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Li H, Cao GM, Gu GL, Li SY, Yan Y, Fu Z, Du XH. Expression characteristics of peripheral lymphocyte programmed death 1 and FoxP3 + Tregs in gastric cancer during surgery and chemotherapy. World J Gastroenterol 2023; 29:5582-5592. [PMID: 37970473 PMCID: PMC10642441 DOI: 10.3748/wjg.v29.i40.5582] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 08/31/2023] [Accepted: 10/11/2023] [Indexed: 10/27/2023] Open
Abstract
BACKGROUND Programmed death 1 (PD-1) and CD4+CD25+FoxP3+ expression in peripheral blood T-cells has been previously reported in various types of cancer. However, the specific variation tendency during surgery and chemotherapy, as well as their relationship in gastric cancer patients, still remain unclear. Understanding this aspect may provide some novel insights for future studies on tumor recurrence and tumor immune escape, and also serve as a reference for determining the optimal timing and dose of clinical anti-PD-1 antibodies. AIM To observe and analyze the expression characteristics of peripheral lymphocyte PD-1 and FoxP3+ regulatory T cells (FoxP3+ Tregs) before and after surgery or chemotherapy in gastric cancer patients. METHODS Twenty-nine stomach cancer patients undergoing chemotherapy after a D2 gastrectomy provided 10 mL peripheral blood samples at each phase of the perioperative period and during chemotherapy. This study also included 29 age-matched healthy donors as a control group. PD-1 expression was detected on lymphocytes, including CD4+CD8+CD45RO+, CD4+CD45RO+, and CD8+CD45RO+ lymphocytes as well as regulatory T cells. RESULTS We observed a significant increase of PD-1 expression on immune subsets and a larger number of FoxP3+ Tregs in gastric cancer patients (P < 0.05). Following D2 gastrectomy, peripheral lymphocytes PD-1 expression and the number of FoxP3+ Tregs notably decrease (P < 0.05). However, during postoperative chemotherapy, we only observed a decrease in PD-1 expression on lymphocytes in the CD8+CD45RO+ and CD8+CD45RO+ populations. Additionally, linear correlation analysis indicated a positive correlation between PD-1 expression and the number of CD4+CD45RO+FoxP3high activated Tregs (aTregs) on the total peripheral lymphocytes (r = 0.5622, P < 0.0001). CONCLUSION The observed alterations in PD-1 expression and the activation of regulatory T cells during gastric cancer treatment may offer novel insights for future investigations into tumor immune evasion and the clinical application of anti-PD-1 antibodies in gastric cancer.
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Affiliation(s)
- Hao Li
- Graduate School, Medical School of Chinese People’s Liberation Army, Beijing 100039, China
- Department of General Surgery, Air Force Medical Center, Air Force Medical University, Beijing 100142, China
| | - Guan-Mei Cao
- Department of Radiology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - Guo-Li Gu
- Department of General Surgery, Air Force Medical Center, Air Force Medical University, Beijing 100142, China
| | - Song-Yan Li
- Department of General Surgery, Chinese PLA General Hospital, Beijing 100039, China
| | - Yang Yan
- Department of General Surgery, Chinese PLA General Hospital, Beijing 100039, China
| | - Ze Fu
- Graduate School, Medical School of Chinese People’s Liberation Army, Beijing 100039, China
| | - Xiao-Hui Du
- Department of General Surgery, Chinese PLA General Hospital, Beijing 100039, China
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Chen F, Chao M, Huang T, Guo S, Zhai Y, Wang Y, Wang N, Xie X, Wang L, Ji P. The role of preoperative inflammatory markers in patients with central nervous system tumors, focus on glioma. Front Oncol 2022; 12:1055783. [PMID: 36483052 PMCID: PMC9723353 DOI: 10.3389/fonc.2022.1055783] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 11/03/2022] [Indexed: 11/09/2023] Open
Abstract
BACKGROUND CNS tumors, particularly gliomas, are associated with a high rate of disability and lethality, and are typically diagnosed with histopathology and immunohistochemistry. Our research aims to develop a minimally invasive method for diagnosing, grading and molecular typing glioma. METHODS We collected patients who underwent surgery for glioma, Trigeminal neuralgia/Hemifacial spasm, schwannoma, pituitary adenomas and meningioma at our hospital from June 2019 to June 2021. Preoperative WBCs, neutrophils, lymphocytes, monocytes, platelet counts and albumin levels were collected. Preoperative NLR, dNLR, PLR, LMR and PNI were calculated, and the correlation between them and glioma diagnosis as well as grading was analyzed. We also evaluated the diagnostic significance of NLR, dNLR, PLR, LMR, PNI and their combinations for gliomas, particularly GBM, as well as the diagnostic significance of IDH molecular typing of gliomas. RESULTS There were 182 healthy samples and 3101 diseased samples in our study. Compared with other groups, glioma patients had significantly higher preoperative NLR, dNLR and PLR values, but lower LMR and PNI values. Further analysis showed that NLR, dNLR, and PLR were positively correlated with glioma grading, while LMR and PNI were negatively correlated with glioma grading. For the diagnosis of glioma, NLR showed a maximum AUC value of 0.8099 (0.7823-0.8374). For GBM, NLR showed a maximum AUC value of 0.9585 (0.9467-0.9703). In the combination, NLR+dNLR showed the highest AUC value of 0.8070(0.7849-0.8291). NLR showed significant statistical significance in all grades of glioma IDH molecular typing, while PLR did not show statistical significance. CONCLUSIONS NLR has the greatest value for the diagnosis, differential diagnosis, grading and molecular typing of gliomas. The NLR+dNLR combination also showed high sensitivity and specificity. We believe that inflammatory parameters may serve as economical and specific markers for glioma diagnosis, grading, molecular typing, and progression.
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Affiliation(s)
- Fan Chen
- Department of Neurosurgery, Tangdu Hospital of Fourth Military Medical University, Xi’an, China
| | - Min Chao
- Department of Neurosurgery, Tangdu Hospital of Fourth Military Medical University, Xi’an, China
| | - Tao Huang
- Department of Neurosurgery, Tangdu Hospital of Fourth Military Medical University, Xi’an, China
| | - Shaochun Guo
- Department of Neurosurgery, Tangdu Hospital of Fourth Military Medical University, Xi’an, China
| | - Yulong Zhai
- Department of Neurosurgery, Tangdu Hospital of Fourth Military Medical University, Xi’an, China
| | - Yuan Wang
- Department of Neurosurgery, Tangdu Hospital of Fourth Military Medical University, Xi’an, China
| | - Na Wang
- Department of Neurosurgery, Tangdu Hospital of Fourth Military Medical University, Xi’an, China
| | - Xuan Xie
- Reproductive Medicine Center, Department of Gynecology & Obstetrics, Xijing Hospital of Fourth Military Medical University, Xi’an, China
| | - Liang Wang
- Department of Neurosurgery, Tangdu Hospital of Fourth Military Medical University, Xi’an, China
| | - Peigang Ji
- Department of Neurosurgery, Tangdu Hospital of Fourth Military Medical University, Xi’an, China
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Sharma R, Katiyar V, Gurjar H, Sharma M, Goda R, Vora Z. Is medulloblastoma associated with systemic immunomodulation? - A comparative analysis of preoperative inflammatory markers. Surg Neurol Int 2020; 11:86. [PMID: 32494368 PMCID: PMC7265425 DOI: 10.25259/sni_336_2019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Accepted: 04/02/2020] [Indexed: 01/05/2023] Open
Abstract
Background: We attempt to compare preoperative inflammatory markers among children with medulloblastoma and pilocytic astrocytoma and establish their diagnostic efficacy to distinguish these tumors. Methods: Children (<18 years) with biopsy-proven medulloblastoma and pilocytic astrocytoma operated at our institute from January 2012 to January 2018 were enrolled in this study. The hematological parameters were compared between the two groups and with healthy controls. Children with a history of disease or medications that may confound these parameters were excluded from the study. Receiver operator characteristic curves were made to assess the diagnostic accuracy of markers found to be significant. Results: Patients with medulloblastoma were found to have higher neutrophil-lymphocyte ratio (NLR), derived neutrophil-lymphocyte ratio (dNLR), platelet-lymphocyte ratio (PLR), and platelet counts compared with pilocytic astrocytoma. Absolute lymphocyte count (ALC) was significantly lower in medulloblastoma group as compared to healthy controls but not with pilocytic astrocytoma. NLR and dNLR demonstrated maximum diagnostic accuracy in distinguishing patients with medulloblastoma from healthy controls and pilocytic astrocytoma. Using a cutoff of 2.45 for NLR distinguishes medulloblastoma from healthy controls as well as pilocytic astrocytoma with a sensitivity of 75.5% and specificity of 66.7%. Similarly, dNLR cutoff of 1.47 distinguishes medulloblastoma from healthy controls with a sensitivity of 83% and specificity of 76% and a cutoff of 1.53 distinguishes medulloblastoma from pilocytic astrocytoma with a sensitivity of 81.1% and specificity of 81.8%. Combination of NLR and dNLR performed only marginally better than individual variables with area under the curve being 0.856 for medulloblastoma versus healthy controls and 0.86 for medulloblastoma versus pilocytic astrocytoma. Conclusion: NLR and dNLR can be used as a preoperative predictive marker in medulloblastoma. There is decreased ALC in patients with medulloblastoma contributing to raised NLR and dNLR suggestive of systemic immunosuppression.
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Affiliation(s)
- Ravi Sharma
- Departments of Neurosurgery, All India Institute of Medical sciences, CNC, AIIMS, New Delhi, India
| | - Varidh Katiyar
- Departments of Neurosurgery, All India Institute of Medical sciences, CNC, AIIMS, New Delhi, India
| | - Hitesh Gurjar
- Departments of Neurosurgery, All India Institute of Medical sciences, CNC, AIIMS, New Delhi, India
| | - Mehar Sharma
- Departments of Pathology, All India Institute of Medical sciences, CNC, AIIMS, New Delhi, India
| | - Revanth Goda
- Departments of Neurosurgery, All India Institute of Medical sciences, CNC, AIIMS, New Delhi, India
| | - Zainab Vora
- Departments of Radio diagnosis, All India Institute of Medical sciences, CNC, AIIMS, New Delhi, India
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Huang Z, Wu L, Hou Z, Zhang P, Li G, Xie J. Eosinophils and other peripheral blood biomarkers in glioma grading: a preliminary study. BMC Neurol 2019; 19:313. [PMID: 31805879 PMCID: PMC6894118 DOI: 10.1186/s12883-019-1549-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Accepted: 11/28/2019] [Indexed: 02/07/2023] Open
Abstract
Background Many peripheral blood biomarkers are associated with glioma grade, but eosinophils (Eo) are scarcely reported. This study assessed preoperative peripheral eosinophil levels and other peripheral biomarkers presented in prior literature, probing their associations and diagnostic value in the grading of glioma, including its most aggressive type, glioblastoma (GBM). Methods Patients newly diagnosed with neuroepithelial tumors were included and divided into low-grade glioma (LGG)/high-grade glioma (HGG) groups and non-GBM/GBM groups separately. Preoperative peripheral biomarkers were collected, such as the counts of Eo, neutrophils (Neu), and lymphocytes (Ly), and values such as the eosinophil to lymphocyte ratio (ELR) and neutrophil to lymphocyte ratio (NLR) were calculated. Correlation analyses were also performed between these biomarkers and the groups. Receiver operating characteristic curves were utilized to assess the individual and joint diagnostic values of the biomarkers. Results The HGG patients presented lower Eo and ELR values, which had negative correlations with glioma grade. The diagnostic efficiency of Eo and ELR could be enhanced when combined other biomarkers. In the non-GBM vs GBM analysis, GBM patients displayed reduced Eo and a negative correlation between Eo and a GBM diagnosis The combination of Eo and other biomarkers enhanced the diagnostic efficiency. Conclusions A negative correlation between peripheral eosinophils and glioma grade was found in our study. Numerous cytokines derived from eosinophils could regulate the immune response and affect the tumor microenvironment; moreover, eosinophils may inhibit the tumorigenesis of glioma, which should be explored in the future and may enlighten some new paths for glioma therapy.
