scholarly journals Targeting STAT3 Abrogates Tim-3 Upregulation of Adaptive Resistance to PD-1 Blockade on Regulatory T Cells of Melanoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Lili Huang ◽  
Yu Xu ◽  
Juemin Fang ◽  
Weixing Liu ◽  
Jianhua Chen ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Genomic Analysis ◽  
Enrichment Analysis ◽  
Treg Cells ◽  
The Cancer Genome Atlas ◽  
Molecular Characteristics ◽  
Pathway Enrichment Analysis ◽  
Peripheral Blood Mononuclear ◽  
Adaptive Resistance ◽  
Melanoma Patients

BackgroundLess than 20% of melanoma patients respond to programmed cell death-1 (PD-1) blockade immunotherapies. Thus, it is crucial to understand the dynamic changes in the tumor microenvironment (TME) after PD-1 blockade, for developing immunotherapy efficacy.MethodsA genomic analysis was conducted by The Cancer Genome Atlas (TCGA) datasets and web platform TIMER2.0 datasets. Pathway enrichment analysis was performed using the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. Peripheral blood mononuclear cells (PBMCs), regulatory T (Treg) cells, and B16-F10 melanoma mice were used as models. The cellular and molecular characteristics and mechanisms of Treg cells in melanoma were assessed by performing gene expression studies, immunohistochemistry, RNA sequencing, and flow cytometry.ResultsHere, we evaluate the countenance of T cell immunoglobulin and mucin-domain containing-3 (Tim-3), and various immunosuppressive factors within tumor-infiltrated Treg cells after treatment with anti-PD-1 or the indicator transduction and activator of transcription 3 (STAT3) inhibitors. Increased expression of Tim-3 is markedly observed within the tissues of the PD-1 blockade resistance of melanoma patients. Targeting STAT3 significantly boosts the response of resistant-PD-1 therapy within the melanoma mouse model. Mechanistically, the manifestation of STAT3 decreases the expression of Tim-3 and various cytokines in the purified Treg cells from individual PBMCs and the murine melanoma model, limiting the immunosuppression of Treg cells.ConclusionsOur findings indicate that Tim-3 expression on Treg cells within the TME is STAT3-dependent, providing support to STAT3 as a target and enhancing the immunotherapy for patients suffering from melanoma.

scholarly journals Targeting STAT3 abrogates Tim-3 upregulation of adaptive resistance to PD-1 blockade on regulatory T cells of melanoma

2020 ◽  
Author(s):  
Lili Huang ◽  
Yu Xu ◽  
Juemin Fang ◽  
Weixing Liu ◽  
Jianhua Chen ◽  
...  
Keyword(s):  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Treg Cells ◽  
The Cancer Genome Atlas ◽  
Molecular Characteristics ◽  
Pathway Enrichment Analysis ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells ◽  
Melanoma Patients

Abstract Background Programmed cell death-1 (PD-1) blockade immunotherapies have demonstrated excellent clinical benefits in multiple cancers, but < 20% of melanoma patients respond to these treatments. Thus, it is crucial to understand for getting awareness of the dynamic changes vibrant transformations in the tumor microenvironment (TME) after PD-1 blockade, in exploring novel intervention targets as a potential therapy, for developing immunotherapy efficacy. MethodsTo ascertain the differentially expressed between PDCD1low and PDCD1high subsets and further PDCD1 related genes in skin cutaneous melanoma (SKCM) patients, a genomic analysis was conducted by The Cancer Genome Atlas (TCGA) datasets and web platform TIMER2.0 datasets. Pathway enrichment analysis was performed using the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. Peripheral blood mononuclear cells (PBMCs), regulatory T (Treg) cells and B16F10 melanoma mouse were used as models. The cellular and molecular characteristics and mechanisms of Treg cells in melanoma were assessed by performing gene expression studies, immunohistochemistry, RNA sequencing, and flow cytometry.ResultsHere, we evaluate the countenance of T cell immunoglobulin and mucin-domain containing-3 (Tim-3), various immunosuppressive factors within tumor infiltrated regulatory T (Treg) cells after treated with anti-PD-1 or the indicator transduction and activator of transcription 3 (STAT3) inhibitors. Tim-3 gene is expressed differentially between PD-1low and PD-1high subsets from TCGA datasets and melanoma patients’ biopsies. Increased expression of Tim-3 is markedly observed within the tissues of the PD-1 blockade resistance of melanoma patients. Targeting STAT3 significantly boosts the response of resistant-PD-1 therapy within the melanoma mouse model. Mechanistically, the manifestation of STAT3 decreases the expression of Tim-3 and various cytokines in the purified Treg cells from individual peripheral blood mononuclear cells (PBMCs) and murine melanoma model, limiting the immunosuppression of Treg cells. ConclusionsOur findings indicate that Tim-3 expression on Treg cells within the TME is STAT3-dependent, providing support to STAT3 as a target and enhancing the immunotherapy for patients suffering from melanoma.

