Afsar
- Department of Medical Oncology, Istinye University Medical Faculty, Liv Vadi Hospital, Istanbul, Turkey
| | - F Koksal
- Department of Microbiology, Çukurova University School of Medicine, Adana, Turkey
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Impact of the Tumor Microenvironment for Esophageal Tumor Development—An Opportunity for Prevention? Cancers (Basel) 2022; 14:cancers14092246. [PMID: 35565378 PMCID: PMC9100503 DOI: 10.3390/cancers14092246] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 04/26/2022] [Accepted: 04/28/2022] [Indexed: 02/05/2023] Open
Abstract
Simple Summary Researchers increasingly appreciate the tumor microenvironment (TME) for its role in the development and therapy resistance of cancers like esophageal adenocarcinoma. A better understanding of the TME fueling carcinogenesis is necessary for tailored prevention and therapies. Here, we highlight recent insights into tumor initiation, interactions with the immune system and possible novel preventative measures. Abstract Despite therapeutical advancements, and in contrast to other malignancies, esophageal adenocarcinoma (EAC) prognosis remains dismal while the incidence has markedly increased worldwide over the past decades. EAC is a malignancy of the distal esophageal squamous epithelium at the squamocolumnar junction with gastric cells expanding into the esophagus. Most EAC patients have a history of Barret’s esophagus (BE), a metaplastic adaption to chronic reflux, initially causing an inflammatory microenvironment. Thus, the immune system is highly involved early on in disease development and progression. Normally, anti-tumor immunity could prevent carcinogenesis but in rare cases BE still progresses over a dysplastic intermediate state to EAC. The inflammatory milieu during the initial esophagitis phase changes to a tolerogenic immune environment in BE, and back to pro-inflammatory conditions in dysplasia and finally to an immune-suppressive tumor microenvironment in EAC. Consequently, there is a huge interest in understanding the underpinnings that lead to the inflammation driven stepwise progression of the disease. Since knowledge about the constellations of the various involved cells and signaling molecules is currently fragmentary, a comprehensive description of these changes is needed, allowing better preventative measures, diagnosis, and novel therapeutic targets.
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Zhang Y, Huo L, Wei Z, Tang Q, Sui H. Hotspots and Frontiers in Inflammatory Tumor Microenvironment Research: A Scientometric and Visualization Analysis. Front Pharmacol 2022; 13:862585. [PMID: 35370647 PMCID: PMC8968939 DOI: 10.3389/fphar.2022.862585] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 02/11/2022] [Indexed: 12/13/2022] Open
Abstract
Methods: Articles on inflammatory tumor microenvironment were retrieved from the Web of Science Core Collection, and the characteristics of the articles were analyzed by CiteSpace software. Background: The inflammatory tumor microenvironment is an essential feature of the tumor microenvironment. The way in which it promotes or inhibits tumor progression plays an important role in the outcome of a tumor treatment. This research aims to explore a scientific collaboration network, describe evolution of hotspots, and predict future trends through bibliometric analysis. Results: A total of 3,534 papers published by 390 institutions in 81 countries/regions were screened, and the annual quantity has been increasing rapidly in the past decades. United States was the leading country and has the most productive institutions in this field. The research topics were mainly focused on inflammation and immunity mediated by crucial factors as well as the mechanisms of angiogenesis. Additionally, the development and application of nanoparticles is currently a novel research frontier with bright prospect. Conclusion: The present scientometric study provides an overview of inflammatory tumor microenvironment research over the previous decades using quantitative and qualitative methods, and the findings of this study can provide references for researchers focusing on tumor treatment.
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Affiliation(s)
- Yuli Zhang
- Medical Experiment Center, Jiading Branch of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of Traditional Chinese Medicine, Jiading Branch of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Long Huo
- Department of Gastroenterology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhenzhen Wei
- Medical Experiment Center, Jiading Branch of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qingfeng Tang
- Department of Clinical Laboratory, Jiading Branch of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of Clinical Laboratory and Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hua Sui
- Medical Experiment Center, Jiading Branch of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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10
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Colombani T, Eggermont LJ, Hatfield SM, Rogers ZJ, Rezaeeyazdi M, Memic A, Sitkovsky MV, Bencherif SA. Oxygen-Generating Cryogels Restore T Cell Mediated Cytotoxicity in Hypoxic Tumors. ADVANCED FUNCTIONAL MATERIALS 2021; 31:2102234. [PMID: 37745940 PMCID: PMC10516343 DOI: 10.1002/adfm.202102234] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Indexed: 09/26/2023]
Abstract
Solid tumors are protected from antitumor immune responses due to their hypoxic microenvironments. Weakening hypoxia-driven immunosuppression by hyperoxic breathing of 60% oxygen has shown to be effective in unleashing antitumor immune cells against solid tumors. However, efficacy of systemic oxygenation is limited against solid tumors outside of lungs and has been associated with unwanted side effects. As a result, it is essential to develop targeted oxygenation alternatives to weaken tumor hypoxia as novel approaches to restore immune responses against cancer. Herein, we report on injectable oxygen-generating cryogels (O2-cryogels) to reverse tumor-induced hypoxia. These macroporous biomaterials were designed to locally deliver oxygen, inhibit the expression of hypoxia-inducible genes in hypoxic melanoma cells, and reduce the accumulation of immunosuppressive extracellular adenosine. Our data show that O2-cryogels enhance T cell-mediated secretion of cytotoxic proteins, restoring the killing ability of tumor-specific CTLs, both in vitro and in vivo. In summary, O2-cryogels provide a unique and safe platform to supply oxygen as a co-adjuvant in hypoxic tumors and have the potential to improve cancer immunotherapies.
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Affiliation(s)
- Thibault Colombani
- Department of Chemical Engineering, Northeastern University, Boston, MA 02115, USA
| | - Loek J. Eggermont
- Department of Chemical Engineering, Northeastern University, Boston, MA 02115, USA
| | - Stephen M. Hatfield
- New England Inflammation and Tissue Protection Institute, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA
| | - Zachary J. Rogers
- Department of Chemical Engineering, Northeastern University, Boston, MA 02115, USA
| | | | - Adnan Memic
- Center of Nanotechnology, King Abdulaziz University, Jeddah, Makkah 21589, Saudi Arabia
| | - Michail V. Sitkovsky
- New England Inflammation and Tissue Protection Institute, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA
| | - Sidi A. Bencherif
- Department of Chemical Engineering, Northeastern University, Boston, MA 02115, USA
- Department of Bioengineering, Northeastern University, Boston, MA 02115, USA
- Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA
- Biomechanics and Bioengineering (BMBI), UTC CNRS UMR 7338, University of Technology of Compiègne, Sorbonne University, 60203 Compiègne, France
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11
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Zhu SQ, Zhou BH, Tan PP, Chai J, Yu YM, Wang HW. Based on G-Series Mouse TH17 Array Study the Effect of Fluoride on C2C12 Cells Cytokines Expression. Biol Trace Elem Res 2021; 199:3402-3410. [PMID: 33244669 DOI: 10.1007/s12011-020-02464-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 10/28/2020] [Indexed: 01/22/2023]
Abstract
C2C12 cells were cultured on medium containing fluoride (0, 1, and 2.5 mmol/L) for 48 h to investigate the effect of excessive fluoride on T helper 17 (Th17)-related cytokine expression profile in skeletal muscle cells, and the culture supernatant was collected and subjected for the detection of 18 cytokines via Th17 array. Results showed that compared with the control group, no differential expression proteins (DEPs) were found in the 1 mmol/L fluoride group; however, eight DEPs were upregulated in the 2.5 mmol/L fluoride group, including macrophage inflammatory protein-3α (MIP-3α), interleukin-21 (IL-21), IL-13, IL-17F, IL-28A, transforming growth factor type beta 1 (TGF-β1), IL-23, and IL-17A. In addition, five DEPs (MIP-3α, IL-13, IL-21, TGF-β1, and IL-17F) were upregulated in the 2.5 mmol/L fluoride group compared with the 1 mmol/L fluoride group. Gene ontology analysis revealed that the positive regulation of cytokine production, cytokine activity, receptor ligand activity, and cytokine receptor binding accounted for high percent of DEPs present. Kyoto Encyclopedia of Genes and Genomes analysis showed that these DEPs primarily involved 12 pathways enriched in the cytokine-cytokine receptor interaction and IL-17 signaling pathway after 2.5 mmol/L fluoride treatment. The results indicated that fluoride might induce cytotoxicity by disturbing Th17-related cytokine expression.
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Affiliation(s)
- Shi-Quan Zhu
- College of Animal Science and Technology, Henan University of Science and Technology, 263 Kaiyuan Avenue, Luoyang, 471023, Henan, People's Republic of China
| | - Bian-Hua Zhou
- College of Animal Science and Technology, Henan University of Science and Technology, 263 Kaiyuan Avenue, Luoyang, 471023, Henan, People's Republic of China.
| | - Pan-Pan Tan
- College of Animal Science and Technology, Henan University of Science and Technology, 263 Kaiyuan Avenue, Luoyang, 471023, Henan, People's Republic of China
| | - Jun Chai
- School of Information Technology and Urban Construction, Luoyang Polytechnic, Keji Avenue 6, Yibin District, Luoyang, 471934, Henan, People's Republic of China
| | - Ya-Ming Yu
- College of Animal Science and Technology, Henan University of Science and Technology, 263 Kaiyuan Avenue, Luoyang, 471023, Henan, People's Republic of China
| | - Hong-Wei Wang
- College of Animal Science and Technology, Henan University of Science and Technology, 263 Kaiyuan Avenue, Luoyang, 471023, Henan, People's Republic of China
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12
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Lei MML, Lee TKW. Cancer Stem Cells: Emerging Key Players in Immune Evasion of Cancers. Front Cell Dev Biol 2021; 9:692940. [PMID: 34235155 PMCID: PMC8257022 DOI: 10.3389/fcell.2021.692940] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 05/31/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer stem cells (CSCs) are subpopulations of undifferentiated cancer cells within the tumor bulk that are responsible for tumor initiation, recurrence and therapeutic resistance. The enhanced ability of CSCs to give rise to new tumors suggests potential roles of these cells in the evasion of immune surveillance. A growing body of evidence has described the interplay between CSCs and immune cells within the tumor microenvironment (TME). Recent data have shown the pivotal role of some major immune cells in driving the expansion of CSCs, which concurrently elicit evasion of the detection and destruction of various immune cells through a number of distinct mechanisms. Here, we will discuss the role of immune cells in driving the stemness of cancer cells and provide evidence of how CSCs evade immune surveillance by exerting their effects on tumor-associated macrophages (TAMs), dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs), T-regulatory (Treg) cells, natural killer (NK) cells, and tumor-infiltrating lymphocytes (TILs). The knowledge gained from the interaction between CSCs and various immune cells will provide insight into the mechanisms by which tumors evade immune surveillance. In conclusion, CSC-targeted immunotherapy emerges as a novel immunotherapy strategy against cancer by disrupting the interaction between immune cells and CSCs in the TME.