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Affiliation(s)
- Zhenxing Huang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China, No.119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, China.,Department of International Medical Services, Beijing Tiantan Hospital, Capital Medical University, No.119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, China
| | - Liang Wu
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China, No.119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, China.,Department of International Medical Services, Beijing Tiantan Hospital, Capital Medical University, No.119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, China
| | - Zonggang Hou
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China, No.119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, China.,Department of International Medical Services, Beijing Tiantan Hospital, Capital Medical University, No.119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, China
| | - Pengfei Zhang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China, No.119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, China.,Department of International Medical Services, Beijing Tiantan Hospital, Capital Medical University, No.119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, China
| | - Gen Li
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China, No.119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, China.,Department of International Medical Services, Beijing Tiantan Hospital, Capital Medical University, No.119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, China
| | - Jian Xie
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China, No.119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, China. .,Department of International Medical Services, Beijing Tiantan Hospital, Capital Medical University, No.119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, China.
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Zheng SH, Huang JL, Chen M, Wang BL, Ou QS, Huang SY. Diagnostic value of preoperative inflammatory markers in patients with glioma: a multicenter cohort study. J Neurosurg 2018; 129:583-592. [PMID: 29099300 DOI: 10.3171/2017.3.jns161648] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVEGlioma is the most common form of brain tumor and has high lethality. The authors of this study aimed to elucidate the efficiency of preoperative inflammatory markers, including neutrophil/lymphocyte ratio (NLR), derived NLR (dNLR), platelet/lymphocyte ratio (PLR), lymphocyte/monocyte ratio (LMR), and prognostic nutritional index (PNI), and their paired combinations as tools for the preoperative diagnosis of glioma, with particular interest in its most aggressive form, glioblastoma (GBM).METHODSThe medical records of patients newly diagnosed with glioma, acoustic neuroma, meningioma, or nonlesional epilepsy at 3 hospitals between January 2011 and February 2016 were collected and retrospectively analyzed. The values of NLR, dNLR, PLR, LMR, and PNI were compared among patients suffering from glioma, acoustic neuroma, meningioma, and nonlesional epilepsy and healthy controls by using nonparametric tests. Correlations between NLR, dNLR, PLR, LMR, PNI, and tumor grade were analyzed. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic significance of NLR, dNLR, PLR, LMR, PNI, and their paired combinations for glioma, particularly GBM.RESULTSA total of 750 patients with glioma (Grade I, 81 patients; Grade II, 208 patients; Grade III, 169 patients; Grade IV [GBM], 292 patients), 44 with acoustic neuroma, 271 with meningioma, 102 with nonlesional epilepsy, and 682 healthy controls were included in this study. Compared with healthy controls and patients with acoustic neuroma, meningioma, or nonlesional epilepsy, the patients with glioma had higher values of preoperative NLR and dNLR as well as lower values of LMR and PNI, whereas PLR was higher in glioma patients than in healthy controls and patients with nonlesional epilepsy. Subgroup analysis revealed a positive correlation between NLR, dNLR, PLR, and tumor grade but a negative correlation between LMR, PNI, and tumor grade in glioma. For glioma diagnosis, the area under the curve (AUC) obtained from the ROC curve was 0.722 (0.697–0.747) for NLR, 0.696 (0.670–0.722) for dNLR, 0.576 (0.549–0.604) for PLR, 0.760 (0.738–0.783) for LMR, and 0.672 (0.646–0.698) for PNI. The best diagnostic performance was obtained with the combination of NLR+LMR and dNLR+LMR, with AUCs of 0.777 and 0.778, respectively. Additionally, NLR (AUC 0.860, 95% CI 0.832–0.887), dNLR (0.840, 0.810–0.869), PLR (0.678, 0.641–0.715), LMR (0.837, 0.811–0.863), and PNI (0.740, 0.706–0.773) had significant predictive value for GBM compared with healthy controls and other disease groups. As compared with the Grade I–III glioma patients, the GBM patients had an AUC of 0.811 (95% CI 0.778–0.844) for NLR, 0.797 (0.763–0.832) for dNLR, 0.662 (0.622–0.702) for PLR, 0.743 (0.707–0.779) for LMR, and 0.661(0.622–0.701) for PNI. For the paired combinations, NLR+LMR demonstrated the highest accuracy.CONCLUSIONSThe NLR+LMR combination was revealed as a noninvasive biomarker with relatively high sensitivity and specificity for glioma diagnosis, the differential diagnosis of glioma from acoustic neuroma and meningioma, GBM diagnosis, and the differential diagnosis of GBM from low-grade glioma.
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Affiliation(s)
- Shi-hao Zheng
- 1Department of Neurosurgery, Fujian Provincial Hospital
| | - Jin-lan Huang
- 2Department of Clinical Laboratory, First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian
- 4Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China
| | - Ming Chen
- 3Department of Neurosurgery, Xin Hua Hospital, Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai; and
| | - Bing-long Wang
- 2Department of Clinical Laboratory, First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian
| | - Qi-shui Ou
- 2Department of Clinical Laboratory, First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian
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Toyama M, Kudo D, Aoyagi T, Miyasaka T, Ishii K, Kanno E, Kaku M, Kushimoto S, Kawakami K. Attenuated accumulation of regulatory T cells and reduced production of interleukin 10 lead to the exacerbation of tissue injury in a mouse model of acute respiratory distress syndrome. Microbiol Immunol 2018; 62:111-123. [PMID: 29266409 DOI: 10.1111/1348-0421.12564] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Revised: 11/27/2017] [Accepted: 12/03/2017] [Indexed: 01/12/2023]
Abstract
Acute respiratory distress syndrome (ARDS) is a pathological condition that involves diffuse lung injury and severe hypoxemia caused by pulmonary and systemic diseases. We have established a mouse model of severe ARDS, developed by intratracheal injection of α-galactosylceramide (α-GalCer), an activator of natural killer T (NKT) cells, followed by LPS. In the present study, we used this model to investigate the regulatory mechanism in the early inflammatory response during acute lung injury. In α-GalCer/LPS-treated mice, the number of CD4+ CD25+ Foxp3+ regulatory T (Treg) cells and the expression of a Treg cell-tropic chemokine, secondary lymphoid-tissue chemokine (SLC), in the lungs was significantly lower than in mice treated with LPS alone. Giving recombinant (r)SLC increased the number of Treg cells in α-GalCer/LPS-treated mice. Treatment with anti-IFN-γ mAb enhanced the expression of SLC and the accumulation of Treg cells in the lungs of α-GalCer/LPS-treated mice, whereas giving recombinant (r)IFN-γ reduced the number of Treg cells in mice treated with LPS alone. IL-10 production was significantly lower in α-GalCer/LPS-treated mice than in mice treated with LPS alone. Giving rIL-10 prolonged survival and attenuated lung injury as a result of reduced production of inflammatory cytokines (such as IL-1β, IL-6, TNF-α, and IFN-γ) and chemokines (including MCP-1, RANTES, IP-10, Mig, MIP-2, and KC) in α-GalCer/LPS-treated mice. Treatment with anti-IFN-γ mAb enhanced IL-10 production in α-GalCer/LPS-treated mice. These results suggest that the attenuated accumulation of Treg cells may be involved in the development of severe ARDS through a reduction in the synthesis of IL-10.
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Affiliation(s)
- Masahiko Toyama
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi 980-8575, Japan
| | - Daisuke Kudo
- Department of Emergency Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi 980-8574, Japan
| | - Tetsuji Aoyagi
- Department of Infection Control and Laboratory Diagnostics, Internal Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi 980-8574, Japan
| | - Tomomitsu Miyasaka
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi 980-8575, Japan
| | - Keiko Ishii
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi 980-8575, Japan
| | - Emi Kanno
- Department of Science of Nursing Practice, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi 980-8575, Japan
| | - Mitsuo Kaku
- Department of Infection Control and Laboratory Diagnostics, Internal Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi 980-8574, Japan
| | - Shigeki Kushimoto
- Department of Emergency Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi 980-8574, Japan
| | - Kazuyoshi Kawakami
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi 980-8575, Japan
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Cao T, Zhang X, Chen D, Zhang P, Li Q, Muhammad A. The epigenetic modification during the induction of Foxp3 with sodium butyrate. Immunopharmacol Immunotoxicol 2018; 40:309-318. [DOI: 10.1080/08923973.2018.1480631] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Tengli Cao
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Xiuxiu Zhang
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Dingding Chen
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Peiyan Zhang
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Qing Li
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Abbas Muhammad
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
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Chen M, Zheng SH, Yang M, Chen ZH, Li ST. The diagnostic value of preoperative inflammatory markers in craniopharyngioma: a multicenter cohort study. J Neurooncol 2018; 138:113-122. [PMID: 29388032 DOI: 10.1007/s11060-018-2776-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Accepted: 01/22/2018] [Indexed: 02/06/2023]
Abstract
To compare the different levels of preoperative inflammatory markers in peripheral blood samples between craniopharyngioma (CP) and other sellar region tumors so as to explore their differential diagnostic value. The level of white blood cell (WBC), neutrophil, lymphocyte, monocyte, platelet, albumin, neutrophil lymphocyte ratio (NLR), derived NLR (dNLR), platelet lymphocyte ratio (PLR), monocyte lymphocyte ratio (MLR) and prognostic nutritional index (PNI) were compared between the CP and other sellar region tumors. A receiver operating characteristics (ROC) curve analysis was performed to evaluate the diagnostic significance of the peripheral blood inflammatory markers and their paired combinations for CP including its pathological types. Patients with CP had higher levels of pre-operative WBC, lymphocyte and PNI. The papillary craniopharyngioma (PCP) group had higher neutrophil count and NLR than the adamantinomatous craniopharyngioma (ACP) and healthy control groups whereas the ACP group had higher platelet count and PNI than the PCP and healthy control groups. There were not any significant differences in preoperative inflammatory markers between the primary and recurrent CP groups. The AUC values of WBC, neutrophil, NLR + PLR and dNLR + PLR in PCP were all higher than 0.7. Inflammation seems to be closely correlated with CP's development. The preoperative inflammatory markers including WBC, neutrophil, NLR + PLR and dNLR + PLR may differentially diagnose PCP, pituitary tumor (PT) and Rathke cleft cyst (RCC). In addition, some statistical results in this study indirectly proved previous experimental conclusions and strictly matched CP's biological features.
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Affiliation(s)
- Ming Chen
- Department of Neurosurgery, XinHua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200092, China
| | - Shi-Hao Zheng
- Department of Neurosurgery, Fujian Provincial Hospital, Fuzhou, Fujian, China
| | - Min Yang
- Department of Neurosurgery, XinHua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200092, China
| | - Zhi-Hua Chen
- Department of Neurosurgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Shi-Ting Li
- Department of Neurosurgery, XinHua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200092, China.