scholarly journals Analysis of Peripheral Blood Mononuclear Cells Gene Expression Highlights the Role of Extracellular Vesicles in the Immune Response following Hematopoietic Stem Cell Transplantation in Children

Genes ◽  
2021 ◽  
Vol 12 (12) ◽  
pp. 2008
Author(s):  
Wojciech Strojny ◽  
Kinga Kwiecińska ◽  
Przemysław Hałubiec ◽  
Wojciech Kowalczyk ◽  
Karol Miklusiak ◽  
...  
Keyword(s):  
Immune Response ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Mononuclear Cells ◽  
Enrichment Analysis ◽  
Pathway Enrichment Analysis ◽  
Peripheral Blood Mononuclear ◽  
Hematopoietic Stem ◽  
Pathway Enrichment ◽  
Blood Mononuclear Cells

Hematopoietic stem cell transplantation (HSCT) is an effective treatment method used in many neoplastic and non-neoplastic diseases that affect the bone marrow, blood cells, and immune system. The procedure is associated with a risk of adverse events, mostly related to the immune response after transplantation. The aim of our research was to identify genes, processes and cellular entities involved in the variety of changes occurring after allogeneic HSCT in children by performing a whole genome expression assessment together with pathway enrichment analysis. We conducted a prospective study of 27 patients (aged 1.5–18 years) qualified for allogenic HSCT. Blood samples were obtained before HSCT and 6 months after the procedure. Microarrays were used to analyze gene expressions in peripheral blood mononuclear cells. This was followed by Gene Ontology (GO) functional enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and protein–protein interaction (PPI) analysis using bioinformatic tools. We found 139 differentially expressed genes (DEGs) of which 91 were upregulated and 48 were downregulated. “Blood microparticle”, “extracellular exosome”, “B-cell receptor signaling pathway”, “complement activation” and “antigen binding” were among GO terms found to be significantly enriched. The PPI analysis identified 16 hub genes. Our results provide insight into a broad spectrum of epigenetic changes that occur after HSCT. In particular, they further highlight the importance of extracellular vesicles (exosomes and microparticles) in the post-HSCT immune response.

scholarly journals Role of T cells in intrauterine administration of activated peripheral blood mononuclear cells in recurrent implantation failure.

2021 ◽  
Author(s):  
Guillaume Ricaud ◽  
Cathy Vaillancourt ◽  
Veronique Blais ◽  
Marjorie Disdier ◽  
Fabien Joao ◽  
...  
Keyword(s):  
T Cells ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Treg Cells ◽  
Implantation Failure ◽  
Recurrent Implantation Failure ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells