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Affiliation(s)
- Martina Mang Leng Lei
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Kowloon, Hong Kong
| | - Terence Kin Wah Lee
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Kowloon, Hong Kong.,State Key Laboratory of Chemical Biology and Drug Discovery, The Hong Kong Polytechnic University, Kowloon, Hong Kong
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13
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Roy D, Bose S, Pati S, Guin A, Banerjee K, Saha S, Singhal AK, Chakraborty J, Sarkar DK, Sa G. GFI1/HDAC1-axis differentially regulates immunosuppressive CD73 in human tumor-associated FOXP3 + Th17 and inflammation-linked Th17 cells. Eur J Immunol 2021; 51:1206-1217. [PMID: 33555624 DOI: 10.1002/eji.202048892] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 11/11/2020] [Accepted: 02/04/2021] [Indexed: 12/17/2022]
Abstract
Plasticity between Th17 and Treg cells is regarded as a crucial determinant of tumor-associated immunosuppression. Classically Th17 cells mediate inflammatory responses through production of cytokine IL17. Recently, Th17 cells have also been shown to acquire suppressive phenotypes in tumor microenvironment. However, the mechanism by which they acquire such immunosuppressive properties is still elusive. Here, we report that in tumor microenvironment Th17 cell acquires immunosuppressive properties by expressing Treg lineage-specific transcription factor FOXP3 and ectonucleotidase CD73. We designate this cell as Th17reg cell and perceive that such immunosuppressive property is dependent on CD73. It was observed that in classical Th17 cell, GFI1 recruits HDAC1 to change the euchromatin into tightly-packed heterochromatin at the proximal-promoter region of CD73 to repress its expression. Whereas in Th17reg cells GFI1 cannot get access to CD73-promoter due to heterochromatin state at its binding site and, thus, cannot recruit HDAC1, failing to suppress the expression of CD73.
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Affiliation(s)
- Dia Roy
- Division of Molecular Medicine, Bose Institute, Kolkata, India
| | - Sayantan Bose
- Division of Molecular Medicine, Bose Institute, Kolkata, India
| | - Subhadip Pati
- Division of Molecular Medicine, Bose Institute, Kolkata, India
| | - Aharna Guin
- Division of Molecular Medicine, Bose Institute, Kolkata, India
| | | | - Sudipto Saha
- Department of Bioinformatics, Bose Institute, Kolkata, India
| | | | | | | | - Gaurisankar Sa
- Division of Molecular Medicine, Bose Institute, Kolkata, India
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14
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Boyle ST, Johan MZ, Samuel MS. Tumour-directed microenvironment remodelling at a glance. J Cell Sci 2020; 133:133/24/jcs247783. [PMID: 33443095 DOI: 10.1242/jcs.247783] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The tissue microenvironment supports normal tissue function and regulates the behaviour of parenchymal cells. Tumour cell behaviour, on the other hand, diverges significantly from that of their normal counterparts, rendering the microenvironment hostile to tumour cells. To overcome this problem, tumours can co-opt and remodel the microenvironment to facilitate their growth and spread. This involves modifying both the biochemistry and the biophysics of the normal microenvironment to produce a tumour microenvironment. In this Cell Science at a Glance article and accompanying poster, we outline the key processes by which epithelial tumours influence the establishment of the tumour microenvironment. As the microenvironment is populated by genetically normal cells, we discuss how controlling the microenvironment is both a significant challenge and a key vulnerability for tumours. Finally, we review how new insights into tumour-microenvironment interactions has led to the current consensus on how these processes may be targeted as novel anti-cancer therapies.
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Affiliation(s)
- Sarah T Boyle
- Centre for Cancer Biology, An Alliance between SA Pathology and the University of South Australia, Adelaide, SA 5001, Australia
| | - M Zahied Johan
- Centre for Cancer Biology, An Alliance between SA Pathology and the University of South Australia, Adelaide, SA 5001, Australia
| | - Michael S Samuel
- Centre for Cancer Biology, An Alliance between SA Pathology and the University of South Australia, Adelaide, SA 5001, Australia .,Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5005, Australia
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15
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Myeloid-derived suppressor cell depletion therapy targets IL-17A-expressing mammary carcinomas. Sci Rep 2020; 10:13343. [PMID: 32770025 PMCID: PMC7414122 DOI: 10.1038/s41598-020-70231-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Accepted: 07/20/2020] [Indexed: 12/11/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is an invasive subtype of breast cancer but paradoxically associated with increased tumor-infiltrating leukocytes. The molecular and cellular mechanisms underlying TNBC immunobiology are incompletely understood. Interleukin (IL)-17A is a pro-inflammatory cytokine that has both pro- and anti-tumor effects and found in 40-80% of TNBC samples. We report here that IL-17A mRNA and protein are detectable in some human TNBC cell lines and further upregulated by IL-23 and LPS stimulation. Furthermore, the impact of tumor-derived IL-17A in host immune response and tumor growth was examined using murine TNBC 4T1 mammary carcinoma cells transduced with an adenoviral vector expressing IL-17A (AdIL-17A) or control vector (Addl). Compared to Addl-transduction, AdIL-17A-transduction enhanced 4T1 tumor growth and lung metastasis in vivo, which was associated with a marked expansion of myeloid-derived suppressor cells (MDSCs). However, AdIL-17A-transduction also induced strong organ-specific and time-dependent immune activation indicated by dynamic changes of NK cells, B cells, CD4, and CD8 T cells in peripheral blood, lung, and tumor site, as well as the plasma levels of IFNγ. Such findings highlight that tumor-associated IL-17A induces concurrent immune activation and immune suppression. Administration of anti-Gr1 or anti-G-CSF antibody effectively depleted MDSCs in vivo, markedly reducing the growth of AdIL-17A-transduced 4T1 tumors, and eliminating lung metastasis. Collectively, our study demonstrates that MDSC depletion is an effective and practical approach for treating IL-17A-enriched mammary carcinomas.
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16
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IL-17 Signaling in the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1240:47-58. [DOI: 10.1007/978-3-030-38315-2_4] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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17
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Shahid A, Bharadwaj M. The connection between the Th17 cell related cytokines and cancer stem cells in cancer: Novel therapeutic targets. Immunol Lett 2019; 213:9-20. [PMID: 31278971 DOI: 10.1016/j.imlet.2019.07.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 06/25/2019] [Accepted: 07/02/2019] [Indexed: 02/08/2023]
Abstract
Cancer Stem Cells (CSCs) are the subpopulation of cells present in the different types of cancers with capabilities of self-renewal, differentiation, and tumorigenicity when transplanted into an animal host. The research work on the CSC has been providing a promising approach for the improvement of cancer therapies in the future. The CSCs have a close connection with the cytokines related with the T helper 17 (Th17) cell and other factors present in the tumor microenvironment, and these play a pivotal role in tumor progression and metastasis. The properties of CSCs are well defined in various type of tumor which is mainly developed by chemically and spontaneously in murine cancer model but in human defined primarily on acute myeloid leukemia, glioma, and breast cancer. The role of Th1, Th2, Natural Killer cells are well described in the cancer biology, but the Th17 cells are the subset which is recently exploited, and lots of research are going on. In this Review, we summarize current findings of the characteristics and functions of the Th17 cell and its signature cytokines in different cancers and their interconnections with cancer stem cells and with their markers. We have also discussed the functional properties of CSCs and how the CSCs markers can be distinguished from normal stem cells markers. We have also talked about the strategies that are efficiently targeting of CSCs and Th17 cells in different cancers.
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Affiliation(s)
- Ayaz Shahid
- Molecular Biology Group, National Institute of Cancer Prevention and Research, Indian Council of Medical Research (ICMR), Department of Health Research, Noida, 201301, India
| | - Mausumi Bharadwaj
- Molecular Biology Group, National Institute of Cancer Prevention and Research, Indian Council of Medical Research (ICMR), Department of Health Research, Noida, 201301, India.
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18
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Chen R, Chen QT, Dong YH. Clinical efficacy of apatinib in treating metastatic gastric cancer and its effect on IL-17. Oncol Lett 2019; 17:5447-5452. [PMID: 31186764 PMCID: PMC6507486 DOI: 10.3892/ol.2019.10270] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Accepted: 03/22/2019] [Indexed: 01/20/2023] Open
Abstract
Clinical efficacy of apatinib in treating metastatic gastric cancer and its effect on the levels of serum IL-17 were investigated. A retrospective analysis was performed on 129 patients who had metastatic gastric cancer after first-line chemotherapy and were treated in Xiangyang No. 1 People's Hospital from February 2012 to February 2015. Of these patients, 78 received oral apatinib and were assigned to experimental group; and 51 received oral tegafur-gimeracil-oteracil and were assigned to control group. Clinical efficacy was compared between the two groups, and the levels of serum IL-17 were measured for all the patients. The treatment response rate in the experimental group was 52.56% and in the control group 31.37%. Apparently, the treatment response rate in the experimental group was higher than that in the control group, and the difference was statistically significant (P<0.05). The incidence of adverse drug reactions in the experimental group was significantly lower than that in the control group (P<0.05). The serum level of IL-17 after one course of medication was significantly lower than that before medication in both groups (P<0.05). In comparison between groups, the serum level of IL-17 after one course of medication was clearly lower in the experimental group than that in the control group (P<0.05). Apatinib regimen was demonstrated to have less toxic side-effects in the treatment of metastatic gastric cancer than tegafur-gimeracil-oteracil regimen, indicating that apatinib has favorable safety. In addition, apatinib can downregulate IL-17 expression, which is helpful in attenuating tumor proliferation and improving the clinical efficacy. Therefore, apatinib has potential use in a wide range of clinical applications.
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Affiliation(s)
- Ran Chen
- Department of Oncology, Xiangyang No. 1 People's Hospital, Huibei University of Medicine, Xiangyang, Hubei 441000, P.R. China
| | - Qi-Tian Chen
- Department of Oncology, Xiangyang No. 1 People's Hospital, Huibei University of Medicine, Xiangyang, Hubei 441000, P.R. China
| | - You-Hong Dong
- Department of Oncology, Xiangyang No. 1 People's Hospital, Huibei University of Medicine, Xiangyang, Hubei 441000, P.R. China
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19
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Bedoui S, Dallel M, Barbirou M, Stayoussef M, Mokrani A, Mezlini A, Bouhaouala B, Almawi WY, Yacoubi-Loueslati B. Interleukin-17A polymorphisms predict the response and development of tolerance to FOLFOX chemotherapy in colorectal cancer treatment. Cancer Gene Ther 2019; 27:311-318. [PMID: 31138901 DOI: 10.1038/s41417-019-0102-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Revised: 03/16/2019] [Accepted: 04/27/2019] [Indexed: 02/07/2023]
Abstract
Polymorphic variants in IL-17A gene were differentially associated with colorectal cancer (CRC) susceptibility but their link with response and toxicity to CRC treatment have not yet been evaluated. We investigated association between seven IL-17A variants with the response and toxicity to CRC treatment in 294 patients with CRC. IL-17A genotyping was done by real-time PCR. MAF of rs3748067 was significantly higher in CRC cases resistant to FOLFOX treatment (R+) than non resistant (R-). Significantly higher rs3804513 MAF was noted in R+ versus R- colon cancer (CC). Higher rs2275913 and rs10484879, and reduced rs3804513 MAF were seen in rectal cancer (RC) tolerant to FOLFOX (T+) compared to (T-) patients. Strong association of rs3819025, rs3804513, and rs7747909 was found with tolerance to RC treatment. rs3748067 was associated with FOLFOX tolerance in CC but not RC. Significant higher frequency of AGGCAGG and GAGCAGG haplotypes was seen among R + CC, thus assigning non-favorable nature to these haplotypes. Higher and lower frequencies of GAGTAAG and AGGCTGA haplotypes, respectively, were observed in T + RC, thereby assigning FOLFOX-tolerant and non-tolerant nature to these haplotypes. The obtained results suggest that IL-17A variants and haplotypes may be a target for future management of CRC treatment.
