scholarly journals Changes in the Peripheral Blood Treg Cell Proportion in Hepatocellular Carcinoma Patients After Transarterial Chemoembolization With Microparticles

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhizhong Ren ◽  
Yuanxun Yue ◽  
Yuewei Zhang ◽  
Jiahong Dong ◽  
Ying Liu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Immune Function ◽  
Treg Cell ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Transarterial Chemoembolization ◽  
Treg Cells ◽  
Regulatory Effect ◽  
Cell Proportion

ObjectiveTransarterial chemoembolization (TACE) stands for an ideal therapy for patients with intermediate stage HCC. This study was carried out to observe the effect of microparticles-transarterial chemoembolization (microparticles-TACE, m-TACE) on the immune function of hepatocellular carcinoma (HCC) patients by detecting the proportion of regulatory (Treg) cells in the peripheral blood of HCC patients before and after m-TACE, and to determine whether m-TACE has a positive regulatory effect on the immune function of HCC patients.Methods33 HCC patients treated with Gelatn Sponge Microparticles (GSMs-TACE) were enrolled. Flow cytometry was used to determine the proportion of Treg cells and CD4+/CD8+ T cells in peripheral blood of HCC patients 1 day before GSMs-TACE, 1 to 2 weeks and 3 to 5 weeks after GSMs-TACE, respectively.ResultsThe Tregs cell proportion of HCC patients was significantly higher than that of the healthy and cirrhosis controls and was associated with various clinical indicators of HCC patients. The Treg cell proportion in HCC patients with BCLC stage C was higher than that of stage B patients; The Treg cell proportion at 1 to 2 weeks postoperatively was 8.54 ± 1.27%, which was significantly lower than that before the GSMs-TACE. The Treg cell proportion at 3 to 5 weeks postoperatively was 7.59 ± 1.27%, which continued to decline. The ratio of CD4+/CD8+ T cells was 1.31 ± 0.56, 1.86 ± 0.73, 1.76 ± 0.58% (P<0.01) respectively.ConclusionThese results indicated that m-TACE could exert a positive regulatory effect on the anticancer immune function of HCC patients, which may be used in combination with immune adjuvant therapies to enhance the efficacy of HCC.

scholarly journals FOXP3 expression accurately defines the population of intratumoral regulatory T cells that selectively accumulate in metastatic melanoma lesions

Blood ◽  
2008 ◽  
Vol 112 (13) ◽  
pp. 4953-4960 ◽  
Author(s):  
Mojgan Ahmadzadeh ◽  
Aloisio Felipe-Silva ◽  
Bianca Heemskerk ◽  
Daniel J. Powell ◽  
John R. Wunderlich ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Metastatic Melanoma ◽  
Treg Cell ◽  
Peripheral Blood ◽  
Ex Vivo ◽  
Production Capacity ◽  
Biological Marker ◽  
Foxp3 Expression ◽  
Treg Cells

Abstract Regulatory T (Treg) cells are often found in human tumors; however, their functional characteristics have been difficult to evaluate due to low cell numbers and the inability to adequately distinguish between activated and Treg cell populations. Using a novel approach, we examined the intracellular cytokine production capacity of tumor-infiltrating T cells in the single-cell suspensions of enzymatically digested tumors to differentiate Treg cells from effector T cells. Similar to Treg cells in the peripheral blood of healthy individuals, tumor-infiltrating FOXP3+CD4 T cells, unlike FOXP3− T cells, were unable to produce IL-2 and IFN-γ upon ex vivo stimulation, indicating that FOXP3 expression is a valid biological marker for human Treg cells even in the tumor microenvironment. Accordingly, we enumerated FOXP3+CD4 Treg cells in intratumoral and peritumoral sections of metastatic melanoma tumors and found a significant increase in proportion of FOXP3+CD4 Treg cells in the intratumoral compared with peritumoral areas. Moreover, their frequencies were 3- to 5-fold higher in tumors than in peripheral blood from the same patients or healthy donors, respectively. These findings demonstrate that the tumor-infiltrating CD4 Treg cell population is accurately depicted by FOXP3 expression, they selectively accumulate in tumors, and their frequency in peripheral blood does not properly reflect tumor microenvironment.