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Anai L, Munhoz T, Semolin L, Reis Filho N, Terra E, Jark P, Fonseca D, Nogueira A, Tinucci-Costa M, Santana A. Quantification of Treg cells in peripheral blood and lymph nodes of dogs with multicentric lymphoma. ARQ BRAS MED VET ZOO 2017. [DOI: 10.1590/1678-4162-9599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
ABSTRACT Lymphoma is a malignant tumor characterized by cell proliferation of lymphoid origin and corresponds to 90% of all hematopoietic neoplasms of dogs. Regulatory T cells (Tregs) have been the target of many investigations in oncology due to their potential of down-regulating immune responses, as well as ensuring the maintenance of active mechanisms of tumor suppression. The aims of the present study were to compare the percentage of Tregs in peripheral blood between dogs with multicentric lymphoma and healthy animals, together with the percentage of Tregs in peripheral blood and lymph nodes of dogs with multicentric lymphoma. Twenty-six animals were enrolled in the study: 10 healthy dogs comprised the control group (CG) and 16 dogs with multicentric lymphoma comprised the Lymphoma Group (LG). We observed that dogs in the LG showed a significantly higher Tregs expression in peripheral blood compared to the CG. No significant difference was observed between Tregs expression in lymph nodes and peripheral blood of the LG, however. With these results, it is possible to conclude that multicentric lymphoma is a neoplasm with high Tregs expression, which poses this as a condition of interest when investigating treatments that can suppress Regulatory T cells.
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Affiliation(s)
- L.A. Anai
- Universidade Júlio Mesquita Filho, Brazil
| | | | | | | | - E.M. Terra
- Universidade Júlio Mesquita Filho, Brazil
| | - P.C. Jark
- Universidade Júlio Mesquita Filho, Brazil
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Aggarwal S, Sharma SC, N Das S. Dynamics of regulatory T cells (T regs ) in patients with oral squamous cell carcinoma. J Surg Oncol 2017; 116:1103-1113. [PMID: 28833201 DOI: 10.1002/jso.24782] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Accepted: 07/01/2017] [Indexed: 12/21/2022]
Abstract
BACKGROUND AND OBJECTIVES The immune dysfunction in oral squamous cell carcinoma (OSCC) patients is one of the major factors for growth and dissemination of tumor affecting disease-free survival. METHODS The phenotypic and functional characteristics of Regulatory T (Treg ) CD4+ CD25+ FoxP3+ subsets in OSCC patients were assessed by multicolor flow cytometry and its effector component (TGF-β) by Western blot and qRT-PCR. RESULTS An increased (P < 0.05) prevalence of Treg phenotypes (CD4+ CD25+ , CD4+ FoxP3+ , CD8+ FoxP3+ , CD4+ CD25+ FoxP3+ ) was observed in the peripheral circulation of OSCC patients that positively correlated with clinicopathological features. The increased frequency of CD4+ CD8+ CD25+ FoxP3+ , a unique T cell subset, CTLA-4+ , GITR+ , NrP1+ , HLA-DR+ , CD127+ , Tbet+ , TGF-β+ , and granzyme B+ (GzmB) Tregs also showed a significantly higher prevalence in OSCC patients. Functionally, CD4+ FoxP3+ Tregs showed skewed expression of IL-2, IL-10, and IL-35 in patients as compared with the normal controls. Further, enhanced expression of CCR5 and CCR7 on Tregs with up regulation of their ligands (CCL5, CCL19, and CCL21) in tumor cells indicates efficient recruitment and trafficking of Tregs to the tumor site. CONCLUSION It seems reasonable to assume that modulation of functional dynamics of selective Treg subsets may be useful in developing immunotherapeutic strategy for OSCC patients.
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Affiliation(s)
- Sadhna Aggarwal
- Department of Biotechnology, All India Institute of Medical Sciences, New Delhi, India
| | - Suresh C Sharma
- Department of Otorhinolaryngology, All India Institute of Medical Sciences, New Delhi, India
| | - Satya N Das
- Department of Biotechnology, All India Institute of Medical Sciences, New Delhi, India
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Morandi F, Pozzi S, Barco S, Cangemi G, Amoroso L, Carlini B, Pistoia V, Corrias MV. CD4 +CD25 hiCD127 - Treg and CD4 +CD45R0 +CD49b +LAG3 + Tr1 cells in bone marrow and peripheral blood samples from children with neuroblastoma. Oncoimmunology 2016; 5:e1249553. [PMID: 28123887 DOI: 10.1080/2162402x.2016.1249553] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Revised: 10/12/2016] [Accepted: 10/12/2016] [Indexed: 10/20/2022] Open
Abstract
Metastatic spread in the bone marrow (BM) at diagnosis is the worst prognostic factor for neuroblastoma (NB) patients. Here, we analyzed the presence of two immunosuppressive cell subsets, CD4+CD25hiCD127- regulatory T (Treg) cells and CD4+CD45R0+CD49b+LAG3+ type 1 regulatory (Tr1) cells, in BM and peripheral blood (PB) samples from NB patients and controls. Frequency of both regulatory cell subsets was lower in BM and PB samples from NB patients than in respective healthy controls. No correlation was found between the frequency of Treg and Tr1 cells and prognostic factors at diagnosis, such as age and stage. Only MYCN amplification correlated to a higher number of Treg in BM and of Tr1 in PB. These findings suggested an altered trafficking of regulatory T cells in NB, but delineated a limited role of these subsets in BM microenvironment and/or periphery in NB. These observations should be considered designing immunotherapeutic approaches for metastatic NB.
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Affiliation(s)
- Fabio Morandi
- Laboratorio di Oncologia, Istituto Giannina Gaslini , Genoa, Italy
| | - Sarah Pozzi
- Centro Cellule Staminali, IRCCS AOU San Martino-IST , Genoa, Italy
| | - Sebastiano Barco
- Laboratorio Centrale di Analisi, Istituto Giannina Gaslini , Genoa, Italy
| | - Giuliana Cangemi
- Laboratorio Centrale di Analisi, Istituto Giannina Gaslini , Genoa, Italy
| | | | - Barbara Carlini
- Laboratorio di Oncologia, Istituto Giannina Gaslini , Genoa, Italy
| | - Vito Pistoia
- Laboratorio di Oncologia, Istituto Giannina Gaslini, Genoa, Italy; Immunology Area, Ospedale Pediatrico Bambino Gesú, Rome, Italy
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Liesz A, Kleinschnitz C. Regulatory T Cells in Post-stroke Immune Homeostasis. Transl Stroke Res 2016; 7:313-21. [DOI: 10.1007/s12975-016-0465-7] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Revised: 03/15/2016] [Accepted: 03/21/2016] [Indexed: 01/01/2023]
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Chang DK, Peterson E, Sun J, Goudie C, Drapkin RI, Liu JF, Matulonis U, Zhu Q, Marasco WA. Anti-CCR4 monoclonal antibody enhances antitumor immunity by modulating tumor-infiltrating Tregs in an ovarian cancer xenograft humanized mouse model. Oncoimmunology 2015; 5:e1090075. [PMID: 27141347 PMCID: PMC4839340 DOI: 10.1080/2162402x.2015.1090075] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Revised: 08/27/2015] [Accepted: 08/29/2015] [Indexed: 12/21/2022] Open
Abstract
Recent studies have demonstrated that regulatory T cells (Tregs) are recruited to tumor sites where they can suppress antitumor immunity. The chemokine receptor CCR4 is expressed at high levels on functional CD4+CD25+FoxP3+ Tregs and production of the CCR4 ligand CCL22 by tumor cells and tumor-associated macrophages is associated with Treg recruitment to the tumor site. Here, we tested IgG1 and IgG4 isotypes of human anti-CCR4 mAb2-3 for their in vitro activity and in vivo capacity in a NSG mouse model bearing CCL22-secreting ovarian cancer (OvCA) xenograft to modulate Tregs and restore antitumor activity. Both mAb2-3 isotypes blocked in vitro chemoattraction of Tregs to CCL22-secreting OvCA cells. However, they differed in their in vivo mode of action with IgG1 causing Treg depletion and IgG4 blocking migration to the tumors. Primary T cells that were primed with OvCA-pulsed dendritic cells (DCs) demonstrated INFγ secretion that could be enhanced through Treg depletion by mAb2-3. Humanized mice reconstructed with allogeneic tumor-primed T cells (TP-T) were used to evaluate the restoration of OvCA immunity by depletion or blockade of Tregs with mAb2-3. We observed that IgG1 was more potent than IgG4 in inhibiting tumor growth. Mechanism studies demonstrated that mAb2-3 treatment lead to inhibition of IL-2 binding to its receptor. Further studies showed that mAb2-3 induced CD25 shedding (sCD25) from Tregs which lead to a decrease in IL-2-dependent survival. Together, the results demonstrate that mAb2-3 is an agonist antibody that can restore anti-OvCA immunity through modulation of Treg activity.
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Affiliation(s)
- De-Kuan Chang
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Eric Peterson
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute , Boston, MA, USA
| | - Jiusong Sun
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute , Boston, MA, USA
| | - Calum Goudie
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute , Boston, MA, USA
| | - Ronny I Drapkin
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA; Ovarian Cancer Research Center, Department of Obstetrics & Gynecology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Joyce F Liu
- Department of Medicine, Harvard Medical School, Boston, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Ursula Matulonis
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute , Boston, MA, USA
| | - Quan Zhu
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Wayne A Marasco
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
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Liesz A, Hu X, Kleinschnitz C, Offner H. Functional role of regulatory lymphocytes in stroke: facts and controversies. Stroke 2015; 46:1422-30. [PMID: 25791715 DOI: 10.1161/strokeaha.114.008608] [Citation(s) in RCA: 123] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2014] [Accepted: 02/24/2015] [Indexed: 01/02/2023]
Affiliation(s)
- Arthur Liesz
- From the Institute for Stroke and Dementia Research, Klinikum der Universität München, Munich, Germany (A.L.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (A.L.); Department of Neurology, University of Pittsburgh, PA (X.H.); Department of Neurology, University Hospital Würzburg, Würzburg, Germany (C.K.); Department of Neurology and Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland (H.O.); and Neuroimmunology Research, Portland, OR (H.O.).
| | - Xiaoming Hu
- From the Institute for Stroke and Dementia Research, Klinikum der Universität München, Munich, Germany (A.L.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (A.L.); Department of Neurology, University of Pittsburgh, PA (X.H.); Department of Neurology, University Hospital Würzburg, Würzburg, Germany (C.K.); Department of Neurology and Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland (H.O.); and Neuroimmunology Research, Portland, OR (H.O.)
| | - Christoph Kleinschnitz
- From the Institute for Stroke and Dementia Research, Klinikum der Universität München, Munich, Germany (A.L.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (A.L.); Department of Neurology, University of Pittsburgh, PA (X.H.); Department of Neurology, University Hospital Würzburg, Würzburg, Germany (C.K.); Department of Neurology and Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland (H.O.); and Neuroimmunology Research, Portland, OR (H.O.)
| | - Halina Offner
- From the Institute for Stroke and Dementia Research, Klinikum der Universität München, Munich, Germany (A.L.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (A.L.); Department of Neurology, University of Pittsburgh, PA (X.H.); Department of Neurology, University Hospital Würzburg, Würzburg, Germany (C.K.); Department of Neurology and Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland (H.O.); and Neuroimmunology Research, Portland, OR (H.O.)