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Affiliation(s)
- Sinda Bedoui
- Department of Biology, Faculty of Sciences of Tunis, Laboratory of Mycology Pathologies and Biomarkers, El Manar University, LR16ES05, Tunis, Tunisia
| | - Meriem Dallel
- Lab. Human Genome and Multifactorial Diseases, University of Monastir, Monastir, Tunisia
| | - Mouadh Barbirou
- Laboratory of Venoms and Therapeutic Molecules, Pasteur Institute of Tunis, University of Tunis El Manar, 13 Place Pasteur, BP74, 1002, Tunis, Tunisia
| | - Mouna Stayoussef
- Department of Biology, Faculty of Sciences of Tunis, Laboratory of Mycology Pathologies and Biomarkers, El Manar University, LR16ES05, Tunis, Tunisia
| | | | | | - Balkiss Bouhaouala
- Laboratory of Venoms and Therapeutic Molecules, Pasteur Institute of Tunis, University of Tunis El Manar, 13 Place Pasteur, BP74, 1002, Tunis, Tunisia.,Medical School of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Wassim Y Almawi
- Department of Biology, Faculty of Sciences of Tunis, Laboratory of Mycology Pathologies and Biomarkers, El Manar University, LR16ES05, Tunis, Tunisia.,Department of Biomedical Sciences, School of Medicine, Nazarbayev University, Astana, Kazakhstan
| | - Besma Yacoubi-Loueslati
- Department of Biology, Faculty of Sciences of Tunis, Laboratory of Mycology Pathologies and Biomarkers, El Manar University, LR16ES05, Tunis, Tunisia.
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20
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Saleh ME, Gadalla R, Hassan H, Afifi A, Götte M, El-Shinawi M, Mohamed MM, Ibrahim SA. The immunomodulatory role of tumor Syndecan-1 (CD138) on ex vivo tumor microenvironmental CD4+ T cell polarization in inflammatory and non-inflammatory breast cancer patients. PLoS One 2019; 14:e0217550. [PMID: 31145753 PMCID: PMC6542534 DOI: 10.1371/journal.pone.0217550] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2018] [Accepted: 05/14/2019] [Indexed: 12/24/2022] Open
Abstract
Herein, we aimed to identify the immunomodulatory role of tumor Syndecan-1 (CD138) in the polarization of CD4+ T helper (Th) subsets isolated from the tumor microenvironment of inflammatory breast cancer (IBC) and non-IBC patients. Lymphocytes and mononuclear cells isolated from the axillary tributaries of non-IBC and IBC patients during modified radical mastectomy were either stimulated with the secretome as indirect co-culture or directly co-cultured with control and Syndecan-1-silenced SUM-149 IBC cells. In addition, peripheral blood mononuclear cells (PBMCs) of normal subjects were used for the direct co-culture. Employing flow cytometry, we analyzed the expression of the intracellular IFN-γ, IL-4, IL-17, and Foxp3 markers as readout for basal and co-cultured Th1, Th2, Th17, and Treg CD4+ subsets, respectively. Our data revealed that IBC displayed a lower basal frequency of Th1 and Th2 subsets than non-IBC. Syndecan-1-silenced SUM-149 cells significantly upregulated only Treg subset polarization of normal subjects relative to controls. However, Syndecan-1 silencing significantly enhanced the polarization of Th17 and Treg subsets of non-IBC under both direct and indirect conditions and induced only Th1 subset polarization under indirect conditions compared to control. Interestingly, qPCR revealed that there was a negative correlation between Syndecan-1 and each of IL-4, IL-17, and Foxp3 mRNA expression in carcinoma tissues of IBC and that the correlation was reversed in non-IBC. Mechanistically, Syndecan-1 knockdown in SUM-149 cells promoted Th17 cell expansion via upregulation of IL-23 and the Notch ligand DLL4. Overall, this study indicates a low frequency of the circulating antitumor Th1 subset in IBC and suggests that tumor Syndecan-1 silencing enhances ex vivo polarization of CD4+ Th17 and Treg cells of non-IBC, whereby Th17 polarization is possibly mediated via upregulation of IL-23 and DLL4. These findings suggest the immunoregulatory role of tumor Syndecan-1 expression in Th cell polarization that may have therapeutic implications for breast cancer.
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Affiliation(s)
| | - Ramy Gadalla
- Department of Zoology, Faculty of Science, Cairo University, Giza, Egypt
| | - Hebatallah Hassan
- Department of Zoology, Faculty of Science, Cairo University, Giza, Egypt
| | - Ahmed Afifi
- Department of Zoology, Faculty of Science, Cairo University, Giza, Egypt
| | - Martin Götte
- Department of Gynecology and Obstetrics, Münster University Hospital, Münster, Germany
| | - Mohamed El-Shinawi
- Department of General Surgery, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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21
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Paaso A, Jaakola A, Syrjänen S, Louvanto K. From HPV Infection to Lesion Progression: The Role of HLA Alleles and Host Immunity. Acta Cytol 2019; 63:148-158. [PMID: 30783048 DOI: 10.1159/000494985] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Accepted: 10/29/2018] [Indexed: 01/27/2023]
Abstract
Persistent high-risk human papillomavirus (HPV) infection has been associated with increased risk for cervical precancerous lesions and cancer. The host's genetic variability is known to play a role in the development of cervical cancer. The human leukocyte antigen (HLA) genes are highly polymorphic and have shown to be important risk determinants of HPV infection persistence and disease progression. HLA class I and II cell surface molecules regulate the host's immune system by presenting HPV-derived peptides to T-cells. The activation of T-cell response may vary depending on the HLA allele polymorphism. The engagement of the T-cell receptor with the HPV peptide-HLA complex to create an active costimulatory signal is essential for the activation of the T-cell response. Functional peptide presentation by both HLA class I and II molecules is needed to activate efficient helper and effector T-cell responses in HPV infection recognition and clearance. Some of these HLA risk alleles could also be used as preventive tools in the detection of HPV-induced cervical lesions and cancer. These HLA alleles, together with HPV vaccines, could potentially offer possible solutions for reducing HPV-induced cervical cancer as well as other HPV-related cancers.
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Affiliation(s)
- Anna Paaso
- Department of Oral Pathology, Institute of Dentistry, Faculty of Medicine, University of Turku, Turku, Finland,
- Department of Obstetrics and Gynecology, Turku University Hospital, University of Turku, Turku, Finland,
| | - Anna Jaakola
- Department of Obstetrics and Gynecology, Turku University Hospital, University of Turku, Turku, Finland
- Department of Obstetrics and Gynecology, Kymenlaakso Central Hospital, Kotka, Finland
| | - Stina Syrjänen
- Department of Oral Pathology, Institute of Dentistry, Faculty of Medicine, University of Turku, Turku, Finland
- Department of Pathology, Turku University Hospital, University of Turku, Turku, Finland
| | - Karolina Louvanto
- Department of Oral Pathology, Institute of Dentistry, Faculty of Medicine, University of Turku, Turku, Finland
- Department of Obstetrics and Gynecology, Turku University Hospital, University of Turku, Turku, Finland
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22
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Jacouton E, Torres Maravilla E, Boucard AS, Pouderous N, Pessoa Vilela AP, Naas I, Chain F, Azevedo V, Langella P, Bermúdez-Humarán LG. Anti-tumoral Effects of Recombinant Lactococcus lactis Strain Secreting IL-17A Cytokine. Front Microbiol 2019; 9:3355. [PMID: 30728820 PMCID: PMC6351453 DOI: 10.3389/fmicb.2018.03355] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Accepted: 12/31/2018] [Indexed: 01/02/2023] Open
Abstract
Interleukin-17A (IL-17A) is a pro-inflammatory cytokine produced by TH17 cells that participates and contributes in host defense and autoimmune disease. We have recently reported antitumor properties of the probiotic strain of Lactobacillus casei BL23 in mice and TH17 cells was shown to play an important role in this beneficial effect. In order to better understand the role of IL-17A in cancer, we constructed a recombinant strain of Lactococcus lactis producing this cytokine and we determined its biological activity in: (i) a bioassay test for the induction of IL-6 production by murine fibroblasts 3T3 L1 cells line and (ii) in a mouse allograft model of human papilloma virus (HPV)-induced cancer. Our data show that recombinant L. lactis produces and efficiently secretes biologically active IL-17A cytokine. Interestingly, ∼26% of mice intranasally treated with L. lactis-IL-17A and challenged with TC-1 cells remained tumor free over the experiment, in contrast to control mice treated with the wild type strain of L. lactis which developed 100% of aggressive tumors. In addition, the median size of the ∼74% tumor-bearing mice treated with recombinant L. lactis-IL-17A, was significantly lower than mice treated with L. lactis-wt. Altogether, our results demonstrate that intranasal administration with L. lactis secreting IL-17A results in a partial protection against TC-1-induced tumors in mice, confirming antitumor effects of this cytokine in our cancer model.
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Affiliation(s)
- Elsa Jacouton
- Micalis Institute, AgroParisTech, INRA, Université Paris-Saclay, Jouy-en-Josas, France
| | | | - Anne-Sophie Boucard
- Micalis Institute, AgroParisTech, INRA, Université Paris-Saclay, Jouy-en-Josas, France
| | - Nicolas Pouderous
- Micalis Institute, AgroParisTech, INRA, Université Paris-Saclay, Jouy-en-Josas, France
| | - Ana Paula Pessoa Vilela
- Micalis Institute, AgroParisTech, INRA, Université Paris-Saclay, Jouy-en-Josas, France.,Instituto de Ciências Biológicas, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Isabelle Naas
- Micalis Institute, AgroParisTech, INRA, Université Paris-Saclay, Jouy-en-Josas, France
| | - Florian Chain
- Micalis Institute, AgroParisTech, INRA, Université Paris-Saclay, Jouy-en-Josas, France
| | - Vasco Azevedo
- Instituto de Ciências Biológicas, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Philippe Langella
- Micalis Institute, AgroParisTech, INRA, Université Paris-Saclay, Jouy-en-Josas, France
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23
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Kido LA, de Almeida Lamas C, Maróstica MR, Cagnon VHA. Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model: A good alternative to study PCa progression and chemoprevention approaches. Life Sci 2019; 217:141-147. [DOI: 10.1016/j.lfs.2018.12.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Revised: 11/26/2018] [Accepted: 12/02/2018] [Indexed: 12/15/2022]
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24
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Associations of the IL-17A rs2275913 and IL-17F rs763780 polymorphisms with the risk of digestive system neoplasms: A meta-analysis. Int Immunopharmacol 2018; 67:248-259. [PMID: 30562686 DOI: 10.1016/j.intimp.2018.12.016] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Revised: 12/07/2018] [Accepted: 12/07/2018] [Indexed: 01/17/2023]
Abstract
OBJECTIVE To clarify the associations between the IL-17A rs2275913 and IL-17F rs763780 polymorphisms and the risk of digestive system neoplasms. METHODS An internet search was used to identify relevant articles from CNKI, Wanfang, VIP, PubMed, EMBASE and Elsevier up to December 2017. The meta-analysis was performed using Stata 11.0 software. RESULTS Twenty-three studies were included. Among these, 21 studies with 6978 cases and 8000 controls were related to IL-17A rs2275913, while 18 studies that included 5073 cases and 6040 controls were related to IL-17F rs763780. The meta-analysis results demonstrated that the overall effects of the two polymorphisms were significantly different (P < 0.05) in the allele model, dominant model, recessive model and codominant model. Subgroup analysis showed that both polymorphisms were significantly associated with susceptibility to gastric cancer but not with hepatocellular carcinoma or colorectal cancer. In the ethnicity analysis, these two polymorphisms were associated with Asian populations but not with Caucasians. Similar results were observed in the hospital-based and population-based control subgroups. CONCLUSIONS The IL-17A rs2275913 and IL-17F rs763780 polymorphisms were associated with susceptibility to digestive system neoplasms.