Inhibiting IL-2 Signaling and the Regulatory T-Cell Pathway Using Computationally Designed Novel Peptides

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3875-3875
Author(s):  
Tammy Price-Troska ◽  
David Diller ◽  
Alexander Bayden ◽  
Mark Jarosinski ◽  
Joseph Audies ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Function ◽  
Treg Cell ◽  
Immune Cell ◽  
Conflicts Of Interest ◽  
Interleukin 2 ◽  
Computational Design ◽  
Treg Cells ◽  
Cell Numbers

Abstract Regulatory T-cells (TREG) are the gateway to immune function and typically regulate immune cell activation. Cytokines, including interleukin-2 (IL-2), induce T-cell differentiation and promote a regulatory phenotype. Once activated via the IL-2 receptor (IL-2R), a cascade of events in T-cells initiate signal transducer and activator of transcription 5 (STAT5) and Forkhead box P3 (FOXP3) activation which appear to function as important regulators of this immunologic pathway and promote the development and function of TREG cells. In non-Hodgkin lymphoma (NHL), we have found that intratumoral TREG cells are increased in number and suppress immune function. In previous work, we have found that TREG cells inhibit T-cell proliferation, suppress cytokine production and limit effector cell cytotoxicity. We have also shown that increased serum levels of soluble sIL-2Rα is a prognostic factor in NHL and that sIL-2Rα can bind to IL-2 and promote its signaling thereby increasing TREG cell numbers. In this study, we developed a strategy to inhibit the binding of IL-2 to sIL-2Rα with the goal of suppressing the induction of FOXP3 and decreasing TREG cell numbers. To do this, we developed peptides designed to disrupt the interaction between IL2 and sILRα. In collaboration with CMDBioscienceSM, we developed and analyzed 22 peptide compounds derived by structure-based computational design. Initially, we screened each peptide at increasing concentrations using an ELISA assay to test the inhibition of IL-2/IL-2Rα binding by the solubilized peptide. Candidate peptides were then further tested using upregulation of pSTAT5 and FOXP3 in T-cells measured by flow cytometry as a measure of inhibition of IL-2 signaling. The peptides were developed according to different design hypotheses and grouped into different families; the screening ELISA results indicated 4 promising peptides that inhibited IL2/IL2Rα binding (up to 100% inhibition; max peptide concentration of 100uM). These peptides were then used to determine their effect on STAT5 and FOXP3 expression. A lead candidate peptide consistently reduced the expression of FOXP3 and STAT5 expression compared to cells not exposed to peptide. Use of the peptide to disrupt IL-2 signaling inhibited the development of cells with a TREG phenotype. We conclude that structure-based peptide design can be used to identify novel peptide inhibitors that block IL-2/IL-2Rα signaling and inhibit STAT5 and FOXP3 upregulation. These peptides could be used as new therapeutic agents to limit immune suppression by TREG cells and promote a more effective anti-tumor immune response in NHL. Disclosures No relevant conflicts of interest to declare.

Human CD4+ CD25+ Regulatory T Cells Effectively Control Xenogeneic-GvHD Induced by Autologous T Cells in Rag2−/− γc−/− Immune-Deficient Mice.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 301-301
Author(s):  
Tuna Mutis ◽  
Rozemarijn S. van Rijn ◽  
Elles R. Simonetti ◽  
Tineke Aarts ◽  
Maarten Emmelot ◽  
...  
Keyword(s):  
T Cells ◽  
Treg Cell ◽  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Treg Cells ◽  
Effector T Cells ◽  
Graft Versus Host ◽  
Cell Engraftment ◽  
High Doses ◽  
The Impact