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15
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Liu Y, Yun X, Gao M, Yu Y, Li X. Analysis of regulatory T cells frequency in peripheral blood and tumor tissues in papillary thyroid carcinoma with and without Hashimoto's thyroiditis. Clin Transl Oncol 2014; 17:274-80. [PMID: 25387566 DOI: 10.1007/s12094-014-1222-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2013] [Accepted: 08/24/2014] [Indexed: 01/15/2023]
Abstract
PURPOSE Regulatory T cells (Treg) suppress the immune reaction. The aim of the present study was to investigate the clinicopathologic significance and roles of Treg in papillary thyroid carcinoma (PTC) patients with and without Hashimoto's thyroiditis. METHODS Flow cytometry was used to detect the percentage of CD4+CD25+CD127low/- Treg among CD4+ T cells in peripheral blood. FoxP3+ Treg were detected by immunohistochemistry in the tumor tissues. RESULTS The percentage of CD4+CD25+CD127low/- Treg among CD4+ T cells was significantly higher in PTC patients than that in multinodular goiter (MNG) patients. There were large numbers of tumor-infiltrating FoxP3+ Treg in primary PTC and metastatic lymph nodes tissues; however, there was no FoxP3 expression in the MNG tissues. Higher percentage of Treg both in peripheral blood and tumor tissues was associated with extrathyroidal extension and lymph nodes metastasis. The percentage of CD4+CD25+CD127low/- Treg among CD4+ T cells in peripheral blood of PTC patients with Hashimoto's thyroiditis (HT) was significantly lower, whereas the infiltration of FoxP3+ Treg in tissues of PTC with HT tended to be increased. CONCLUSIONS We concluded that the percentage of Treg increased in peripheral blood as well as in the tumor tissues of PTC patients compared with that of MNG patients. The high percentage of Treg was associated with aggressiveness. There may be a compensatory expansion of Treg at the sites of inflammation in tissues of PTC with HT contributing to the immune response suppression.
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Affiliation(s)
- Y Liu
- Department of Head and Neck Tumor, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Huanhuxi Road, Ti-Yuan-Bei, Hexi District, Tianjin, 300060, People's Republic of China
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Imam S, Paparodis R, Sharma D, Jaume JC. Lymphocytic profiling in thyroid cancer provides clues for failure of tumor immunity. Endocr Relat Cancer 2014; 21:505-16. [PMID: 24623740 PMCID: PMC4038677 DOI: 10.1530/erc-13-0436] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Thyroid cancers are usually surrounded by a significant number of immune-reactive cells. Tumor-associated lymphocytes as well as background lymphocytic thyroiditis are frequently mentioned in pathology reports of patients who have undergone surgery for thyroid cancer. The nature of this lymphocytic reaction is not well understood. The fact that cancer can survive in this adverse microenvironment is indicative of immune regulation. We characterized the lymphocytic infiltration that accompanies thyroid cancer and compared it with that present in thyroid autoimmunity. We found that double-negative (DN) T cells were significantly more abundant in thyroid cancer than in thyroid autoimmunity. Although FOXP3(+) regulatory T cells were also present, DN T cells were the dominant cell type, associated with thyroid cancer. Furthermore, upon stimulation, the DN T cells associated with cancer remained unchanged, while the few (<5%) DN T cells associated with thyroid autoimmunity increased in numbers (>20%). CD25 expression on DN T cells remained unchanged after stimulation, which indicates that the increase in the absolute number of DN T cells in thyroid autoimmunity was at the expense of inactivation of single-positive T cells. We concluded that in the setting of thyroid cancer, DN T cells appear to suppress tumor immunity. In contrast, in thyroid autoimmunity, DN T cells were barely present and only increased at the expense of inactivated, single-positive T cells upon induction. Together, these findings indicate that thyroid cancer-associated DN T cells might regulate proliferation and effector function of T cells and thereby contribute to tumor tolerance and active avoidance of tumor immunity.
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Affiliation(s)
- Shahnawaz Imam
- Endocrine Autoimmunity UnitDivision of Endocrinology, Diabetes and Metabolism, Department of Medicine, School of Medicine and Public HealthVeterans Affairs Medical CenterUniversity of Wisconsin-Madison, 1685 Highland Avenue, MFCB 4163, Madison, Wisconsin 53705, USA
| | - Rodis Paparodis
- Endocrine Autoimmunity UnitDivision of Endocrinology, Diabetes and Metabolism, Department of Medicine, School of Medicine and Public HealthVeterans Affairs Medical CenterUniversity of Wisconsin-Madison, 1685 Highland Avenue, MFCB 4163, Madison, Wisconsin 53705, USAEndocrine Autoimmunity UnitDivision of Endocrinology, Diabetes and Metabolism, Department of Medicine, School of Medicine and Public HealthVeterans Affairs Medical CenterUniversity of Wisconsin-Madison, 1685 Highland Avenue, MFCB 4163, Madison, Wisconsin 53705, USA
| | - Deepak Sharma
- Endocrine Autoimmunity UnitDivision of Endocrinology, Diabetes and Metabolism, Department of Medicine, School of Medicine and Public HealthVeterans Affairs Medical CenterUniversity of Wisconsin-Madison, 1685 Highland Avenue, MFCB 4163, Madison, Wisconsin 53705, USA
| | - Juan Carlos Jaume
- Endocrine Autoimmunity UnitDivision of Endocrinology, Diabetes and Metabolism, Department of Medicine, School of Medicine and Public HealthVeterans Affairs Medical CenterUniversity of Wisconsin-Madison, 1685 Highland Avenue, MFCB 4163, Madison, Wisconsin 53705, USAEndocrine Autoimmunity UnitDivision of Endocrinology, Diabetes and Metabolism, Department of Medicine, School of Medicine and Public HealthVeterans Affairs Medical CenterUniversity of Wisconsin-Madison, 1685 Highland Avenue, MFCB 4163, Madison, Wisconsin 53705, USA
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Abstract
Human papillomavirus (HPV) infection is a major cause of cervical cancer, the second most common cancer in women worldwide. Currently, a HPV L1-based virus-like particle has been approved as a prophylactic vaccine against HPV infection, which will probably lead to a reduction in cervical cancer incidence within a few decades. Therapeutic vaccines, however, are expected to have an impact on cervical cancer or its precursor lesions, by taking advantage of the fact that the regulatory proteins (E6 and E7) of HPV are expressed constantly in HPV-associated cervical cancer cells. Vaccine types targeting these regulatory proteins include the recombinant protein and DNA vaccines, peptide vaccines, dendritic-cell vaccines, and viral and bacterial vector deliveries of vaccines, and these may provide an opportunity to control cervical cancer. Further approaches incorporating these vaccine types with either conventional therapy modalities or the modulation of CD4(+) regulatory T cells appear to be more promising in achieving increased therapeutic efficacy. In this review, we summarize current and future therapeutic vaccine strategies against HPV-associated malignancies at the animal and clinical levels.
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Affiliation(s)
- Jeong-Im Sin
- Catholic University of Daegu, Department of Microbiology, School of Medicine, 3056-6, Daemyung-4-Dong, Namgu, Daegu, 705-718, Korea.
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18
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Si TG, Wang JP, Guo Z. Analysis of circulating regulatory T cells (CD4+CD25+CD127-) after cryosurgery in prostate cancer. Asian J Androl 2013; 15:461-5. [PMID: 23728588 DOI: 10.1038/aja.2013.22] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2012] [Revised: 10/27/2012] [Accepted: 02/02/2013] [Indexed: 12/31/2022] Open
Abstract
This study was performed to assess the response of regulatory T cells (Tregs) following cryosurgery in prostate cancer (PCa) patients by measuring their frequency and immune function. Blood was collected prior to and at 4 and 8 weeks after treatment in 30 patients with high-risk PCa who underwent cryosurgery and from 15 healthy volunteers. Circulating CD4(+)CD25(+)CD127(-) Tregs were isolated. Their frequency was detected by flow cytometry, and immune suppressive function was evaluated by measuring the proliferation of CD4(+)CD25(-) T cells cocultured with Tregs. The results showed that the percentage of circulating CD4(+)CD25(+)CD127(-) Tregs was increased in PCa patients compared to healthy volunteers (7.6% ± 0.73% vs. 5.8% ± 0.54%, P<0.001). The frequency of circulating CD4(+)CD25(+)CD127(-) Tregs was reduced 4 weeks after cryosurgery compared to before surgery (6.3% ± 0.58% vs. 7.6% ± 0.73%, P<0.001), and the decrease persisted for 8 weeks. However, the suppressive function of Tregs was increased in eight of 12 patients, which might contribute to cancer recurrence. Then the response of circulating Tregs is complicated after cryosurgery for PCa, and further studies are warranted.
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Affiliation(s)
- Tong-Guo Si
- Department of Interventional Therapy, Tianjin Cancer Hospital, Tianjin Medical University, Tianjin 300060, China
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Sofra M, Fei PC, Fabrizi L, Marcelli ME, Claroni C, Gallucci M, Ensoli F, Forastiere E. Immunomodulatory effects of total intravenous and balanced inhalation anesthesia in patients with bladder cancer undergoing elective radical cystectomy: preliminary results. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2013; 32:6. [PMID: 23374147 PMCID: PMC3577511 DOI: 10.1186/1756-9966-32-6] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/10/2012] [Accepted: 01/27/2013] [Indexed: 01/05/2023]
Abstract
Background Although surgery and anesthesia induce immunesuppression, remains largely unknown whether various anesthetic techniques have different immunosuppressive effects on cancer patients. Therefore, the aim of this study was to investigate the influence of total intravenous anesthesia with target-controlled infusion (TIVA-TCI) and balanced inhalation anesthesia (BAL) on the peri-operative levels of inflammatory cytokines and regulatory T cells (Tregs) in patients with bladder cancer undergoing surgery. Methods Twenty eight consecutive patients with bladder cancer who underwent radical cystectomy were prospectively randomized into two groups to receive TIVA-TCI (n = 14) or BAL (n = 14). Before the induction of anesthesia (T0), 6–8 hours (T1) post-surgery, and 5 days post-surgery (T2), Tregs and serum levels of interleukin -1beta (IL-1β), interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), interleukin −2 (IL-2), interleukin −6 (IL-6), and interleukin −10 (IL-10) were measured. Results In the peri-operative period all cancer patients showed a marked and significant increase in IL-6. Moreover, TIVA-TCI patients also showed a higher increase in IFN-γ, whereas in BAL patients Tregs were reduced by approximately 30% during surgery. The incidence of infections, metastases, and death was similar in both groups. Conclusions The increase in the Th1 response in the TIVA-TCI group and the reduction in Tregs in the BAL group seem to balance the immunosuppressive effect induced by IL-6. Therefore TIVA-TCI and BAL can be both used in major surgery in patients with bladder cancer without worsening the outcome.
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Affiliation(s)
- Maria Sofra
- Department of Anesthesiology, Regina Elena, Rome National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy
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Zaccone P, Cooke A. Helminth mediated modulation of Type 1 diabetes (T1D). Int J Parasitol 2013; 43:311-8. [PMID: 23291464 DOI: 10.1016/j.ijpara.2012.12.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2012] [Revised: 12/05/2012] [Accepted: 12/07/2012] [Indexed: 01/11/2023]
Abstract
Type 1 diabetes is increasing dramatically in incidence in the developed world. While there may be several reasons for this, improved sanitation and public health measures have altered our interactions with certain infectious agents such as helminths. There is increasing interest in the use of helminths or their products to alleviate inflammatory or allergic conditions. Using rodent models of diabetes, it has been possible to explore the therapeutic potential of both live infections as well as helminth-derived products on the development of autoimmunity. This review provides an overview of the findings from animal models and additionally explores the potential for translation to the clinic.