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25
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Darvishi B, Majidzadeh-A K, Ghadirian R, Mosayebzadeh M, Farahmand L. Recruited bone marrow derived cells, local stromal cells and IL-17 at the front line of resistance development to anti-VEGF targeted therapies. Life Sci 2018; 217:34-40. [PMID: 30472294 DOI: 10.1016/j.lfs.2018.11.033] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 11/14/2018] [Accepted: 11/15/2018] [Indexed: 12/11/2022]
Abstract
Although anti-angiogenic agents targeting VEGF have shown affordable beneficial outcomes in several human cancer types, in most pre-clinical and clinical studies, these effects are transient and followed by rapid relapse and tumor regrowth. Recently, it has been suggested that recruited bone marrow derived cells (BMDCs) to the tumor-microenvironment together with stromal cells play an important role in development of resistance to anti-VEGF therapies. Additionally, acquired resistance to anti-VEGF therapies has shown to be mediated partly through overexpression of different pro-angiogenic cytokines and growth factors including G-CSF, IL-6, IL-8, VEGF and FGF by these cells. Alongside, IL-17, a pro-inflammatory cytokine, mostly secreted by infiltrated CD4+ T helper cells, has shown to mediate resistance to anti-VEGF therapies, through recruiting BMDCs and modulating stromal cells activities including endothelial cells, tumor associated macrophages and cancer associated fibroblasts. Here, we examined the role of BMDCs, tumor stromal cells, IL-17 and their negotiation in development of resistance to anti-VEGF targeted therapies.
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Affiliation(s)
- Behrad Darvishi
- Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
| | - Keivan Majidzadeh-A
- Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran; Tasnim Biotechnology Research Center, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran
| | - Reihane Ghadirian
- Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
| | - Marjan Mosayebzadeh
- Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
| | - Leila Farahmand
- Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran.
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26
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Chraa D, Naim A, Olive D, Badou A. T lymphocyte subsets in cancer immunity: Friends or foes. J Leukoc Biol 2018; 105:243-255. [DOI: 10.1002/jlb.mr0318-097r] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Revised: 09/15/2018] [Accepted: 09/19/2018] [Indexed: 12/17/2022] Open
Affiliation(s)
- Dounia Chraa
- Cellular and Molecular Pathology LaboratoryFaculty of Medicine and Pharmacy of CasablancaHassan II University Casablanca Morocco
- Team Immunity and Cancer, Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, U1068, CNRS, UMR7258Institut Paoli‐CalmettesAix‐Marseille University, UM 105 Marseille France
| | - Asmaa Naim
- Cellular and Molecular Pathology LaboratoryFaculty of Medicine and Pharmacy of CasablancaHassan II University Casablanca Morocco
- University Mohammed VI for Health ScienceCheick Khalifa Hospital Casablanca Morocco
| | - Daniel Olive
- Team Immunity and Cancer, Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, U1068, CNRS, UMR7258Institut Paoli‐CalmettesAix‐Marseille University, UM 105 Marseille France
| | - Abdallah Badou
- Cellular and Molecular Pathology LaboratoryFaculty of Medicine and Pharmacy of CasablancaHassan II University Casablanca Morocco
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27
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Sabzevary-Ghahfarokhi M, Shirzad H, Rafieian-Kopaei M, Ghatreh-Samani M, Shohan M. The Role of Inflammatory Cytokines in Creating T Cell Exhaustion in Cancer. Cancer Biother Radiopharm 2018; 33:267-273. [DOI: 10.1089/cbr.2018.2449] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Affiliation(s)
- Milad Sabzevary-Ghahfarokhi
- Department of Microbiology and Immunology, Faculty of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Hedayatollah Shirzad
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Mahmoud Rafieian-Kopaei
- Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Mahdi Ghatreh-Samani
- Cellular and Molecular Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Mojtaba Shohan
- Department of Microbiology and Immunology, Faculty of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
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28
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Gaur P, Shukla NK, Das SN. Phenotypic and Functional Characteristics of Th17 (CD4 +IL17A +) Cells in Human Oral Squamous Cell Carcinoma and Its Clinical Relevance. Immunol Invest 2018; 46:689-702. [PMID: 28872971 DOI: 10.1080/08820139.2017.1360344] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Recent studies have suggested an important role of T helper 17 (Th17) cells in tumor biology however, their phenotypic and functional aspects are poorly understood in context with oral cancer. We therefore, investigated the various phenotypic and functional markers of Th17 cells elucidating their relevance in oral squamous cell carcinoma (OSCC). Multi-color flow cytometry (FACs) was used to analyze the frequency and different markers of circulating Th17 cells ex vivo in peripheral blood mono-nuclear cells (PBMCs) from 69 OSCC patients and 35 healthy controls. Percent Mean ± SEM of different types of cells were compared between the two groups using Mann-Whitney U test. We found significantly (p < 0.0001) increased frequency of Th17 cells in patients as compared to controls. These cells were found to express CCR6 profoundly but not CXCR4, CD62L, and CCR7 as chemokine receptors. Additionally, it expressed HLA-DR, CD69, and CD25 moderately but CD28 and CD161 highly. The cytokine profiling revealed 3 subsets namely Th17/1 (IL17A+IFNγ+), Th17/inflammatory (IL17A+IL8+), and Th17/2 (IL17A+IL4+) which were found to be elevated in patients as compared to controls. The early stage patients had a shift toward Th17/1 type and vice versa. Our results suggest that Th17 cells may have effector immune functions in oral cancer immunity through CCR6, CD161, HLA-DR, CD69, CD28 receptors and inducing Th17/1 type of cells expressing polyfunctional antitumor IFNγ cytokine. Thus, novel immune-boosting regimens based on enhancement of Th17 cells in oral cancer patients may provide therapeutic benefits in them.
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Affiliation(s)
- Poonam Gaur
- a Departments of Biotechnology , All India Institute of Medical Sciences , Ansari Nagar, New Delhi , India
| | - Nootan K Shukla
- b Surgical Oncology, BRA-IRCH , All India Institute of Medical Sciences , Ansari Nagar, New Delhi , India
| | - Satya N Das
- a Departments of Biotechnology , All India Institute of Medical Sciences , Ansari Nagar, New Delhi , India
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29
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Merrouche Y, Fabre J, Cure H, Garbar C, Fuselier C, Bastid J, Antonicelli F, Al-Daccak R, Bensussan A, Giustiniani J. IL-17E synergizes with EGF and confers in vitro resistance to EGFR-targeted therapies in TNBC cells. Oncotarget 2018; 7:53350-53361. [PMID: 27462789 PMCID: PMC5288192 DOI: 10.18632/oncotarget.10804] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Accepted: 07/13/2016] [Indexed: 12/22/2022] Open
Abstract
Estrogen receptor-, progesterone receptor- and HER2-negative breast cancers, also known as triple-negative breast cancers (TNBCs), have poor prognoses and are refractory to current therapeutic agents, including epidermal growth factor receptor (EGFR) inhibitors. Resistance to anti-EGFR therapeutic agents is often associated with sustained kinase phosphorylation, which promotes EGFR activation and translocation to the nucleus and prevents these agents from acting on their targets. The mechanisms underlying this resistance have not been fully elucidated. In addition, the IL-17E receptor is overexpressed in TNBC tumors and is associated with a poor prognosis. We have previously reported that IL-17E promotes TNBC resistance to anti-mitotic therapies. Here, we investigated whether IL-17E promotes TNBC resistance to anti-EGFR therapeutic agents by exploring the link between the IL-17E/IL-17E receptor axis and EGF signaling. We found that IL-17E, similarly to EGF, activates the EGFR in TNBC cells that are resistant to EGFR inhibitors. It also activates the PYK-2, Src and STAT3 kinases, which are essential for EGFR activation and nuclear translocation. IL-17E binds its specific receptor, IL-17RA/IL17RB, on these TNBC cells and synergizes with the EGF signaling pathway, thereby inducing Src-dependent EGFR transactivation and pSTAT3 and pEGFR translocation to the nucleus. Collectively, our data indicate that the IL-17E/IL-17E receptor axis may underlie TNBC resistance to EGFR inhibitors and suggest that inhibiting IL-17E or its receptor in combination with EGFR inhibitor administration may improve TNBC management.
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Affiliation(s)
- Yacine Merrouche
- Institut Jean Godinot, Unicancer, F-51726 Reims, France.,Université Reims-Champagne-Ardenne, DERM-I-C, EA7319, 51095 Reims, France
| | - Joseph Fabre
- Institut Jean Godinot, Unicancer, F-51726 Reims, France.,Université Reims-Champagne-Ardenne, DERM-I-C, EA7319, 51095 Reims, France
| | - Herve Cure
- CHU-Grenoble Alpes, CS 10217, 38043 La Tronche, France.,Institut National de la Santé et de la Recherche Médicale (INSERM) U823, Centre de Recherche (CRI), Institut Albert Bonniot, 38043 La Tronche, France
| | - Christian Garbar
- Institut Jean Godinot, Unicancer, F-51726 Reims, France.,Université Reims-Champagne-Ardenne, DERM-I-C, EA7319, 51095 Reims, France
| | - Camille Fuselier
- Institut Jean Godinot, Unicancer, F-51726 Reims, France.,Université Reims-Champagne-Ardenne, DERM-I-C, EA7319, 51095 Reims, France
| | | | - Frank Antonicelli
- Université Reims-Champagne-Ardenne, DERM-I-C, EA7319, 51095 Reims, France
| | - Reem Al-Daccak
- Institut National de la Santé et de la Recherche Médicale (INSERM) UMR-S 976, Hôpital Saint Louis, 75010 Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, Laboratoire Immunologie Dermatologie and Oncologie, UMR-S 976, F-75475, Paris, France
| | - Armand Bensussan
- OREGA Biotech, F-69130 Ecully, France.,Institut National de la Santé et de la Recherche Médicale (INSERM) UMR-S 976, Hôpital Saint Louis, 75010 Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, Laboratoire Immunologie Dermatologie and Oncologie, UMR-S 976, F-75475, Paris, France
| | - Jerome Giustiniani
- Institut Jean Godinot, Unicancer, F-51726 Reims, France.,Université Reims-Champagne-Ardenne, DERM-I-C, EA7319, 51095 Reims, France
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30
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Interleukin 17 and peripheral IL-17-expressing T cells are negatively correlated with the overall survival of head and neck cancer patients. Oncotarget 2018. [PMID: 29515773 PMCID: PMC5839404 DOI: 10.18632/oncotarget.23934] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The presence and clinical significance of interleukin (IL)-17 and IL-17-expressing cells have recently been studied in several types of cancer, but their correlation to tumor development remains controversial. Additionally, the contribution of peripheral IL-17-expressing cells to head and neck cancer (HNC) progression is still poorly understood. We collected peripheral blood from healthy donors and HNC patients to isolate PBMCs. The percentages of IL-17-expressing cells and the production of inflammatory cytokines in PBMCs were measured to determine their association with clinical outcomes and overall survival in HNC. We evaluated the effect and potential mechanism of IL-17 on human oral squamous carcinomas in vitro using exogenous IL-17 stimulation. In comparison to healthy donors, the PBMCs of HNC patients have a significant accumulation of IL-17-expressing T cells and their frequencies were positively correlated with the disease stage. A significantly higher production of PBMC IL-17, TGF-β and IL-21 and plasma VEGF-A were found in HNC patients. Importantly, the 5-years overall survival of HNC patients with a higher percentage of IL-17-expressing cells is significantly decreased. Furthermore, the addition of IL-17 appeared to promote human oral squamous carcinoma cell proliferation via the production of IL-6 and VEGF-A. Our findings suggest that IL-17 has the potential to mediate pro-tumor immunity in the HNC tumor microenvironment. Enhanced IL-17-expressing cells, including Th17 and Tc17 cells, in the peripheral blood could be a significant predictor of a poor prognosis for HNC patients.