Abstract The curative Graft-versus-Leukemia (GvL) effect of allogeneic stem cell transplantation (SCT) and Donor Lymphocyte Infusions (DLI) is frequently complicated by Graft-versus-Host Disease (GvHD). To date, it is not possible to prevent GvHD without sacrificing the GvL effect. Recently, in a number of murine transplantation studies, administration of naturally occurring CD4+CD25+ regulatory T (Treg) cells in recipients of allogeneic bone marrow effectively prevented GvHD without abrogating GvL. If human (hu)CD4+CD25+ Treg cells also possess such properties, they may become new cellular immunotherapeutics for the prevention of GvHD. Therefore, we have started to investigate the impact of huTreg cells on GvHD in a recently developed, highly relevant xenogeneic(x)-GvHD model in immunodeficient Rag2−/− γc−/− mice. This model represents several features of human allo-GvHD, such as the involvement of both CD4 and CD8 T cells, the association of GvHD with a “cytokine storm” of several Th1/Th2 and inflammatory cytokines and the similarity of skin histopathology to the human allo-GvHD(1). As in this model the x-GvHD is induced by the i.v. injection of huPBMC and the severity of x-GvHD correlates with the number of T cells in the administered PBMC, we explored the impact of Treg cells on x-GvHD either by depletion of Treg cells from huPBMC at different administration doses of effector T cells (4-15 x106 CD25− T cells) and or co-injection of autologous Treg cells at high doses of effector T cells (12-15 x106 T cells). PBMC were isolated from the buffycoats of healthy blood bank donors. Part of the PBMC was used as effector cells, the remaining cells were fractionated into CD25+ and CD25− subsets, which contain Treg cells and conventional T cells, respectively. Different groups of mice were injected with low to high doses of Treg-cell-depleted-PBMC or with high doses PBMC supplemented with 4-6 x106 Treg cell-enriched CD25+ cells. Control mice received equivalent numbers of unmodified PBMC only. The development of x-GvHD was monitored weekly by determination of body weight, clinical scores (ruffled fur, alopecia, mobility) and survival. Peripheral blood obtained from orbital vein was analyzed for human T cell engraftment and expansion. In three independent experiments, depletion of Treg cells significantly exacerbated the x-GvHD signs and lethality. In striking contrast, the development of x-GvHD was significantly inhibited by the co-injection of Treg cell enriched cell fractions. In two independent experiments Treg cells completely protected mice from lethal x-GvHD. Phenotypical analyses of peripheral blood revealed that addition of Treg cells did not disturb huT cell engraftment, but inhibited the expansion of huT cells between 3-5 weeks of administration. These results demonstrate the effective control of x-GvHD in Rag2−/− γc−/− mice by huTreg cells. Studies are underway to reveal the mechanism of GvHD inhibition and the impact of huTreg cells on GvL. (1) R.S. van Rijn, E.R. Simonetti, M.C.H. Hogenes, G. Storm, A. Hagenbeek, H. Spits, K. Weijer, A. C. M. Martens, and S.B. Ebeling. A new in vivo model for graft-versus-host disease by intravenous transfer of human peripheral blood mononuclear cells in RAG2−/− γc−/− double mutant mice.

R404 – Regulatory T Cells and Clinical Outcome in HNSCC Patients

2008 ◽  
Vol 139 (2_suppl) ◽  
pp. P178-P178
Author(s):  
Osama Alhamarneh ◽  
Nicholas D. Stafford ◽  
John Greenman
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Clinical Outcome ◽  
Treg Cell ◽  
Cell Population ◽  
Peripheral Blood ◽  
Treg Cells ◽  
Clinicopathological Parameters ◽  
Pre Treatment ◽  
Disease Stages

Problem To determine the correlation between peripheral blood CD4+CD25high regulatory T cells (Treg), a suppressor cell population that dampen the immune response, and clinical outcome and survival in HNSCC patients. Methods Treg cell numbers in the peripheral blood of newly-presenting, untreated HNSCC patients (n=65) were determined pre-operatively, 4–6 weeks after treatment (n=30) and in a cohort of healthy controls (n=35) of similar age and sex, after Treg cell isolation using magnetic microbeads (Miltenyi Biotec) by flow cytometry. The Mann-Whitney U test was used to analyse the correlations between Treg cell levels and clinical outcome. Results Treg cells were significantly higher in patients pre-operatively vs. controls (p=0.002). After treatment, patients showed a significant rise compared with their pre-treatment levels (p=0.022). Pre-treatment Treg cells levels did not correlate with survival or any of the other conventional clinicopathological parameters. However, higher Treg cells levels were discovered in the advanced disease stages (III/IV vs. I/II, median 6.3 vs 4.3) in the pre-treatment group that turned into significantly higher levels in the early disease stages post treatment (I/II vs. III/IV, median 10.8 vs. 5.67 p=0.044). Conclusion Although peripheral blood Treg cells levels were higher in patients when compared to controls, no correlation was found between this cell population and clinical outcome or survival. In contrast with gastric, colorectal and ovarian tumors, Treg cell levels did not normalize 4–6 weeks after curative treatment in this cohort of HNSCC patients. Studies into Treg cell function are thus required to try and elucidate the apparent paradox in Treg cell levels observed in HNSCC. Significance The presence of Regulatory T cells in the peripheral blood of HNSCC patients may be detrimental to host defence against tumor. Further studies are needed to explore their role in the tumor microenvironment and their correlation with clinical outcome.