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Affiliation(s)
- Paola Zaccone
- Department of Pathology, University of Cambridge, Tennis Court Rd, Cambridge CB2 1QP, UK
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Chen YL, Chang MC, Chen CA, Lin HW, Cheng WF, Chien CL. Depletion of regulatory T lymphocytes reverses the imbalance between pro- and anti-tumor immunities via enhancing antigen-specific T cell immune responses. PLoS One 2012; 7:e47190. [PMID: 23082146 PMCID: PMC3474819 DOI: 10.1371/journal.pone.0047190] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2012] [Accepted: 09/12/2012] [Indexed: 12/03/2022] Open
Abstract
Background The regulatory T cells (Tregs) can actively suppress the immune responses. However, literature about detailed changes of host effective and suppressive immunities before and after depletion of Tregs in ovarian carcinomas, is rare. Materials and Methods Ovarian cancer patients and the ascitogenic animal model were employed. Immunologic profiles with flow cytometric analyses, immunohistochemistric staining, RT-PCR, ELISA, and ELISPOT assays were performed. In vivo depletion of Treg cells with the mAb PC61was also performed in the animal model. Results The cytokines, including IL-4 (p = 0.017) and TNF-α (p = 0.046), significantly decreased while others such as TGF-β (p = 0.013), IL-6 (p = 0.016), and IL-10 (p = 0.018) were elevated in ascites of ovarian cancer patients, when the disease progressed to advanced stages. The ratio of CD8+ T cell/Treg cell in ascites was also lower in advanced diseases than in early diseases (advanced 7.37±0.64 vs. early 14.25±3.11, p = 0.037). The kinetic low-dose CD25 Ab depletion group had significantly lower intra-peritoneal tumor weight (0.20±0.03 g) than the sequential high-dose (0.69±0.06 g) and sequential low-dose (0.67±0.07 g) CD25 Ab deletion groups (p = 0.001) after 49 days of tumor challenge in the animal. The kinetic low-dose CD25 Ab depletion group generated the highest number of IFN-γ-secreting, mesothelin-specific T lymphocytes compared to the other groups (p<0.001). Conclusions The imbalance between effective and suppressive immunities becomes more severe as a tumor progresses. The depletion of Treg cells can correct the imbalance of immunologic profiles and generate potent anti-tumor effects. Targeting Treg cells can be a new strategy for the immunotherapy of ovarian carcinoma.
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Affiliation(s)
- Yu-Li Chen
- Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
- Gynecologic Cancer Center, Department of Obstetrics and Gynecology, Cathay General Hospital, Taipei, Taiwan
- Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ming-Cheng Chang
- Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan
- Department of Anesthesiology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chi-An Chen
- Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Han-Wei Lin
- Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Wen-Fang Cheng
- Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei, Taiwan
- Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
- * E-mail: (C-LC); (W-FC)
| | - Chung-Liang Chien
- Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
- * E-mail: (C-LC); (W-FC)
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Jiang LN, Yao YM, Sheng ZY. The role of regulatory T cells in the pathogenesis of sepsis and its clinical implication. J Interferon Cytokine Res 2012; 32:341-9. [PMID: 22799563 DOI: 10.1089/jir.2011.0080] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Sepsis is denoted as a complex syndrome that results from a serious infection followed by amplified and dysregulated inflammatory response. The complex immune response associated with sepsis results in a high rate of morbidity and mortality, despite substantial basic science and clinical advances. Recently, accumulating evidence have demonstrated that regulatory T cells (Tregs) play important roles in suppression of immune response, as demonstrated by the number increase and functional enhancement following the onset of severe sepsis or septic shock. This article reviews recent advances in understanding the potential role of Tregs in the pathophysiology of septic response, as well as implications in the development of novel therapeutic strategies for improving the clinical outcome of patients with severe injury and subsequent septic complications.
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Affiliation(s)
- Li-Na Jiang
- Department of Microbiology and Immunology, Burns Institute, First Hospital Affiliated to the Chinese PLA General Hospital, Beijing, People's Republic of China
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23
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Boenisch O, Lopez M, Elyaman W, Magee CN, Ahmad U, Najafian N. Ex vivo expansion of human Tregs by rabbit ATG is dependent on intact STAT3-signaling in CD4⁺ T cells and requires the presence of monocytes. Am J Transplant 2012; 12:856-66. [PMID: 22390202 PMCID: PMC3777828 DOI: 10.1111/j.1600-6143.2011.03978.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
The addition of low, nondepleting doses of rabbit antithymocyte globulin (ATG) to human peripheral blood mononuclear cells has been shown to expand functional CD4(+) CD25(+) FoxP3(+) regulatory T cells (Tregs) in vitro. This report is the first to elucidate the exact cellular mechanisms of ATG-mediated Treg expansion. CD4(+) T cells require monocytes, but not other antigen presenting cell subsets, to be present in coculture to expand Tregs. However, T cells do not require direct cell-cell contact with monocytes, suggesting the importance of soluble factors. Moreover, ATG initially "reprograms" CD4(+) T cells, but not monocytes, and induces STAT3 and STAT5 signaling in CD4(+) cells. These reprogrammed CD4(+) T cells subsequently secrete GM-CSF and IL-10 only in case of intact STAT3 signaling, which in turn promote the generation of tolerogenic CD14(+) CD11c(+) dendritic cells characterized by enhanced IL-10 and decreased IL-12 production. Treg expansion following ATG treatment is accompanied by enhanced gene expression of both GM-CSF and Bcl-2, but not TGF-β, in peripheral blood mononuclear cells. These results demonstrate that ex vivo expansion of human Tregs by ATG is due to its ability to reprogram CD4(+) T cells in a STAT3-dependent but TGF-β-independent manner, leading to the generation of monocyte-derived dendritic cells with a tolerogenic cytokine profile.
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Affiliation(s)
- O. Boenisch
- Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital Boston, Harvard Medical School, Boston, MA,Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
| | - M. Lopez
- Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital Boston, Harvard Medical School, Boston, MA
| | - W. Elyaman
- Center of Neurologic Diseases, Brigham and Women’s Hospital Boston, Harvard Medical School, Boston, MA
| | - C. N. Magee
- Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital Boston, Harvard Medical School, Boston, MA
| | - U. Ahmad
- Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital Boston, Harvard Medical School, Boston, MA
| | - N. Najafian
- Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital Boston, Harvard Medical School, Boston, MA,Corresponding author: Nader Najafian,
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Burton J, Mitchell L, Thamm D, Dow S, Biller B. Low-Dose Cyclophosphamide Selectively Decreases Regulatory T Cells and Inhibits Angiogenesis in Dogs with Soft Tissue Sarcoma. J Vet Intern Med 2011; 25:920-6. [DOI: 10.1111/j.1939-1676.2011.0753.x] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
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Cipolletta D, Kolodin D, Benoist C, Mathis D. Tissular T(regs): a unique population of adipose-tissue-resident Foxp3+CD4+ T cells that impacts organismal metabolism. Semin Immunol 2011; 23:431-7. [PMID: 21724410 DOI: 10.1016/j.smim.2011.06.002] [Citation(s) in RCA: 100] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2011] [Accepted: 06/07/2011] [Indexed: 10/18/2022]
Abstract
Foxp3+CD4+ regulatory T (T(reg)) cells are a key population in controlling the immune response. Recently, their roles have been expanded to broader, non-immune, contexts, in particular the metabolic consequences downstream of obesity-induced inflammation, e.g. type-2 diabetes and cardiovascular disease. This review highlights the major innate and adaptive immune cell subsets contributing to adipose-tissue inflammation, the key role played by fat-resident T(regs), and the potential of T(reg)-based therapies for treatment of the metabolic syndrome.
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Affiliation(s)
- Daniela Cipolletta
- Department of Pathology, Harvard Medical School, Boston, MA 02115, United States
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Mechanisms of tumor escape from the immune system: adenosine-producing Treg, exosomes and tumor-associated TLRs. Bull Cancer 2011; 98:E25-31. [PMID: 21339097 DOI: 10.1684/bdc.2010.1294] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Human tumors utilize many different mechanisms of immunosuppression to prevent immune cells from exercising their antitumor activities. These mechanisms, which enable the tumor to escape from the host immune system and to progress, are being intensively investigated in hope of finding therapeutically safe and effective inhibitors able to counteract tumor-induced immunosuppression. Three of more recently discovered tumor-related suppression mechanisms, i.e. accumulations of adenosine-producing regulatory T-cells (Treg) in the tumor microenvironment, release by tumors of suppressive microvesicles (TMV) and expression of toll-like receptors (TLR) on the tumor cell surface, are described in this review. All contribute in a varying degree to creating a milieu favorable for the tumor and unfavorable for immune effector cells. Tumor escape has been a major problem in cancer immunotherapy and it has been held responsible for the failure of many immune interventions in cancer. For this reason, it is important to study and understand the various suppressive pathways human tumors utilize. Future antitumor immunotherapies are likely to include inhibitors of tumor-induced suppression with the goal of restoring antitumor immune responses in patients with cancer.
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CD28 costimulation Impairs the efficacy of a redirected t-cell antitumor attack in the presence of regulatory t cells which can be overcome by preventing Lck activation. Mol Ther 2011; 19:760-7. [PMID: 21326215 DOI: 10.1038/mt.2011.9] [Citation(s) in RCA: 104] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Adoptive T-cell transfer showed promising efficacy in recent trials raising interest in T cells with redirected specificity against tumors. T cells were engineered with a chimeric antigen receptor (CAR) with predefined binding and CD3ζ signaling to initiate T-cell activation. CD28 costimulation provided by a CD28-CD3ζ signaling CAR moreover improved T cell activation and persistence; however, it failed to meet the expectations with respect to mounting attacks against solid tumors infiltrated with regulatory T (Treg) cells. We revealed that a CD28 CAR-redirected T-cell attack is accompanied by higher numbers of Treg cells infiltrating the tumor and is less efficient against cancer cells in presence of Treg cells than a CD3ζ CAR T-cell attack. Deletion of the lck binding moiety in the CD28 CAR endodomain, however, improved redirected anti-tumor activity in presence of Treg cells without impairing interferon-γ (IFN-γ) secretion, proliferation, and cytolysis. CD28 modification abrogated interleukin-2 (IL-2) induction upon CAR engagement which in turn is no longer available to sustain Treg cell persistence. CARs with the modified CD28 endodomain thereby expedite the implementation of adoptive T-cell therapy in patients with a variety of cancer types that are heavily infiltrated by Treg cells.
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Voelkl S, Gary R, Mackensen A. Characterization of the immunoregulatory function of human TCR-αβ+ CD4- CD8- double-negative T cells. Eur J Immunol 2011; 41:739-48. [PMID: 21287552 DOI: 10.1002/eji.201040982] [Citation(s) in RCA: 89] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2010] [Revised: 11/12/2010] [Accepted: 12/15/2010] [Indexed: 12/21/2022]
Abstract
Regulatory T cells (Tregs) play an important role in the maintenance of immune tolerance to self-antigens and are involved in modulating immune responses in autoimmunity, transplant rejection, and tumor immunity. Recently, a novel subset of TCR-αβ(+) CD4(-) CD8(-) (double negative, DN) T cells has been described to specifically suppress T-cell responses in mice. Here, we demonstrate that human DN T cells are highly potent suppressors of both CD4(+) and CD8(+) T-cell responses. In contrast to naturally occurring CD4(+) CD25(+) Tregs, DN T cells have to be activated by antigen-presenting cells (APCs) to induce their regulatory potential. The suppressive activity of DN T cells is neither mediated indirectly by modulation of APCs nor by competition for T-cell growth factors. Furthermore, DN T-cell-mediated suppression toward responder T cells is TCR dependent and requires novel protein synthesis. In contrast to murine DN T cells, which eliminate effector T cells via Fas/FasL or perforin/granzyme, human DN T cells suppress proliferation of responder T cells by cell contact-dependent mechanisms. Taken together, our data indicate that human DN T cells exert strong immunosuppressive effects on both CD4(+) and CD8(+) T cells and may serve as a new therapeutic approach to treat autoimmunity and transplant rejection.