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31
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Alves LF, da Silva RF, Cagnon VHA. Nintedanib effects on delaying cancer progression and decreasing COX-2 and IL-17 in the prostate anterior lobe in TRAMP mice. Tissue Cell 2017; 50:96-103. [PMID: 29429524 DOI: 10.1016/j.tice.2017.12.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Revised: 12/15/2017] [Accepted: 12/24/2017] [Indexed: 12/13/2022]
Abstract
Prostate cancer is the most prevalent type of cancer in men around the world. Due to its high incidence, new therapies have been evaluated, including drugs capable of inhibiting the FGF/VEGF pathways, as Nintedanib. The aim herein was to evaluate the Nintedanib therapeutic effects on morphology and COX-2 and IL-17 levels in the prostate anterior lobe in different grades of the tumor progression in TRAMP mice. Animals were treated with Nintedanib at a dose of 10 mg/kg/day in initial and intermediate grades of tumor development. At the end of treatment, the prostate anterior lobe was collected and submitted to morphological, immunohistochemical and Western Blotting analyses. The results showed that Nintedanib delayed the prostate carcinogenesis progression, with over 20% of reduction in frequency of tissue injuries, particularly in the group treated from 12 to 16 weeks of age. Also, decreased COX-2 and IL-17 levels were observed in both groups treated with Nintedanib in the prostate anterior lobe. Thus, we concluded that Nintedanib was effective in delaying tumor progression and, despite not directly acting on inflammation, Nintedanib may adversely affect inflammatory pathways, favoring prostate cancer delay.
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Affiliation(s)
- Letícia Ferreira Alves
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), São Paulo, Brazil
| | - Raquel Frenedoso da Silva
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), São Paulo, Brazil
| | - Valéria Helena Alves Cagnon
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), São Paulo, Brazil.
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32
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Asadzadeh Z, Mohammadi H, Safarzadeh E, Hemmatzadeh M, Mahdian-Shakib A, Jadidi-Niaragh F, Azizi G, Baradaran B. The paradox of Th17 cell functions in tumor immunity. Cell Immunol 2017; 322:15-25. [PMID: 29103586 DOI: 10.1016/j.cellimm.2017.10.015] [Citation(s) in RCA: 153] [Impact Index Per Article: 19.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2017] [Accepted: 10/29/2017] [Indexed: 02/08/2023]
Abstract
Immune system acts as a host defensive mechanism protecting against attacking pathogens and transformed cells, including cancer cells. Th17 cells are a specific subset of T helper lymphocytes determined by high secretion of IL-17 and other inflammatory cytokines. Th17 cells increase tumor progression by activating angiogenesis and immunosuppressive activities. They can also mediate antitumor immune responses through recruiting immune cells into tumors, stimulating effector CD8+ T cells, or surprisingly by altering toward Th1 phenotype and producing IFN-γ, so Th17 cells are supposed as a double-edged sword in cancer. A comprehensive approach to indicating the activity of Th17 cells in tumor progression could help in the planning of new therapeutic approaches specially targeting Th17 cells in cancer.
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Affiliation(s)
- Zahra Asadzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hamed Mohammadi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Elham Safarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Hemmatzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ahmad Mahdian-Shakib
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Farhad Jadidi-Niaragh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Gholamreza Azizi
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran; Department of Laboratory Medicine, Imam Hassan Mojtaba Hospital, Alborz University of Medical Sciences, Karaj, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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33
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Janiak MK, Wincenciak M, Cheda A, Nowosielska EM, Calabrese EJ. Cancer immunotherapy: how low-level ionizing radiation can play a key role. Cancer Immunol Immunother 2017; 66:819-832. [PMID: 28361232 PMCID: PMC5489643 DOI: 10.1007/s00262-017-1993-z] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Accepted: 03/22/2017] [Indexed: 12/17/2022]
Abstract
The cancer immunoediting hypothesis assumes that the immune system guards the host against the incipient cancer, but also "edits" the immunogenicity of surviving neoplastic cells and supports remodeling of tumor microenvironment towards an immunosuppressive and pro-neoplastic state. Local irradiation of tumors during standard radiotherapy, by killing neoplastic cells and generating inflammation, stimulates anti-cancer immunity and/or partially reverses cancer-promoting immunosuppression. These effects are induced by moderate (0.1-2.0 Gy) or high (>2 Gy) doses of ionizing radiation which can also harm normal tissues, impede immune functions, and increase the risk of secondary neoplasms. In contrast, such complications do not occur with exposures to low doses (≤0.1 Gy for acute irradiation or ≤0.1 mGy/min dose rate for chronic exposures) of low-LET ionizing radiation. Furthermore, considerable evidence indicates that such low-level radiation (LLR) exposures retard the development of neoplasms in humans and experimental animals. Here, we review immunosuppressive mechanisms induced by growing tumors as well as immunomodulatory effects of LLR evidently or likely associated with cancer-inhibiting outcomes of such exposures. We also offer suggestions how LLR may restore and/or stimulate effective anti-tumor immunity during the more advanced stages of carcinogenesis. We postulate that, based on epidemiological and experimental data amassed over the last few decades, whole- or half-body irradiations with LLR should be systematically examined for its potential to be a viable immunotherapeutic treatment option for patients with systemic cancer.
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Affiliation(s)
- Marek K Janiak
- Department of Radiobiology and Radiation Protection, Military Institute of Hygiene and Epidemiology, 4 Kozielska St., 01-163, Warsaw, Poland.
| | - Marta Wincenciak
- Department of Radiobiology and Radiation Protection, Military Institute of Hygiene and Epidemiology, 4 Kozielska St., 01-163, Warsaw, Poland
| | - Aneta Cheda
- Department of Radiobiology and Radiation Protection, Military Institute of Hygiene and Epidemiology, 4 Kozielska St., 01-163, Warsaw, Poland
| | - Ewa M Nowosielska
- Department of Radiobiology and Radiation Protection, Military Institute of Hygiene and Epidemiology, 4 Kozielska St., 01-163, Warsaw, Poland
| | - Edward J Calabrese
- Department of Environmental Health Sciences, School of Public Health and Health Sciences, Morrill I, N344, University of Massachusetts, Amherst, MA, 01003, USA
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34
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Li N, Xu W, Yuan Y, Ayithan N, Imai Y, Wu X, Miller H, Olson M, Feng Y, Huang YH, Jo Turk M, Hwang ST, Malarkannan S, Wang L. Immune-checkpoint protein VISTA critically regulates the IL-23/IL-17 inflammatory axis. Sci Rep 2017; 7:1485. [PMID: 28469254 PMCID: PMC5431161 DOI: 10.1038/s41598-017-01411-1] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Accepted: 04/04/2017] [Indexed: 01/01/2023] Open
Abstract
V-domain Immunoglobulin Suppressor of T cell Activation (VISTA) is an inhibitory immune-checkpoint molecule that suppresses CD4+ and CD8+ T cell activation when expressed on antigen-presenting cells. Vsir -/- mice developed loss of peripheral tolerance and multi-organ chronic inflammatory phenotypes. Vsir -/- CD4+ and CD8+ T cells were hyper-responsive towards self- and foreign antigens. Whether or not VISTA regulates innate immunity is unknown. Using a murine model of psoriasis induced by TLR7 agonist imiquimod (IMQ), we show that VISTA deficiency exacerbated psoriasiform inflammation. Enhanced TLR7 signaling in Vsir -/- dendritic cells (DCs) led to the hyper-activation of Erk1/2 and Jnk1/2, and augmented the production of IL-23. IL-23, in turn, promoted the expression of IL-17A in both TCRγδ+ T cells and CD4+ Th17 cells. Furthermore, VISTA regulates the peripheral homeostasis of CD27- γδ T cells and their activation upon TCR-mediated or cytokine-mediated stimulation. IL-17A-producing CD27- γδ T cells were expanded in the Vsir -/- mice and amplified the inflammatory cascade. In conclusion, this study has demonstrated that VISTA critically regulates the inflammatory responses mediated by DCs and IL-17-producing TCRγδ+ and CD4+ Th17 T cells following TLR7 stimulation. Our finding provides a rationale for therapeutically enhancing VISTA-mediated pathways to benefit the treatment of autoimmune and inflammatory disorders.
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Affiliation(s)
- Na Li
- Department of Microbiology and Immunology, Milwaukee, WI, 53226, USA.,Department of Histology and Embryology, Harbin Medical University, Harbin, 150086, P. R. China
| | - Wenwen Xu
- Department of Microbiology and Immunology, Milwaukee, WI, 53226, USA
| | - Ying Yuan
- Department of Microbiology and Immunology, Milwaukee, WI, 53226, USA.,Shanghai University of Traditional Chinese Medicine, College of Pharmacy, Shanghai, 201203, P. R. China
| | - Natarajan Ayithan
- Department of Microbiology and Immunology, Milwaukee, WI, 53226, USA.,Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Yasutomo Imai
- Department of Dermatology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.,Department of Dermatology, Hyogo College of Medicine 1-1, Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Xuesong Wu
- Department of Dermatology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.,Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA
| | - Halli Miller
- Department of Microbiology and Immunology, Milwaukee, WI, 53226, USA
| | - Michael Olson
- Department of Microbiology and Immunology, Milwaukee, WI, 53226, USA
| | - Yunfeng Feng
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA
| | - Yina H Huang
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA
| | - Mary Jo Turk
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA
| | - Samuel T Hwang
- Department of Dermatology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.,Department of Dermatology, University of California Davis, Sacramento, CA, 95816, USA
| | - Subramaniam Malarkannan
- Department of Microbiology and Immunology, Milwaukee, WI, 53226, USA.,Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.,Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.,Department of Blood Research Institute, Milwaukee, WI, 53226, USA
| | - Li Wang
- Department of Microbiology and Immunology, Milwaukee, WI, 53226, USA.
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Madonna S, Scarponi C, Morelli M, Sestito R, Scognamiglio PL, Marasco D, Albanesi C. SOCS3 inhibits the pathological effects of IL-22 in non-melanoma skin tumor-derived keratinocytes. Oncotarget 2017; 8:24652-24667. [PMID: 28445952 PMCID: PMC5421877 DOI: 10.18632/oncotarget.15629] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Accepted: 02/15/2017] [Indexed: 12/21/2022] Open
Abstract
Basal cell carcinomas (BCC) and squamous-cell carcinomas (SCC) are common malignancies in humans, caused by neoplastic transformation of keratinocytes of the basal or suprabasal layers of epidermis, respectively. Tumor-infiltrating lymphocytes (TILs) are frequently found in BCC and SCC, and functionally promote epithelial carcinogenesis. TILs secreting IL-22, in particular, participate to BCC and SCC growth by inducing keratinocyte proliferation and migration, as well as the expression of inflammatory, anti-apoptotic and pro-angiogenic genes.In this study, we identified SOCS3 as a valid candidate to be manipulated for suppressing tumorigenic functions in BCC and SCC. We found that SOCS3 and SOCS1 expression was reduced in vivo, in tumor lesions of BCC and SCC, as compared to other skin inflammatory conditions such as psoriasis, despite the high number of IL-22-secreting TILs. Moreover, IL-22 was not able to induce in vitro the transcriptional expression of SOCS3 in BCC-or SCC-derived keratinocytes, contrarily to healthy cells. Aimed at rescuing SOCS3 activity in these tumor contexts, a SOCS3-derived peptide, named KIR-ESS, was synthesized, and its ability in suppressing IL-22-induced responses was evaluated in healthy and transformed keratinocytes. We found that KIR-ESS peptide efficiently suppressed the IL-22 molecular signaling in keratinocytes, by acting on STAT3 and Erk1/2 cascade, as well as on the expression of STAT3-dependent downstream genes. Interestingly, after treatment with peptide, both healthy and transformed keratinocytes could no longer aberrantly proliferate and migrate in response to IL-22. Finally, treatment of athymic nude mice bearing SCC xenografts with KIR-ESS peptide concomitantly reduced tumor growth and activated STAT3 levels. As a whole, these data provides the rationale for the use in BCC and SCC skin tumors of SOCS3 mimetics, being able to inhibit the deleterious effects of IL-22 in these contexts.