831 E3 ubiquitin ligase Cbl-b deficient CD8+ T cells overcome Treg cell-mediated suppression through IFN-γ and induce robust anti-tumor immunity

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A883-A883
Author(s):  
SeongJun Han ◽  
Zhe Qi Liu ◽  
Douglas Chung ◽  
Michael St Paul ◽  
Carlos Garcia-Batres ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Treg Cell ◽  
Ubiquitin Ligase ◽  
Cd8 T Cells ◽  
Treg Cells ◽  
Adoptive T Cell Therapy ◽  
T Cell Therapy ◽  
Ifn Γ

BackgroundAdoptive T cell therapy (ACT) is reaching its potential in multiple malignancies. However, anti-tumor T cell responses can be attenuated by suppressive cells in the tumor microenvironment, such as CD4+FoxP3+ regulatory T (Treg) cells. Depletion of Treg cells can be technically challenging in ACT and may be associated with unwanted adverse effects. Alternatively, studies suggest that specific modifications in T cell signaling network may render T cells resistant to regulation by Treg cells. Here, we investigated the role of Casitas B- Lineage Lymphoma-b (Cbl-b), an E3 ubiquitin ligase and a negative regulator of TCR signaling pathways, in rendering CD8+ T cells resistant to the effects of Treg cells to bolster ACT.MethodsIn vitro stimulated Cbl-b+/+ or Cbl-b-/- Thy1.1+ P14 TCR-transgenic CD8+ T cells were adoptively transferred into B16-gp33 melanoma-bearing Thy1.2+ FoxP3-GFP/DTR transgenic mice treated with or without diphtheria toxin (n = 15). Tumor size and overall survival were measured. Congenically labelled T cells from tumor, draining lymph node, and spleen were comprehensively profiled using flow cytometry. To further examine the biological mechanism of Treg resistance, we performed in vitro Treg suppression assays and RNA-sequencing.ResultsAdoptively transferred tumor-specific Cbl-b-/- effector CD8+ T cells mediated superior control over tumor growth and increased overall survival in comparison to the wild-type counterpart. Depletion of FoxP3+ cells increased the quantity and percentage of CD25+ 4-1BB+ expressing P14 Thy1.1+ CD8+ T cells in the tumor, whereas the effect of FoxP3+ cell depletion was negligible with Cbl-b deficient CD8+ T cells. Cbl-b deficiency also attenuated sensitivity to Treg cell-mediated suppression in vitro. Transcriptomic analyses suggested that Cbl-b regulates pathways associated with cytokine production and cellular proliferation. Specifically, hyper-secretion of IFN-γ by Cbl-b deficient CD8+ T cells attenuated suppression by Treg cells. In murine models of adoptive T cell therapy, Cbl-b deficient CD8+ T cells were less susceptible to suppression by Treg cells in the tumor through the effects of IFN-γ.ConclusionsWe demonstrate that adoptively transferred effector CD8+ T cells are susceptible to regulation by Treg cells in the tumor, and that ablation of Cbl-b abrogates Treg cell-mediated suppression. We highlight the therapeutic implications of targeting Cbl-b in the context of ACT.AcknowledgementsWe would like to thank Dr. Tak Mak and Dr. Naoto Hirano for their suggestions and insights for this project.

scholarly journals Function of regulatory T-cells improved by dexamethasone in Graves' disease