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Affiliation(s)
- Simon Voelkl
- Department of Internal Medicine 5 - Hematology/Oncology, University of Erlangen-Nürnberg, Erlangen, Germany
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Daayana S, Winters U, Stern PL, Kitchener HC. Clinical and immunological response to photodynamic therapy in the treatment of vulval intraepithelial neoplasia. Photochem Photobiol Sci 2011; 10:802-9. [DOI: 10.1039/c0pp00344a] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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KNUEPPEL A, LANGE S, SEKORA A, ALTMANN S, FREUND M, JUNGHANSS C. Phenotypic and Functional Characterization of Freshly Isolated and Expanded Canine Regulatory T Cells. Exp Anim 2011; 60:471-9. [DOI: 10.1538/expanim.60.471] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Affiliation(s)
- Anne KNUEPPEL
- Division of Medicine, Department of Hematology/Oncology/Palliative Care, University of Rostock
| | - Sandra LANGE
- Division of Medicine, Department of Hematology/Oncology/Palliative Care, University of Rostock
| | - Anett SEKORA
- Division of Medicine, Department of Hematology/Oncology/Palliative Care, University of Rostock
| | - Simone ALTMANN
- Division of Medicine, Department of Hematology/Oncology/Palliative Care, University of Rostock
| | - Mathias FREUND
- Division of Medicine, Department of Hematology/Oncology/Palliative Care, University of Rostock
| | - Christian JUNGHANSS
- Division of Medicine, Department of Hematology/Oncology/Palliative Care, University of Rostock
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Schwartzbaum JA, Xiao Y, Liu Y, Tsavachidis S, Berger MS, Bondy ML, Chang JS, Chang SM, Decker PA, Ding B, Hepworth SJ, Houlston RS, Hosking FJ, Jenkins RB, Kosel ML, McCoy LS, McKinney PA, Muir K, Patoka JS, Prados M, Rice T, Robertson LB, Schoemaker MJ, Shete S, Swerdlow AJ, Wiemels JL, Wiencke JK, Yang P, Wrensch MR. Inherited variation in immune genes and pathways and glioblastoma risk. Carcinogenesis 2010; 31:1770-7. [PMID: 20668009 PMCID: PMC2950934 DOI: 10.1093/carcin/bgq152] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2010] [Revised: 07/14/2010] [Accepted: 07/19/2010] [Indexed: 12/26/2022] Open
Abstract
To determine whether inherited variations in immune function single-nucleotide polymorphisms (SNPs), genes or pathways affect glioblastoma risk, we analyzed data from recent genome-wide association studies in conjunction with predefined immune function genes and pathways. Gene and pathway analyses were conducted on two independent data sets using 6629 SNPs in 911 genes on 17 immune pathways from 525 glioblastoma cases and 602 controls from the University of California, San Francisco (UCSF) and a subset of 6029 SNPs in 893 genes from 531 cases and 1782 controls from MD Anderson (MDA). To further assess consistency of SNP-level associations, we also compared data from the UK (266 cases and 2482 controls) and the Mayo Clinic (114 cases and 111 controls). Although three correlated epidermal growth factor receptor (EGFR) SNPs were consistently associated with glioblastoma in all four data sets (Mantel-Haenzel P values = 1 × 10⁻⁵ to 4 × 10⁻³), independent replication is required as genome-wide significance was not attained. In gene-level analyses, eight immune function genes were significantly (minP < 0.05) associated with glioblastoma; the IL-2RA (CD25) cytokine gene had the smallest minP values in both UCSF (minP = 0.01) and MDA (minP = 0.001) data sets. The IL-2RA receptor is found on the surface of regulatory T cells potentially contributing to immunosuppression characteristic of the glioblastoma microenvironment. In pathway correlation analyses, cytokine signaling and adhesion-extravasation-migration pathways showed similar associations with glioblastoma risk in both MDA and UCSF data sets. Our findings represent the first systematic description of immune genes and pathways that characterize glioblastoma risk.
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Affiliation(s)
- Judith A Schwartzbaum
- Division of Epidemiology, College of Public Health, Ohio State University, Columbus, OH 43210, USA.
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Regulatory T cells are associated with post-cryoablation prognosis in patients with hepatitis B virus-related hepatocellular carcinoma. J Gastroenterol 2010; 45:968-78. [PMID: 20411280 DOI: 10.1007/s00535-010-0243-3] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2010] [Accepted: 03/17/2010] [Indexed: 02/06/2023]
Abstract
BACKGROUND We carried out this study to evaluate the association between regulatory T cells (Treg) and prognosis and progression after cryoablation in patients with hepatitis-B virus-related hepatocellular carcinoma. METHODS Peripheral Treg frequency in 111 patients with hepatocellular carcinoma (HCC) was detected by flow cytometry. Treg frequency and function were re-examined during patient follow up. A possible association between Treg and α-fetoprotein (AFP) was also analyzed, and the distribution of resident CD4(+) and CD8(+) T cells and FoxP3(+) T cells in the liver tissue of patients with HCC was examined by immunohistochemistry. RESULTS Treg frequency significantly increased with disease progression. Our longitudinal study showed that Treg frequency had significantly decreased in 17 patients with HCC regression following cryoablation, but the frequency had dramatically increased in 14 patients with HCC recurrence or progression. Furthermore, AFP levels varied in a way comparable with Treg frequency in patients with elevated AFP recorded before therapy. Significantly increased suppressive effects of Treg on proliferation and cytokine secretion of CD8(+) and CD4(+) T cells were observed during follow up in patients with tumor progression, but not in patients with tumor response. Moreover, the numbers of CD8(+), CD4(+), and FoxP3(+) cells infiltrating the tumors around the cryotherapeutic zones were significantly decreased after argon-helium cryoablation, and this was associated with a reduction in the FoxP3/CD8 ratio. Importantly,increased quantities of circulating CD4(+)CD25(+)FoxP3(+) Treg and tumor infiltrating FoxP3(+) cells before cryoablation were associated with high recurrence or risk of progression in HCC patients after cryoablation. CONCLUSIONS Treg variation is associated with tumor regression or progression in HCC following cryoablation and may be used as a marker to estimate HCC progression.
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Biller BJ, Guth A, Burton JH, Dow SW. Decreased ratio of CD8+ T cells to regulatory T cells associated with decreased survival in dogs with osteosarcoma. J Vet Intern Med 2010; 24:1118-23. [PMID: 20666983 DOI: 10.1111/j.1939-1676.2010.0557.x] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Increased numbers of regulatory T cells (Treg) and decreased ratios of CD8+ T cells to Treg have been shown to correlate with decreased survival times (ST) in humans with certain malignancies. A possible connection between Treg and ST in dogs with cancer has not been investigated previously. HYPOTHESIS The purpose of this study was to compare numbers of Treg and T lymphocyte subsets in dogs with osteosarcoma (OSA) to those of healthy dogs and to determine whether pretreatment values were associated with disease-free interval or with ST. We hypothesized that Treg numbers would be increased in dogs with cancer and that dogs with a high percentage of Treg would have a poorer prognosis. ANIMALS Twelve client-owned dogs with appendicular OSA were entered into a prospective clinical trial. Twenty-two healthy dogs were used as controls. METHODS The percentages and numbers of Treg and CD4+ and CD8+ T cells in blood, lymph nodes, and tumors were determined with flow cytometry and compared between dogs with OSA and control dogs. RESULTS Dogs with OSA had significantly fewer circulating CD8+ T cells and significantly more Treg compared with healthy dogs. The CD8/Treg ratio also was significantly lower in dogs with OSA compared with control dogs. In dogs with OSA, a decreased CD8/Treg ratio was associated with significantly shorter STs. CONCLUSIONS These data support a role for Treg in the immune control of canine OSA and suggest that determination of the CD8/Treg ratio may be useful for assessing outcomes.
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Affiliation(s)
- B J Biller
- Department of Clinical Sciences, Animal Cancer Center, Colorado State University, Fort Collins, Colorado, USA
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Mougiakakos D, Choudhury A, Lladser A, Kiessling R, Johansson CC. Regulatory T cells in cancer. Adv Cancer Res 2010; 107:57-117. [PMID: 20399961 DOI: 10.1016/s0065-230x(10)07003-x] [Citation(s) in RCA: 278] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
At the present time, regulatory T cells (Tregs) are an integral part of immunology but the route from discovery of "suppressive" lymphocytes in the 1980s to the current established concept of Tregs almost 20 years later has been a rollercoaster ride. Tregs are essential for maintaining self-tolerance as defects in their compartment lead to severe autoimmune diseases. This vitally important function exists alongside the detrimental effects on tumor immunosurveillance and antitumor immunity. Beginning with the identification of CD4(+)CD25(+) Tregs in 1995, the list of Treg subsets, suppressive mechanisms, and knowledge about their various origins is steadily growing. Increase in Tregs within tumors and circulation of cancer patients, observed in early studies, implied their involvement in pathogenesis and disease progression. Several mechanisms, ranging from proliferation to specific trafficking networks, have been identified to account for their systemic and/or local accumulation. Since various immunotherapeutic approaches are being utilized for cancer therapy, various strategies to overcome the antagonistic effects exerted by Tregs are being currently explored. An overview on the biology of Tregs present in cancer patients, their clinical impact, and methods for modulating them is given in this review. Despite the extensive studies on Tregs in cancer many questions still remain unanswered. Even the paradigm that Tregs generally are disadvantageous for the control of malignancies is now under scrutiny. Insight into the specific role of Tregs in different types of neoplasias is the key for targeting them in a way that is beneficial for the clinical outcome.
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Affiliation(s)
- Dimitrios Mougiakakos
- Department of Oncology and Pathology, Karolinska University Hospital, Cancer Center Karolinska R8:01, Stockholm, Sweden
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Abstract
The cutaneous surface of a normal adult individual contains approximately 20 billion T cells, nearly twice the number present in the entire circulation. Recent studies have shown a role for these cells in both normal immunity and in inflammatory skin diseases such as psoriasis. Regulatory T cells protect against autoimmune reactions to self antigens and assist in the resolution of cutaneous inflammation. However, they can also shield tumors from immune detection, allow latent infections to persist and can dysfunction under the conditions present in inflammatory skin diseases. Th17 T cells protect organisms against extracellular pathogens but also have a key role in the pathogenesis of psoriasis. Evidence suggests that effector memory T cells produced during immune reactions survive and persist long term within the skin, providing local and rapid protection against pathogen reexposure. This review summarizes the current understanding of how skin-resident T cells contribute to normal and aberrant immunity in the skin.
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Affiliation(s)
- Rachael A Clark
- Department of Dermatology, Harvard Skin Disease Research Center, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
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Ryu WS, Son GS. Cancer Vaccines Targeting HER2/neu for Early Breast Cancer. J Breast Cancer 2010. [DOI: 10.4048/jbc.2010.13.1.5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Affiliation(s)
- Woo Sang Ryu
- Department of Surgery, Ansan Hospital, Korea University School of Medicine, Ansan, Korea
| | - Gil Soo Son
- Department of Surgery, Ansan Hospital, Korea University School of Medicine, Ansan, Korea
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Abstract
Abnormalities of cellular immunity are commonly seen in patients with glioblastoma (GBM), and the subsequent relative immunosuppression likely contributes to poor tumor-specific responses in affected individuals. Endogenous immune regulation is likely to limit the efficacy of a wide array of immunotherapeutic strategies, therefore mandating consideration in the continued development of novel treatments for GBM. Various tumor-associated factors have been implicated as potential generators of the immunosuppressive effect. This article outlines relevant experimentation exploring the nature of immune defects in patients with GBM, including a critical discussion of tumor-secreted factors, cell-surface proteins, and more recently described populations of immunoregulatory leukocytes that have potential roles in the subversion of cellular immunity.
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Affiliation(s)
- Allen Waziri
- Department of Neurosurgery, University of Colorado Health Sciences Center, 12631 E. 17th Avenue, Aurora, CO 80045, USA.