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Affiliation(s)
- Stefania Madonna
- Laboratory of Experimental Immunology, IDI-IRCCS, Fondazione “Luigi M. Monti” (FLMM), Rome, Italy
| | - Claudia Scarponi
- Laboratory of Experimental Immunology, IDI-IRCCS, Fondazione “Luigi M. Monti” (FLMM), Rome, Italy
| | - Martina Morelli
- Laboratory of Experimental Immunology, IDI-IRCCS, Fondazione “Luigi M. Monti” (FLMM), Rome, Italy
| | - Rosanna Sestito
- Laboratory of Experimental Immunology, IDI-IRCCS, Fondazione “Luigi M. Monti” (FLMM), Rome, Italy
- Current address: Preclinical Models and New Therapeutic Agents Unit, Regina Elena National Cancer Institute, Rome, Italy
| | | | - Daniela Marasco
- Department of Pharmacy, CIRPEB, University of Naples “Federico II”, Naples, Italy
| | - Cristina Albanesi
- Laboratory of Experimental Immunology, IDI-IRCCS, Fondazione “Luigi M. Monti” (FLMM), Rome, Italy
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Kan X, Zhang W, You R, Niu Y, Guo J, Xue J. Scutellaria barbata D. Don extract inhibits the tumor growth through down-regulating of Treg cells and manipulating Th1/Th17 immune response in hepatoma H22-bearing mice. Altern Ther Health Med 2017; 17:41. [PMID: 28086772 PMCID: PMC5237169 DOI: 10.1186/s12906-016-1551-9] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Accepted: 12/22/2016] [Indexed: 12/20/2022]
Abstract
BACKGROUND Previous studies showed Scutellaria barbata D. Don extract (SBE) is a potent inhibitor in hepatoma and could improve immune function of hepatoma H22-bearing mice. However, the immunomodulatory function of SBE on the tumor growth of hepatoma remains unclear. This study aimed to investigate the anti-tumor effects of SBE on hepatoma H22-bearing mice and explore the underlying immunomodulatory function. METHODS The hepatoma H22-bearing mice were treated by SBE for 30 days. The effect of SBE on the proliferation of HepG2 cells in vitro, the growth of transplanted tumor, the cytotoxicity of natural killer (NK) cells in spleen, the amount of CD4+CD25+Foxp3+ Treg cells and Th17 cells in tumor tissue, and the levels of IL-10, TGF-β, IL-17A, IL-2, and IFN-γ in serum of the hepatoma H22-bearing mice was observered. IL-17A was injected to the SBE treated mice from day 9 post H22 inoculation to examine its effect on tumor growth. RESULTS SBE treatment inhibited the proliferation of HepG2 cells in vitro with a dose-dependent manner and significantly suppressed the tumor growth of hepatoma H22-bearing mice. Meanwhile, it increased NK cells' cytotoxicity in spleen, down-regulated the amount of CD4+CD25+Foxp3+ Treg cells and Th17 cells in tumor tissue, and decreased IL-10, TGF-β, and IL-17A levels (P < 0.01) whereas increased IL-2 and IFN-γ levels (P < 0.01) in the serum of hepatoma H22-bearing mice. Moreover, administration of recombinant mouse IL-17A reversed the anti-tumor effects of SBE. CONCLUSION SBE could inhibit the proliferation of HepG2 cells in vitro. Meanwhile, SBE also could inhibit the growth of H22 implanted tumor in hepatoma H22-bearing mice, and this function might be associated with immunomodulatory activity through down-regulating of Treg cells and manipulating Th1/Th17 immune response.
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Identification and characterization of distinct IL-17F expression patterns and signaling pathways in chronic lymphocytic leukemia and normal B lymphocytes. Immunol Res 2016; 63:216-27. [PMID: 26478573 PMCID: PMC4648985 DOI: 10.1007/s12026-015-8722-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Chronic lymphocytic leukemia (CLL) is characterized by a progressive accumulation of B lymphocytes. T cell abnormalities are a common feature of CLL and contribute to impaired immune function in these patients. T cells are ineffective in eliminating the leukemic clone and may actually promote tumor growth and survival. Previous work from our laboratory documented elevated circulating levels of IL-17A-producing Th17 cells in CLL patients as compared to healthy age-matched control subjects. These high circulating Th17 levels associated with better prognostic markers and significantly longer overall survival, even among patients whose clones used unmutated IGHVs (U-CLL). Recent studies suggest that Th17 cells are heterogeneous, expressing different profiles of cytokines, and that different subsets of Th17s mediate different biological functions. In the present study, we found significantly higher levels of IL-17F-expressing CD4+ T cells in CLL versus healthy peripheral blood mononuclear cells following in vitro stimulation in the presence of Th17-promoting cytokines. Furthermore, the differentiation of IL-17F-expressing Th17 cells was significantly enhanced when purified CD4+ T cells from CLL patients were cultured in the presence of autologous CLL B cells. Lastly, single-cell network profiling revealed that IL-17F triggers NFκB phosphorylation in T and B cells from patients with CLL, but not age-matched healthy controls. Taken together, our data suggest that the phenotype of Th17 cells in CLL patients is distinct from healthy individuals, expressing higher levels of IL-17F, and that B and T cells from CLL patients are particularly responsive to IL-17F, as compared to healthy age-matched control individuals.
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Shi C, Yang Y, Xia Y, Okugawa Y, Yang J, Liang Y, Chen H, Zhang P, Wang F, Han H, Wu W, Gao R, Gasche C, Qin H, Ma Y, Goel A. Novel evidence for an oncogenic role of microRNA-21 in colitis-associated colorectal cancer. Gut 2016; 65:1470-81. [PMID: 25994220 DOI: 10.1136/gutjnl-2014-308455] [Citation(s) in RCA: 121] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Accepted: 04/24/2015] [Indexed: 12/12/2022]
Abstract
OBJECTIVE miR-21 was found to be overexpressed in the colon tissues and serum of patients with UC and colorectal cancer (CRC); however, the exact roles of miR-21 in colitis-associated CRC remain unclear. The aim of our study was to investigate the biological mechanisms of miR-21 in colitis-associated colon cancer (CAC). DESIGN miR-21 expression was examined in the tumours of 62 patients with CRC from China and 37 colitis-associated neoplastic tissues from Japan and Austria. The biological functions of miR-21 were studied using a series of in vitro, in vivo and clinical approaches. RESULTS miR-21 levels were markedly upregulated in the tumours of 62 patients with CRC, 22 patients with CAC, and in a mouse model of CAC. Following azoxymethane and dextran sulfate sodium intervention, miR-21-knockout mice showed reduced expression of proinflammatory and procarcinogenic cytokines (interleukin (IL) 6, IL-23, IL-17A and IL-21) and a decrease in the size and number of tumours compared with the control mouse group. The absence of miR-21 resulted in the reduced expression of Ki67 and the attenuated proliferation of tumour cells with a simultaneous increase in E-cadherin and decrease in β-catenin and SOX9 in the tumours of CAC mice. Furthermore, the absence of miR-21 increased the expression of its target gene PDCD4 and subsequently modulated nuclear factor (NF)-κB activation. Meanwhile, miR-21 loss reduced STAT3 and Bcl-2 activation, causing an increase in the apoptosis of tumour cells in CAC mice. CONCLUSIONS These observations provide novel evidence for miR-21 blockade to be a key strategy in reducing CAC.
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Affiliation(s)
- Chenzhang Shi
- Department of GI Surgery, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai, China
| | - Yongzhi Yang
- Department of GI Surgery, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai, China
| | - Yang Xia
- Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Yoshinaga Okugawa
- Gastrointestinal Cancer Research Laboratory, Baylor Research Institute and Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas, USA
| | - Jun Yang
- Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Yong Liang
- Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Hongqi Chen
- Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Peng Zhang
- Department of GI Surgery, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai, China
| | - Feng Wang
- Department of GI Surgery, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai, China
| | - Huazhong Han
- Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Wen Wu
- Department of GI Surgery, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai, China
| | - Renyuan Gao
- Department of GI Surgery, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai, China
| | - Christoph Gasche
- Division of Gastroenterology and Hepatology, Department of Medicine 4, Medical University Vienna, Vienna, Austria
| | - Huanlong Qin
- Department of GI Surgery, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai, China
| | - Yanlei Ma
- Department of GI Surgery, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai, China
| | - Ajay Goel
- Gastrointestinal Cancer Research Laboratory, Baylor Research Institute and Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas, USA
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Fabre J, Giustiniani J, Garbar C, Antonicelli F, Merrouche Y, Bensussan A, Bagot M, Al-Dacak R. Targeting the Tumor Microenvironment: The Protumor Effects of IL-17 Related to Cancer Type. Int J Mol Sci 2016; 17:ijms17091433. [PMID: 27589729 PMCID: PMC5037712 DOI: 10.3390/ijms17091433] [Citation(s) in RCA: 106] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 08/10/2016] [Accepted: 08/24/2016] [Indexed: 12/25/2022] Open
Abstract
The inflammatory process contributes to immune tolerance as well as to tumor progression and metastasis. By releasing extracellular signals, cancerous cells constantly shape their surrounding microenvironment through their interactions with infiltrating immune cells, stromal cells and components of extracellular matrix. Recently, the pro-inflammatory interleukin 17 (IL-17)-producing T helper lymphocytes, the Th17 cells, and the IL-17/IL-17 receptor (IL-17R) axis gained special attention. The IL-17 family comprises at least six members, IL-17A, IL-17B, IL-17C, IL-17D, IL-17E (also called IL-25), and IL-17F. Secreted as disulfide-linked homo- or heterodimers, the IL-17 bind to the IL-17R, a type I cell surface receptor, of which there are five variants, IL-17RA to IL-17RE. This review focuses on the current advances identifying the promoting role of IL-17 in carcinogenesis, tumor metastasis and resistance to chemotherapy of diverse solid cancers. While underscoring the IL-17/IL-17R axis as promising immunotherapeutic target in the context of cancer managing, this knowledge calls upon further in vitro and in vivo studies that would allow the development and implementation of novel strategies to combat tumors.
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Affiliation(s)
- Joseph Fabre
- Institut Jean Godinot, Unicancer, 1 rue du Général Koenig, F-51726 Reims, France.
- Université Reims-Champagne-Ardenne, DERM-I-C, EA7319, 51 rue Cognacq-Jay, F-51095 Reims, France.
- Centre Hospitalo-Universitaire Henri Mondor, Service de Radiothérapie, 51 Avenue du Maréchal de Lattre de Tassigny, F-94010 Créteil, France.
| | - Jerome Giustiniani
- Institut Jean Godinot, Unicancer, 1 rue du Général Koenig, F-51726 Reims, France.