2012 ◽  
Vol 166 (4) ◽  
pp. 641-646 ◽  
Author(s):  
Yun Hu ◽  
Wei Tian ◽  
Ling-Ling Zhang ◽  
Hao Liu ◽  
Guo-Ping Yin ◽  
...  
Keyword(s):  
T Cells ◽  
Mrna Expression ◽  
Treg Cell ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Cell Function ◽  
Treg Cells ◽  
Th2 Cells ◽  
Graves Disease ◽  
Treg Cell Function

ObjectiveIntrathyroid injection of dexamethasone (DEX) has been used to treat Graves' disease (GD); however, the mechanism of this treatment remains poorly understood. The objective of this study was to investigate the effects of DEX on the function of regulatory T (Treg) cells (CD4+CD25+T cells) in patients with GD.MethodsPeripheral blood was obtained from 20 patients with GD, and peripheral blood mononuclear cells (PBMCs) were isolated by Ficoll–Hypaque density gradient separation. CD4+CD25–/CD4+CD25+T cells were isolated by immunomagnetic selection and DEX was co-cultured with PBMCs or isolated T-cells for 72 h. Treg cell function was analyzed using the proliferation rate of CD4+CD25–T cells.ResultsThe proportion of Treg cells and the transcription factor forkhead box P3 (FOXP3) mRNA expression in PBMCs decreased in GD patients compared with healthy subjects, and Treg cell function was impaired in patients with GD. Although the proportion of Treg cells and FOXP3 mRNA expression in PBMCs did not increase, the function of Treg cells improved after the treatment with DEX. Moreover, the proportion of T-helper 2 (Th2) cells was decreased by the DEX treatment.ConclusionsDEX could effectively improve the function of Treg cells and set up a new balance of Th1/Th2 in GD patients. This study might help to further understand the immune mechanism of the intrathyroid injection of DEX in the treatment of GD and facilitate the potential use of this therapy.

scholarly journals HUWE1 Causes an Immune Imbalance in Immune Thrombocytopenic Purpura by Reducing the Number and Function of Treg Cells Through the Ubiquitination Degradation of Ets-1

2021 ◽  
Vol 9 ◽  
Author(s):  
Jianqin Li ◽  
Yalin Xia ◽  
Xiaoru Fan ◽  
Xiaofang Wu ◽  
Feiyun Yang ◽  
...  
Keyword(s):  
T Cells ◽  
Treg Cell ◽  
Immune Thrombocytopenic Purpura ◽  
Peripheral Blood ◽  
Mrna Level ◽  
Treg Cells ◽  
Enzyme Linked Immunosorbent Assay ◽  
Thrombocytopenic Purpura ◽  
Immune Imbalance ◽  
And Function

Background: Immune thrombocytopenic purpura (ITP) is an autoimmune bleeding disorder and the decreased number and immunosuppressive dysfunction of Treg cells are key promoters of ITP. However, their mechanisms in ITP development have not been fully clarified.Methods: HUWE1 mRNA and protein levels in CD4+ T cells in peripheral blood from ITP patients were assessed by quantitative real-time PCR and Western blot. HUWE1 function in ITP was estimated using flow cytometry, enzyme-linked immunosorbent assay and immunosuppression assay. Besides, the HUWE1 mechanism in reducing the number and function of Treg cells in ITP was investigated by immunoprecipitation, cycloheximide-chase assay, ubiquitin experiment and immunofluorescence assay.Results: HUWE1 expression was elevated in CD4+ T cells in peripheral blood from ITP patients and HUWE1 mRNA level was negatively correlated with platelet counts and Treg cell percentage. Moreover, the interference with HUWE1 increased the number of Treg cells and enhanced its immunosuppressive function, and the HUWE1 overexpression produced the opposite results. For the exploration of mechanism, HUWE1 interacted with E26 transformation-specific-1 (Ets-1) and this binding was dependent on the negative regulation of the phosphorylation level of Ets-1 (Thr38) and HUWE1 facilitated the ubiquitin degradation of Ets-1 protein to restrain Treg cell differentiation and weaken their immunosuppressive functions. The in vivo assay confirmed that the HUWE1 inhibitor alleviated ITP in mice.Conclusion: HUWE1 induced the immune imbalance in ITP by decreasing the number and weakening the function of Treg cells through the ubiquitination degradation of Ets-1.

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