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Regulation gone wrong: a subset of Sézary patients have malignant regulatory T cells. J Invest Dermatol 2009; 129:2747-50. [PMID: 19901946 DOI: 10.1038/jid.2009.290] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Cutaneous T-cell lymphomas (CTCLs) are non-Hodgkin's lymphomas derived from T cells that home to and inhabit the skin. There are conflicting reports as to whether CTCLs represent a malignancy of regulatory T cells (Tregs), a T-cell subset that can suppress local immune reactions. In this issue, Heid et al. present convincing evidence that the malignant T cells in a subgroup of Sézary patients are FOXP3(+) regulatory T cells. Clonal malignant T cells showed increased expression of the Treg-associated transcription factor FOXP3 and demethylation of the FOXP3 gene locus, and T cells from at least some of these patients suppressed T-cell proliferation in vitro.
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O'Neill K, Guth A, Biller B, Elmslie R, Dow S. Changes in Regulatory T Cells in Dogs with Cancer and Associations with Tumor Type. J Vet Intern Med 2009; 23:875-81. [DOI: 10.1111/j.1939-1676.2009.0333.x] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
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Scott ME, Ma Y, Kuzmich L, Moscicki AB. Diminished IFN-gamma and IL-10 and elevated Foxp3 mRNA expression in the cervix are associated with CIN 2 or 3. Int J Cancer 2009; 124:1379-83. [PMID: 19089920 DOI: 10.1002/ijc.24117] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Cervical mucosal expression of cytokines involved in mediating cellular immunity is believed to influence the persistence of human papillomavirus (HPV) infection, a necessary prerequisite for the development of cervical intraepithelial neoplasia (CIN). Additionally, regulatory T (Treg) cells are increasingly understood to be important modulators of cellular immunity. Using quantitative RT-PCR, we measured, in cross-sectional design, the cervical mRNA expression of IFN-gamma, IL-10, and IL-12, as well as the Treg transcription factor Forkhead box P3 (Foxp3), in a cohort of young women representing CIN 1, 2, and 3, as well as benign histology. Higher levels of IFN-gamma and IL-10 were significantly (p <or= 0.05) associated with decreased odds of having high-grade cervical disease (CIN 2 or 3) in multivariate logistic regression models. In contrast, higher levels of mucosal Foxp3 expression were associated with increased odds of having CIN 2 or 3 (p = 0.004). In a multivariate model including cervical infection with HPV16 and/or another high-risk HPV type, Foxp3 remained higher in the CIN 2/3 group, but the difference was notably less significant (p = 0.05). These findings support a model in which diminished cellular immunity in the cervical mucosa and mucosal enrichment of Treg cells both contribute to the development of high-grade lesions.
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Affiliation(s)
- Mark E Scott
- Department of Pediatrics, University of California, San Francisco, CA 94143-1374, USA.
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A role for regulatory T cells in renal acute kidney injury. Transpl Immunol 2009; 21:50-5. [PMID: 19233269 DOI: 10.1016/j.trim.2009.02.003] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2008] [Revised: 02/06/2009] [Accepted: 02/10/2009] [Indexed: 01/18/2023]
Abstract
Ischemia reperfusion injury (IRI) is a potential contributor for the development of chronic allograft nephropathy. T cells are important mediators of injury, even in the absence of alloantigens. We performed a depletion of TCD4(+)CTLA4(+)Foxp3(+) cells with anti-CD25(PC61), a treatment with anti-GITR (DTA-1) and rat-IgG, followed by 45 min of ischemia and 24/72 h of reperfusion, and then analyzed blood urea, kidney histopathology and gene expression in kidneys by QReal Time PCR. After 24 h of reperfusion, depletion of TCD4(+)CTLA4(+)Foxp3(+) cells reached 30.3%(spleen) and 67.8%(lymph nodes). 72 h after reperfusion depletion reached 43.1%(spleen) and 90.22%(lymph nodes) and depleted animals presented with significantly poorer renal function, while DTA-1(anti-GITR)-treated ones showed a significant protection, all compared to serum urea from control group (IgG: 150.10+/-50.04; PC61: 187.23+/-31.38; DTA-1: 64.53+/-25.65, mg/dL, p<0.05). These data were corroborated by histopathology. We observed an increase of HO-1 expression in animals treated with DTA-1 at 72 h of reperfusion with significant differences. Thus, our results suggest that PC61(anti-CD25) mAb treatment is deleterious, while DTA-1(anti-GITR) mAb treatment presents a protective role in the renal IRI, indicating that some regulatory populations of T cells might have a role in IRI.
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Zhao W, Wang Y, Wang D, Sun B, Wang G, Wang J, Kong Q, Wang Q, Peng H, Jin L, Li H. TGF-beta expression by allogeneic bone marrow stromal cells ameliorates diabetes in NOD mice through modulating the distribution of CD4+ T cell subsets. Cell Immunol 2008; 253:23-30. [PMID: 18675407 DOI: 10.1016/j.cellimm.2008.06.009] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2008] [Revised: 06/19/2008] [Accepted: 06/21/2008] [Indexed: 01/14/2023]
Abstract
BMSCs could promote the regeneration of islet beta-cell, but the status of BMSCs under diabetes is still unknown. Our study verified the effect of allogeneic BMSCs (ICR) transferred into NOD mice on blood glucose and CD4+ T cells subsets function. In vivo experiment, BMSCs could decrease blood glucose, weaken lymphocytes proliferation. In vitro experiment, the distribution of CD4+ T cell subsets was changed after co-culture with BMSCs, resulting in a greater frequency of Treg cells and reduced representation of Th17 cells. After TGF-beta blockade, CD4+ T cells differentiated along a route favoring development of Th17, but not Treg cells. Thus, NOD can be treated by BMSCs which changes the distribution of CD4+ T cells, increases the number of Treg cells, and inhibits the differentiation of Th17 cells. And the positive effects of allogeneic BMSCs in the treatment of NOD mice depend on the regulation of TGF-beta secreted by BMSCs.
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Affiliation(s)
- Wei Zhao
- Department of Neurobiology, Harbin Medical University Provincial Key Lad of Neurobiology, 194 XueFu Road, Harbin, Heilongjiang 150081, China
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Winters U, Daayana S, Lear JT, Tomlinson AE, Elkord E, Stern PL, Kitchener HC. Clinical and immunologic results of a phase II trial of sequential imiquimod and photodynamic therapy for vulval intraepithelial neoplasia. Clin Cancer Res 2008; 14:5292-9. [PMID: 18698049 DOI: 10.1158/1078-0432.ccr-07-4760] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE High-risk human papillomavirus (HPV)-associated vulval intraepithelial neoplasia (VIN) is difficult to treat by excision or ablation because of high recurrence rates. Small studies of photodynamic therapy (PDT) and imiquimod treatments have shown some success and function at least in part through stimulation of local immune responses. Indeed, there is evidence that immunosuppressed individuals have higher rates of VIN, suggesting immune control is relevant. EXPERIMENTAL DESIGN In the study, 20 women with high-grade VIN were treated with topical imiquimod and the PDT sequentially. Vulval biopsy and blood were taken pretreatment and, after imiquimod and PDT, with follow up for 1 year. Clinical response was assessed by measuring lesion size. Biopsies were analyzed for HPV DNA and tumor-infiltrating lymphocytes including T regulatory cells. RESULTS The treatment was well-tolerated. There was an overall response rate of 55% by intention treat and 64% per protocol. The 52-week symptom response was 65% asymptomatic, compared with 5% at baseline. The nonresponders showed a significantly higher level of T regulatory cells in the lesions after imiquimod treatment. CONCLUSIONS The response rates are clinically relevant, and the treatment regimen was feasible for the majority. Initial nonresponders to imiquimod seem to be relatively refractory, and this may derive from their unfavorable local immune environment, in particular, the increased proportions of T regulatory cells, possibly the limiting action and/or development of any HPV T-cell immunity. The potential benefit of this treatment is its ability to treat multifocal disease.
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Affiliation(s)
- Ursula Winters
- School of Cancer and Imaging, University of Manchester, St. Mary's Hospital, Immunology Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, United Kingdom
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Abstract
Despite maximal therapy, malignant gliomas have a very poor prognosis. Patients with glioma express significant immune defects, including CD4 lymphopenia, increased fractions of regulatory T cells in peripheral blood and shifts in cytokine profiles from Th1 to Th2. Recent studies have focused on ways to combat immunosuppression in patients with glioma as well as in animal models for glioma. We concentrate on two specific ways to combat immunosuppression: inhibition of TGF-beta signaling and modulation of regulatory T cells. TGF-beta signaling can be interrupted by antisense oligonucleotide technology, TGF-beta receptor I kinase inhibitors, soluble TGF-beta receptors and antibodies against TGF-beta. Regulatory T cells have been targeted with antibodies against T-cell markers, such as CD25, CTLA-4 and GITR. In addition, vaccination against Foxp3 has been explored. The results of these studies have been encouraging; combating immunosuppression may be one key to improving prognosis in malignant glioma.
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Affiliation(s)
- Eleanor A Vega
- Duke University School of Medicine, Department of Surgery, Division of Neurosurgery, 221 Sands Building, Durham, NC 27710, USA
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Waziri A, Killory B, Ogden AT, Canoll P, Anderson RCE, Kent SC, Anderson DE, Bruce JN. Preferential in situ CD4+CD56+ T cell activation and expansion within human glioblastoma. THE JOURNAL OF IMMUNOLOGY 2008; 180:7673-80. [PMID: 18490770 DOI: 10.4049/jimmunol.180.11.7673] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Recent evidence suggests that suppression of the cellular immune response is often attributable to populations of functionally distinct T cells that act to down-regulate Ag-specific effector T cells. Using flow cytometry, we evaluated tumor-infiltrating lymphocytes (TIL) from patients undergoing neurosurgical resection of glioblastoma multiforme (GBM), metastatic lung carcinoma, and meningioma for markers known to be expressed on immunoregulatory T cells. Ex vivo phenotypic characteristics, cellular proliferation, and cytokine expression patterns were compared between T cell subsets found in the PBMC and within TIL from fresh tumor samples. Interestingly, nearly half of all T cells infiltrating GBM specimens were CD56(+) T cells, while much smaller percentages of similar cells were identified within metastatic lung tumors and meningiomas. CD56(+) T cells identified within GBM were not canonical, or "invariant," NKT cells, as they demonstrated diverse TCR expression, a primarily CD4 single-positive phenotype, and lack of CD1d reactivity. The percentage of CD56(+) T cells exhibiting evidence of proliferation within GBM was 3- to 4-fold higher than the proportion of proliferating CD56(-) T cells from these lesions. In addition, direct ex vivo analysis of cytokine expression by TIL from GBM demonstrated significant numbers of IL-4/IL-13 positive cells, cytokines that are integral in the cell-mediated repression of tumor immunity in experimental models. We propose that GBM has a unique capacity to recruit and activate CD4(+)CD56(+) T cells, a population that has not been previously described within human tumors.