- Université Reims-Champagne-Ardenne, DERM-I-C, EA7319, 51 rue Cognacq-Jay, F-51095 Reims, France.
| | - Christian Garbar
- Institut Jean Godinot, Unicancer, 1 rue du Général Koenig, F-51726 Reims, France.
- Université Reims-Champagne-Ardenne, DERM-I-C, EA7319, 51 rue Cognacq-Jay, F-51095 Reims, France.
| | - Frank Antonicelli
- Université Reims-Champagne-Ardenne, DERM-I-C, EA7319, 51 rue Cognacq-Jay, F-51095 Reims, France.
| | - Yacine Merrouche
- Institut Jean Godinot, Unicancer, 1 rue du Général Koenig, F-51726 Reims, France.
- Université Reims-Champagne-Ardenne, DERM-I-C, EA7319, 51 rue Cognacq-Jay, F-51095 Reims, France.
| | - Armand Bensussan
- Institut National de la Santé et de la Recherche Médicale (INSERM) U976, Hôpital Saint Louis, F-75010 Paris, France.
- Université Paris Diderot, Sorbonne Paris Cité, Laboratoire Immunologie Dermatologie & Oncologie, UMR-S 976, F-75475 Paris, France.
- OREGA Biotech, 69130 Ecully, France.
| | - Martine Bagot
- Institut National de la Santé et de la Recherche Médicale (INSERM) U976, Hôpital Saint Louis, F-75010 Paris, France.
- Université Paris Diderot, Sorbonne Paris Cité, Laboratoire Immunologie Dermatologie & Oncologie, UMR-S 976, F-75475 Paris, France.
| | - Reem Al-Dacak
- Université Paris Diderot, Sorbonne Paris Cité, Laboratoire Immunologie Dermatologie & Oncologie, UMR-S 976, F-75475 Paris, France.
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Basa RCB, Davies V, Li X, Murali B, Shah J, Yang B, Li S, Khan MW, Tian M, Tejada R, Hassan A, Washington A, Mukherjee B, Carethers JM, McGuire KL. Decreased Anti-Tumor Cytotoxic Immunity among Microsatellite-Stable Colon Cancers from African Americans. PLoS One 2016; 11:e0156660. [PMID: 27310868 PMCID: PMC4911070 DOI: 10.1371/journal.pone.0156660] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2016] [Accepted: 05/17/2016] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer is a leading cause of cancer related deaths in the U.S., with African-Americans having higher incidence and mortality rates than Caucasian-Americans. Recent studies have demonstrated that anti-tumor cytotoxic T lymphocytes provide protection to patients with colon cancer while patients deficient in these responses have significantly worse prognosis. To determine if differences in cytotoxic immunity might play a role in racial disparities in colorectal cancer 258 microsatellite-stable colon tumors were examined for infiltrating immune biomarkers via immunohistochemistry. Descriptive summary statistics were calculated using two-sample Wilcoxon rank sum tests, while linear regression models with log-transformed data were used to assess differences in race and Pearson and Spearman correlations were used to correlate different biomarkers. The association between different biomarkers was also assessed using linear regression after adjusting for covariates. No significant differences were observed in CD8+ (p = 0.83), CD57+ (p = 0.55), and IL-17-expressing (p = 0.63) cell numbers within the tumor samples tested. When infiltration of granzyme B+ cells was analyzed, however, a significant difference was observed, with African Americans having lower infiltration of cells expressing this cytotoxic marker than Caucasians (p<0.01). Analysis of infiltrating granzyme B+ cells at the invasive borders of the tumor revealed an even greater difference by race (p<0.001). Taken together, the data presented suggest differences in anti-tumor immune cytotoxicity may be a contributing factor in the racial disparities observed in colorectal cancer.
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Affiliation(s)
- Ranor C. B. Basa
- Department of Biology, Molecular Biology Institute, San Diego State University, San Diego, California, United States of America
| | - Vince Davies
- Department of Biology, Molecular Biology Institute, San Diego State University, San Diego, California, United States of America
| | - Xiaoxiao Li
- Department of Biology, Molecular Biology Institute, San Diego State University, San Diego, California, United States of America
| | - Bhavya Murali
- Department of Biology, Molecular Biology Institute, San Diego State University, San Diego, California, United States of America
| | - Jinel Shah
- Department of Biology, Molecular Biology Institute, San Diego State University, San Diego, California, United States of America
| | - Bing Yang
- Department of Biology, Molecular Biology Institute, San Diego State University, San Diego, California, United States of America
| | - Shi Li
- School of Public Health, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Mohammad W. Khan
- Department of Biology, Molecular Biology Institute, San Diego State University, San Diego, California, United States of America
| | - Mengxi Tian
- Department of Biology, Molecular Biology Institute, San Diego State University, San Diego, California, United States of America
| | - Ruth Tejada
- Department of Biology, Molecular Biology Institute, San Diego State University, San Diego, California, United States of America
| | - Avan Hassan
- Department of Biology, Molecular Biology Institute, San Diego State University, San Diego, California, United States of America
| | - Allen Washington
- Department of Biology, Molecular Biology Institute, San Diego State University, San Diego, California, United States of America
| | - Bhramar Mukherjee
- School of Public Health, University of Michigan, Ann Arbor, Michigan, United States of America
| | - John M. Carethers
- Department of Internal Medicine, Medical School, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Kathleen L. McGuire
- Department of Biology, Molecular Biology Institute, San Diego State University, San Diego, California, United States of America
- * E-mail:
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Role of the tumor stroma in resistance to anti-angiogenic therapy. Drug Resist Updat 2016; 25:26-37. [DOI: 10.1016/j.drup.2016.02.002] [Citation(s) in RCA: 87] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Revised: 02/09/2016] [Accepted: 02/17/2016] [Indexed: 12/13/2022]
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LAP TGF-Beta Subset of CD4(+)CD25(+)CD127(-) Treg Cells is Increased and Overexpresses LAP TGF-Beta in Lung Adenocarcinoma Patients. BIOMED RESEARCH INTERNATIONAL 2015; 2015:430943. [PMID: 26582240 PMCID: PMC4637030 DOI: 10.1155/2015/430943] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Accepted: 05/17/2015] [Indexed: 02/06/2023]
Abstract
Lung cancer is the leading cause of cancer death worldwide. Adenocarcinoma, the most commonly diagnosed histologic type of lung cancer, is associated with smoking. Cigarette smoke promotes inflammation on the airways, which might be mediated by Th17 cells. This inflammatory environment may contribute to tumor development. In contrast, some reports indicate that tumors may induce immunosuppressive Treg cells to dampen immune reactivity, supporting tumor growth and progression. Thus, we aimed to analyze whether chronic inflammation or immunosuppression predominates at the systemic level in lung adenocarcinoma patients, and several cytokines and Th17 and Treg cells were studied. Higher proportions of IL-17-producing CD4+ T-cells were found in smoking control subjects and in lung adenocarcinoma patients compared to nonsmoking control subjects. In addition, lung adenocarcinoma patients increased both plasma concentrations of IL-2, IL-4, IL-6, and IL-10, and proportions of Latency Associated Peptide (LAP) TGF-β subset of CD4+CD25+CD127− Treg cells, which overexpressed LAP TGF-β. This knowledge may lead to the development of immunotherapies that could inhibit the suppressor activity mediated by the LAP TGF-β subset of CD4+CD25+CD127− Treg cells to promote reactivity of immune cells against lung adenocarcinoma cells.
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Chen XW, Zhou SF. Inflammation, cytokines, the IL-17/IL-6/STAT3/NF-κB axis, and tumorigenesis. DRUG DESIGN DEVELOPMENT AND THERAPY 2015; 9:2941-6. [PMID: 26089643 PMCID: PMC4467747 DOI: 10.2147/dddt.s86396] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- Xiao-Wu Chen
- Department of General Surgery, The First People's Hospital of Shunde, Southern Medical University, Shunde, Foshan, Guangdong, People's Republic of China
| | - Shu-Feng Zhou
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA
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Punt S, Houwing-Duistermaat JJ, Schulkens IA, Thijssen VL, Osse EM, de Kroon CD, Griffioen AW, Fleuren GJ, Gorter A, Jordanova ES. Correlations between immune response and vascularization qRT-PCR gene expression clusters in squamous cervical cancer. Mol Cancer 2015; 14:71. [PMID: 25889974 PMCID: PMC4392729 DOI: 10.1186/s12943-015-0350-0] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2014] [Accepted: 03/20/2015] [Indexed: 12/30/2022] Open
Abstract
Background The tumour microenvironment comprises a network of immune response and vascularization factors. From this network, we identified immunological and vascularization gene expression clusters and the correlations between the clusters. We subsequently determined which factors were correlated with patient survival in cervical carcinoma. Methods The expression of 42 genes was investigated in 52 fresh frozen squamous cervical cancer samples by qRT-PCR. Weighted gene co-expression network analysis and mixed-model analyses were performed to identify gene expression clusters. Correlations and survival analyses were further studied at expression cluster and single gene level. Results We identified four immune response clusters: ‘T cells’ (CD3E/CD8A/TBX21/IFNG/FOXP3/IDO1), ‘Macrophages’ (CD4/CD14/CD163), ‘Th2’ (IL4/IL5/IL13/IL12) and ‘Inflammation’ (IL6/IL1B/IL8/IL23/IL10/ARG1) and two vascularization clusters: ‘Angiogenesis’ (VEGFA/FLT1/ANGPT2/ PGF/ICAM1) and ‘Vessel maturation’ (PECAM1/VCAM1/ANGPT1/SELE/KDR/LGALS9). The ‘T cells’ module was correlated with all modules except for ‘Inflammation’, while ‘Inflammation’ was most significantly correlated with ‘Angiogenesis’ (p < 0.001). High expression of the ‘T cells’ cluster was correlated with earlier TNM stage (p = 0.007). High CD3E expression was correlated with improved disease-specific survival (p = 0.022), while high VEGFA expression was correlated with poor disease-specific survival (p = 0.032). Independent predictors of poor disease-specific survival were IL6 (hazard ratio = 2.3, p = 0.011) and a high IL6/IL17 ratio combined with low IL5 expression (hazard ratio = 4.2, p = 0.010). Conclusions ‘Inflammation’ marker IL6, especially in combination with low levels of IL5 and IL17, was correlated with poor survival. This suggests that IL6 promotes tumour growth, which may be suppressed by a Th17 and Th2 response. Measuring IL6, IL5 and IL17 expression may improve the accuracy of predicting prognosis in cervical cancer.
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Affiliation(s)
- Simone Punt
- Department of Pathology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
| | | | - Iris A Schulkens
- Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center, De Boelelaan 1118, 1081HV, Amsterdam, The Netherlands.
| | - Victor L Thijssen
- Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center, De Boelelaan 1118, 1081HV, Amsterdam, The Netherlands.
| | - Elisabeth M Osse
- Department of Pathology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
| | - Cornelis D de Kroon
- Department of Gynaecology, Leiden University Medical Center, Leiden, The Netherlands.
| | - Arjan W Griffioen
- Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center, De Boelelaan 1118, 1081HV, Amsterdam, The Netherlands.
| | - Gert Jan Fleuren
- Department of Pathology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
| | - Arko Gorter
- Department of Pathology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
| | - Ekaterina S Jordanova
- Department of Pathology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. .,Center for Gynecological Oncology Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
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Nardinocchi L, Sonego G, Passarelli F, Avitabile S, Scarponi C, Failla CM, Simoni S, Albanesi C, Cavani A. Interleukin-17 and interleukin-22 promote tumor progression in human nonmelanoma skin cancer. Eur J Immunol 2015; 45:922-31. [PMID: 25487261 DOI: 10.1002/eji.201445052] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2014] [Revised: 10/28/2014] [Accepted: 12/03/2014] [Indexed: 12/17/2022]
Abstract
Interleukin-17 (IL-17) and IL-22 have been reported to play critical roles in autoimmunity and inflammation but information about their role in cancer is limited. In this study, we investigated the role of IL-17 and IL-22 in the progression of human skin basal-cell carcinoma (BCC) and squamous-cell carcinoma (SCC). We found that both tumor types are infiltrated with an high number of IL-17(+) and IL-22(+) T lymphocytes, as demonstrated by immunohistochemistry and by FACS analysis performed on peritumoral T-cell lines isolated from skin biopsies. In vitro studies demonstrated that proliferation and migration of the BCC- and SCC-cell lines M77015 and CAL27 were increased by IL-17 and IL-22. Moreover, IL-17, alone or in combination with TNF-α, was able to induce the production of two cytokines important for tumor progression, IL-6 and IL-8, in CAL27. We also showed that IL-17 upregulated NF-κB signaling, while IL-22 activated the STAT3 pathway and the antiapoptotic AKT protein in M77015 and CAL27. Finally, in vivo experiments demonstrated that IL-17 and IL-22 enhanced tumor growth in nude mice injected with CAL27. Altogether, our findings indicate that high levels of IL-22 and IL-17 in the BCC and SCC microenvironment promote tumor progression.
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Affiliation(s)
- Lavinia Nardinocchi
- Laboratory of Experimental Immunology, Istituto Dermopatico dell'Immacolata, Rome, Italy
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Li N, Zhang C, Chen Z, Bai L, Nie M, Zhou B, Xu H. Interleukin 17A and Interleukin 17F Polymorphisms Are Associated With Oral Squamous Cell Carcinoma Susceptibility in a Chinese Population. J Oral Maxillofac Surg 2015; 73:267-73. [DOI: 10.1016/j.joms.2014.09.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2014] [Revised: 09/10/2014] [Accepted: 09/13/2014] [Indexed: 02/07/2023]
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Serum IL-17F combined with VEGF as potential diagnostic biomarkers for oral squamous cell carcinoma. Tumour Biol 2015; 36:2523-9. [DOI: 10.1007/s13277-014-2867-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Accepted: 11/17/2014] [Indexed: 01/29/2023] Open
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Lafont V, Sanchez F, Laprevotte E, Michaud HA, Gros L, Eliaou JF, Bonnefoy N. Plasticity of γδ T Cells: Impact on the Anti-Tumor Response. Front Immunol 2014; 5:622. [PMID: 25538706 PMCID: PMC4259167 DOI: 10.3389/fimmu.2014.00622] [Citation(s) in RCA: 104] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Accepted: 11/21/2014] [Indexed: 01/17/2023] Open
Abstract
The tumor immune microenvironment contributes to tumor initiation, progression, and response to therapy. Among the immune cell subsets that play a role in the tumor microenvironment, innate-like T cells that express T cell receptors composed of γ and δ chains (γδ T cells) are of particular interest. γδ T cells can contribute to the immune response against many tumor types (lymphoma, myeloma, melanoma, breast, colon, lung, ovary, and prostate cancer) directly through their cytotoxic activity and indirectly by stimulating or regulating the biological functions of other cell types required for the initiation and establishment of the anti-tumor immune response, such as dendritic cells and cytotoxic CD8+ T cells. However, the notion that tumor-infiltrating γδ T cells are a good prognostic marker in cancer was recently challenged by studies showing that the presence of these cells in the tumor microenvironment was associated with poor prognosis in both breast and colon cancer. These findings suggest that γδ T cells may also display pro-tumor activities. Indeed, breast tumor-infiltrating γδ T cells could exert an immunosuppressive activity by negatively regulating dendritic cell maturation. Furthermore, recent studies demonstrated that signals from the microenvironment, particularly cytokines, can confer some plasticity to γδ T cells and promote their differentiation into γδ T cells with regulatory functions. This review focuses on the current knowledge on the functional plasticity of γδ T cells and its effect on their anti-tumor activities. It also discusses the putative mechanisms underlying γδ T cell expansion, differentiation, and recruitment in the tumor microenvironment.
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Affiliation(s)
- Virginie Lafont
- U896, Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM , Montpellier , France ; Centre Régional de Lutte Contre le Cancer CRLC Val d'Aurelle - Paul Lamarque, Université Montpellier 1 , Montpellier , France
| | - Françoise Sanchez
- U896, Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM , Montpellier , France ; Centre Régional de Lutte Contre le Cancer CRLC Val d'Aurelle - Paul Lamarque, Université Montpellier 1 , Montpellier , France
| | - Emilie Laprevotte
- U896, Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM , Montpellier , France ; Centre Régional de Lutte Contre le Cancer CRLC Val d'Aurelle - Paul Lamarque, Université Montpellier 1 , Montpellier , France
| | - Henri-Alexandre Michaud
- U896, Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM , Montpellier , France ; Centre Régional de Lutte Contre le Cancer CRLC Val d'Aurelle - Paul Lamarque, Université Montpellier 1 , Montpellier , France
| | - Laurent Gros
- U896, Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM , Montpellier , France ; Centre Régional de Lutte Contre le Cancer CRLC Val d'Aurelle - Paul Lamarque, Université Montpellier 1 , Montpellier , France
| | - Jean-François Eliaou
- U896, Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM , Montpellier , France ; Centre Régional de Lutte Contre le Cancer CRLC Val d'Aurelle - Paul Lamarque, Université Montpellier 1 , Montpellier , France ; Département d'Immunologie, Centre Hospitalier Régional Universitaire de Montpellier et Faculté de Médecine, Université Montpellier 1 , Montpellier , France
| | - Nathalie Bonnefoy
- U896, Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM , Montpellier , France ; Centre Régional de Lutte Contre le Cancer CRLC Val d'Aurelle - Paul Lamarque, Université Montpellier 1 , Montpellier , France
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Qi H, Yang H, Xu G, Ren J, Hua W, Shi Y, Torsvik M, Florholmen J, Cui G. Therapeutic efficacy of IL-17A antibody injection in preventing the development of colitis associated carcinogenesis in mice. Immunobiology 2014; 220:54-9. [PMID: 25239511 DOI: 10.1016/j.imbio.2014.09.002] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2014] [Revised: 08/28/2014] [Accepted: 09/01/2014] [Indexed: 01/05/2023]
Abstract
Chronic inflammation increases colorectal cancer (CRC) risk as seen in ulcerative colitis (UC). Proinflammatory cytokines play a critical role in mediating the development of colitis associated cancer (CAC). In this study, the therapeutic efficacy of anti-interleukin (IL)-17A by anti-IL-17A antibody injection on the development of CAC was assessed in 1,2-dimethylhydrazine (DMH) plus dextran sulfate sodium (DSS) induced CAC mouse model. The results showed that mice dosed with DMH plus DSS for 10 weeks evoked high degree dysplastic lesion in the large bowel that accompanied with significant increased IL-17A expression, proliferation index and inflammation degree in mice. After anti-IL-17A antibody injection for 2 weeks, the number of tumors, proliferation index and the expression level of IL-17A protein in the large bowel tissues were significantly decreased. Therefore, we concluded that the anti-IL-17A blockade can suppress the development of CAC and is a potential therapeutic agent for the prevention of CAC in colitis mice.
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Affiliation(s)
- Haili Qi
- Department of Gastroenterology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Hang Yang
- Department of Gastroenterology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Gang Xu
- Department of Gastroenterology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Jingli Ren
- Department of Pathology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Wei Hua
- Department of Gastroenterology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yingpeng Shi
- Department of Gastroenterology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Malvin Torsvik
- Faculty of Health, North Trøndelag University College at Levanger, Norway
| | - Jon Florholmen
- Research Group of Gastroenterology & Nutrition, Institute of Clinical Medicine, Faculty of Medicine, University of Tromsø, Tromsø, Norway
| | - Guanglin Cui
- Department of Gastroenterology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; Faculty of Health, North Trøndelag University College at Levanger, Norway.
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50
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Nolin JD, Tully JE, Hoffman SM, Guala AS, van der Velden JL, Poynter ME, van der Vliet A, Anathy V, Janssen-Heininger YMW. The glutaredoxin/S-glutathionylation axis regulates interleukin-17A-induced proinflammatory responses in lung epithelial cells in association with S-glutathionylation of nuclear factor κB family proteins. Free Radic Biol Med 2014; 73:143-53. [PMID: 24816292 PMCID: PMC4111997 DOI: 10.1016/j.freeradbiomed.2014.04.028] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2013] [Revised: 04/22/2014] [Accepted: 04/28/2014] [Indexed: 12/14/2022]
Abstract
Interleukin-17A (IL-17A) is a newly emerging player in the pathogenesis of chronic lung diseases that amplifies inflammatory responses and promotes tissue remodeling. Stimulation of lung epithelial cells with IL-17A leads to activation of the transcription factor nuclear factor κB (NF-κB), a key player in the orchestration of lung inflammation. We have previously demonstrated the importance of the redox-dependent posttranslational modification S-glutathionylation in limiting activation of NF-κB and downstream gene induction. Under physiological conditions, the enzyme glutaredoxin 1 (Grx1) acts to deglutathionylate NF-κB proteins, which restores functional activity. In this study, we sought to determine the impact of S-glutathionylation on IL-17A-induced NF-κB activation and expression of proinflammatory mediators. C10 mouse lung alveolar epithelial cells or primary mouse tracheal epithelial cells exposed to IL-17A show rapid activation of NF-κB and the induction of proinflammatory genes. Upon IL-17A exposure, sulfenic acid formation and S-glutathionylated proteins increased. Assessment of S-glutathionylation of NF-κB pathway components revealed S-glutathionylation of RelA (RelA-SSG) and inhibitory κB kinase α (IKKα-SSG) after stimulation with IL-17A. SiRNA-mediated ablation of Grx1 increased both RelA-SSG and IKKα-SSG and acutely increased nuclear content of RelA and tended to decrease nuclear RelB. SiRNA-mediated ablation or genetic ablation of Glrx1 decreased the expression of the NF-κB-regulated genes KC and CCL20 in response to IL-17A, but conversely increased the expression of IL-6. Last, siRNA-mediated ablation of IKKα attenuated nuclear RelA and RelB content and decreased expression of KC and CCL20 in response to IL-17A. Together, these data demonstrate a critical role for the S-glutathionylation/Grx1 redox axis in regulating IKKα and RelA S-glutathionylation and the responsiveness of epithelial cells to IL-17A.
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Affiliation(s)
- James D Nolin
- Department of Pathology, University of Vermont College of Medicine, Burlington, VT 05405, USA
| | - Jane E Tully
- Department of Pathology, University of Vermont College of Medicine, Burlington, VT 05405, USA
| | - Sidra M Hoffman
- Department of Pathology, University of Vermont College of Medicine, Burlington, VT 05405, USA
| | - Amy S Guala
- Department of Pathology, University of Vermont College of Medicine, Burlington, VT 05405, USA
| | - Jos L van der Velden
- Department of Pathology, University of Vermont College of Medicine, Burlington, VT 05405, USA
| | - Matthew E Poynter
- Department of Medicine, University of Vermont College of Medicine, Burlington, VT 05405, USA
| | - Albert van der Vliet
- Department of Pathology, University of Vermont College of Medicine, Burlington, VT 05405, USA
| | - Vikas Anathy
- Department of Pathology, University of Vermont College of Medicine, Burlington, VT 05405, USA
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