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Affiliation(s)
- Allen Waziri
- Department of Neurological Surgery, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
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Yan W, Chen W, Huang L. Reactive oxygen species play a central role in the activity of cationic liposome based cancer vaccine. J Control Release 2008; 130:22-8. [PMID: 18554742 DOI: 10.1016/j.jconrel.2008.05.005] [Citation(s) in RCA: 101] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2008] [Revised: 04/25/2008] [Accepted: 05/06/2008] [Indexed: 11/17/2022]
Abstract
Recently, we developed a simple and potent therapeutic liposome cancer vaccine consisting of a peptide antigen and a cationic lipid. The molecular mechanism of the adjuvanticity of cationic liposome was studied and described in the current report. First, cationic DOTAP liposome, but not the neutral liposome DOPC, was shown to generate reactive oxygen species (ROS) in mouse bone marrow-derived dendritic cells (BMDC). ROS generation by DOTAP was required for ERK and p38 activation and downstream chemokine/cytokine induction. Furthermore, ROS were shown to be involved in the expression of the co-stimulatory molecules CD86/CD80 induced by DOTAP. However, as the DOTAP concentration increased from 50 to 800 microM, the apoptotic marker Annexin V and ROS double positive cells increased, suggesting that high dose of DOTAP-generated ROS causes cell apoptosis. In vivo, optimal amount of ROS in the draining lymph nodes (DLN) and anti-tumor (HPV positive TC-1 tumor) activity induced by E7 peptide (antigen derived from E7 oncoprotein of human papillomavirus (HPV) type 16) formulated in 100 nmol DOTAP were attenuated by incorporating DOPC in the formulation, suggesting that ROS are essential for the vaccine induced anti-tumor activity. Moreover, 600 nmol DOTAP/E7 generated huge amount of ROS in the DLN and showed no activity of tumor regression. Interestingly, 600 nmol DOTAP/E7-induced ROS were tuned down to the same level induced by 100 nmol DOTAP/E7 by adding DOPC in the formulation and this formulation showed tumor regression activity. In conclusion, DOTAP is an active DC stimulator resulting in the activation of ERK and p38 and induction of chemokines, cytokines and co-stimulatory molecules mediated by appropriate amount of ROS. Our data elucidated an important mechanism of adjuvant activity of cationic liposome and could facilitate rational design of synthetic lipid based adjuvants and vaccine formulation.
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Affiliation(s)
- Weili Yan
- Division of Molecular Pharmaceutics, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, USA
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Bergmann C, Strauss L, Zeidler R, Lang S, Whiteside TL. Expansion and characteristics of human T regulatory type 1 cells in co-cultures simulating tumor microenvironment. Cancer Immunol Immunother 2007; 56:1429-42. [PMID: 17265021 PMCID: PMC11031003 DOI: 10.1007/s00262-007-0280-9] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2006] [Accepted: 12/27/2006] [Indexed: 11/27/2022]
Abstract
OBJECTIVE Chronic inflammation and cancer development are associated with dysregulated immune responses and the presence of regulatory T cells (T(reg)). To study the role of T(reg) in tumor cell escape from immune surveillance, an in vitro model simulating the tumor microenvironment and promoting the induction and expansion of IL-10(+) T(reg )type 1 (Tr1) was established. METHODS An in vitro co-culture system (IVA) included an irradiated head and neck squamous cell carcinoma cell line, immature dendritic cells (iDC), CD4(+)CD25(- )T cells and cytokines, IL-2 (10 IU/ml), IL-10 (20 IU/ml), IL-15 (20 IU/ml) +/- 1 nM rapamycin. Autologous iDC and CD4(+)CD25(-) T cells were obtained from the peripheral blood of 15 normal donors. Co-cultures were expanded for 10 days. Proliferating lymphocytes were phenotyped by multi-color flow cytometry. Their suppressor function was measured in CFSE inhibition assays +/- neutralizing anti-IL-10 mAb and using transwell cultures. Culture supernatants were tested for IL-4, IL-10, TGF-beta and IFN-gamma in ELISA. RESULTS In the IVA, low doses of IL-2, IL-10 and IL-15 promoted induction and expansion of CD3(+)CD4(+)CD25(-)IL2Rbeta(+)IL2Rgamma(+)FoxP3(+)CTLA-4(+)IL-10(+) cells with suppressor activity (mean suppression +/- SD = 58 +/- 12%). These suppressor cells produced IL-10 (mean +/- SD = 535 +/- 12 pg/ml) and TGF-beta (mean +/- SD = 512 +/- 38 pg/ml), but no IL-4 or IFN-gamma. Suppressor function of co-cultures correlated with the percent of expanding IL-10(+) Tr1 cells (r (2 )=( )0.9; P < 0.001). The addition of rapamycin enriched Tr1 cells in all co-cultures. Neutralizing anti-IL-10 mAb abolished suppressive activity. Suppression was cell-contact independent. CONCLUSION The tumor microenvironment promotes generation of Tr1 cells which have the phenotype distinct from that of CD4(+)CD25(high)FoxP3(+) nTreg and mediate IL-10 dependent immune suppression in a cell-contact independent manner. Tr1 cells may play a critical role in cancer progression.
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Affiliation(s)
- Christoph Bergmann
- Research Pavilion at the Hillman Cancer Center, University of Pittsburgh Cancer Institute, 5117 Centre Avenue, Suite 1.27, Pittsburgh, PA 15213-1863 USA
| | - Laura Strauss
- Research Pavilion at the Hillman Cancer Center, University of Pittsburgh Cancer Institute, 5117 Centre Avenue, Suite 1.27, Pittsburgh, PA 15213-1863 USA
| | - Reinhard Zeidler
- Department of Otorhinolaryngology, Ludwig-Maximilians-University of Munich, Marchioninistr. 15, 81377 Munich, Germany
| | - Stephan Lang
- Department of Otorhinolaryngology, University of Duisburg-Essen, Hufelandstrasse 55, 45127 Essen, Germany
| | - Theresa L. Whiteside
- Research Pavilion at the Hillman Cancer Center, University of Pittsburgh Cancer Institute, 5117 Centre Avenue, Suite 1.27, Pittsburgh, PA 15213-1863 USA
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Molenkamp BG, van Leeuwen PAM, Meijer S, Sluijter BJR, Wijnands PGJTB, Baars A, van den Eertwegh AJM, Scheper RJ, de Gruijl TD. Intradermal CpG-B activates both plasmacytoid and myeloid dendritic cells in the sentinel lymph node of melanoma patients. Clin Cancer Res 2007; 13:2961-9. [PMID: 17504997 DOI: 10.1158/1078-0432.ccr-07-0050] [Citation(s) in RCA: 98] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE A decrease in the frequency and activation state of dendritic cells in the sentinel lymph node (SLN) has been observed in early stages of melanoma development. This may hinder the generation of effective antitumor T-cell responses and increase the likelihood of metastatic spread. Immunopotentiation of the melanoma SLN may therefore be a valuable adjuvant treatment option. One way to achieve this is through the use of bacterially derived unmethylated cytosine-phosphate-guanine (CpG) DNA sequences that bind Toll-like receptor 9 and activate plasmacytoid dendritic cells (PDC). CpG-activated PDC, in turn, release IFN alpha and may thus boost T-cell and natural killer cell responses as well as activate conventional myeloid dendritic cells (MDC). EXPERIMENTAL DESIGN We studied the effects of preoperative local administration of the CpG B-type oligodeoxynucleotide (ODN) PF-3512676 (formerly known as CPG 7909) on dendritic cell and T-cell subsets in the SLN of 23 stage I to III melanoma patients, randomized to receive intradermal injections of either PF-3512676 or saline (NaCl 0.9%). RESULTS PF-3512676 administration resulted in bulkier SLN, higher yields of isolated SLN leukocytes, and activation of BDCA-2(+)CD123(+) PDC as well as of CD1a(+) MDC. In addition, PF-3512676 administration was associated with the presence of a newly identified CD11c(hi)CD123(+)CD83(+)TRAIL(+) mature SLN-MDC subset, an increased release of a variety of inflammatory cytokines, and lower frequencies of CD4(+)CD25(hi)CTLA-4(+)FoxP3(+) regulatory T cells in the SLN. CONCLUSIONS These findings point to the possible utility of the conditioning of SLN by PF-3512676 as an adjuvant immunotherapeutic modality for early-stage melanoma.
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Affiliation(s)
- Barbara G Molenkamp
- Department of Surgical Oncology, VU University Medical Center, Amsterdam, the Netherlands
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49
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Perez SA, Karamouzis MV, Skarlos DV, Ardavanis A, Sotiriadou NN, Iliopoulou EG, Salagianni ML, Orphanos G, Baxevanis CN, Rigatos G, Papamichail M. CD4+CD25+ regulatory T-cell frequency in HER-2/neu (HER)-positive and HER-negative advanced-stage breast cancer patients. Clin Cancer Res 2007; 13:2714-21. [PMID: 17473204 DOI: 10.1158/1078-0432.ccr-06-2347] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
PURPOSE CD4(+)CD25(bright) regulatory T cells (Tregs) are increased in patients with several malignancies and correlate with disease stage and prognosis. Breast cancer patients represent a heterogeneous population with unpredictable disease progression even at advanced stages. Circulating Tregs in correlation with HER-2/neu (HER) status and treatment with chemotherapy, either alone or in combination with trastuzumab therapy, were monitored in advanced-stage breast cancer patients. EXPERIMENTAL DESIGN Circulating Treg frequency and absolute counts of 46 HER(+) and 28 HER(-), stage III and IV, breast cancer patients before therapy and during trastuzumab therapy and/or chemotherapy have been compared with 24 healthy donors and correlated with plasma HER extracellular domain concentration and clinical outcome. RESULTS Treg frequency in HER(+) patients was significantly increased compared with both HER(-) patients and healthy donors. Trastuzumab therapy, with or without combined chemotherapy, resulted in a progressive decrease of circulating Tregs. Percentage change in Tregs statistically correlated with percentage change in plasma HER extracellular domain. Furthermore, decrease in Tregs correlated with either objective clinical response or stable disease, whereas increased Treg frequency during trastuzumab therapy coincided with disease progression. No statistically significant change in Treg frequency following chemotherapy was observed in HER(-) patients. CONCLUSIONS Treg cell frequency does not directly correlate with clinical stage in breast cancer, as stage III and IV HER(+) and HER(-) patients exhibit significantly different Treg profiles. Trastuzumab therapy, either alone or combined with chemotherapy, results in decreased Treg frequency in HER(+) advanced patients with an objective clinical response.
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Affiliation(s)
- Sonia A Perez
- Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, Athens, Greece.
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50
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Leon K, Garcia K, Carneiro J, Lage A. How regulatory CD25+CD4+T cells impinge on tumor immunobiology? On the existence of two alternative dynamical classes of tumors. J Theor Biol 2007; 247:122-37. [PMID: 17412365 DOI: 10.1016/j.jtbi.2007.01.029] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2006] [Revised: 01/31/2007] [Accepted: 01/31/2007] [Indexed: 10/23/2022]
Abstract
Aiming to get a better insight on the impact of regulatory CD25(+)CD4(+) T cells in tumor immunobiology, a simple mathematical model was formulated and studied. This model is an extension of a previous model for the dynamics of autoreactive regulatory cells and effector cells that interact upon their co-localized activation at the antigen presenting cells (APCs). It assumes that tumor growth stimulates the activation and migration to the adjacent lymph node of fresh APCs loaded with tumor antigens. These APCs stimulate the growth of both effector and regulatory T cells, which may then migrate to the tumor site and induce tumor cell destruction. Our results predict the existence of two alternative dynamic modes of unbounded tumor growth. In the first mode, the tumor induces the expansion of effector T cells that outcompete regulatory T cells, but nevertheless fail to control the tumor. In the second mode, the tumor induces a balanced expansion of both effector and regulatory T cells, which prevents the tumor from being destroyed by the immune cells. Tumors characterized by a high specific growth rate, low immunogenicity, and that are relatively resistant to T cell destructive functions, will grow in the first mode; conversely, tumors that have a slow specific growth rate, that are immunogenic, and/or that are more sensitive to destruction by T cells will grow in the second mode. Overall, this result provides a simple explanation to the fact that the development of some tumors expands regulatory T cells while others do not, predicting how some key dynamical properties of the tumor determine either one or the other type of behavior.
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Affiliation(s)
- Kalet Leon
- Centro de Inmunología Molecular, Habana, Cuba.
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