Intrauterine administration of autologous peripheral blood mononuclear cells (PBMC) has been recently proposed as new immunotherapy for patients with unexplained recurrent implantation failure (RIF). In these patients, administration of activated PBMC 24-h or 72-h before embryo transfer resulted in a 3-fold increase in biochemical pregnancy rate. In this study we evaluated the role of T cells to promotes human endometrial receptivity. On the day of ovulation, PBMC were isolated from and activated with T cells mitogen, the phytohemagglutinin (PHA) and hCG for 48-h in a conditioned culture medium. Distributions of CD4+ T cells were characterized in 157 patients by flow cytometry before and after PHA/hCG activation. Cytokine production was analyzed by cytometric beads array. We observed in RIF patients a significant decrease in Th2 and natural Treg cells before activation with PHA/hCG and an increase of Th17 cells after activation compared to intrauterine sperm insemination (IUI) and in vitro fertilization (IVF) groups. Furthermore, the hCG/PHA treatment increases anti-inflammatory T cells (Th2 and Treg cells) compared to non-treated T cells. Principal component analysis (PCA) performed on CD4 T cell subtypes revealed a different cellular profile in the RIF compared to the IUI and IVF groups. This inflammatory state change could explain how endometrium immunomodulation by hCG-activated PBMC helps patients with unexplained RIF to reach implantation.

scholarly journals Identification of Key miRNAs in the Treatment of Dabrafenib-Resistant Melanoma

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Guangyu Gao ◽  
Zhen Yao ◽  
Jiaofeng Shen ◽  
Yulong Liu
Keyword(s):  
Drug Resistance ◽  
Molecular Mechanism ◽  
Target Genes ◽  
Enrichment Analysis ◽  
Gene Expression Omnibus ◽  
The Cancer Genome Atlas ◽  
Pathway Enrichment Analysis ◽  
Ppi Network ◽  
Protein Protein Interaction ◽  
Obvious Association

Dabrafenib resistance is a significant problem in melanoma, and its underlying molecular mechanism is still unclear. The purpose of this study is to research the molecular mechanism of drug resistance of dabrafenib and to explore the key genes and pathways that mediate drug resistance in melanoma. GSE117666 was downloaded from the Gene Expression Omnibus (GEO) database and 492 melanoma statistics were also downloaded from The Cancer Genome Atlas (TCGA) database. Besides, differentially expressed miRNAs (DEMs) were identified by taking advantage of the R software and GEO2R. The Database for Annotation, Visualization, and Integrated Discovery (DAVID) and FunRich was used to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis to identify potential pathways and functional annotations linked with melanoma chemoresistance. 9 DEMs and 872 mRNAs were selected after filtering. Then, target genes were uploaded to Metascape to construct protein-protein interaction (PPI) network. Also, 6 hub mRNAs were screened after performing the PPI network. Furthermore, a total of 4 out of 9 miRNAs had an obvious association with the survival rate ( P < 0.05 ) and showed a good power of risk prediction model of over survival. The present research may provide a deeper understanding of regulatory genes of dabrafenib resistance in melanoma.

scholarly journals Predicting Lyme Disease From Patients' Peripheral Blood Mononuclear Cells Profiled With RNA-Sequencing

2021 ◽  
Vol 12 ◽  
Author(s):  
Daniel J. B. Clarke ◽  
Alison W. Rebman ◽  
Allison Bailey ◽  
Megan L. Wojciechowicz ◽  
Sherry L. Jenkins ◽  
...  
Keyword(s):  
Lyme Disease ◽  
Rna Sequencing ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Enrichment Analysis ◽  
Peripheral Blood Mononuclear ◽  
Deconvolution Analysis ◽  
Persistent Symptoms ◽  
Blood Mononuclear Cells

Although widely prevalent, Lyme disease is still under-diagnosed and misunderstood. Here we followed 73 acute Lyme disease patients and uninfected controls over a period of a year. At each visit, RNA-sequencing was applied to profile patients' peripheral blood mononuclear cells in addition to extensive clinical phenotyping. Based on the projection of the RNA-seq data into lower dimensions, we observe that the cases are separated from controls, and almost all cases never return to cluster with the controls over time. Enrichment analysis of the differentially expressed genes between clusters identifies up-regulation of immune response genes. This observation is also supported by deconvolution analysis to identify the changes in cell type composition due to Lyme disease infection. Importantly, we developed several machine learning classifiers that attempt to perform various Lyme disease classifications. We show that Lyme patients can be distinguished from the controls as well as from COVID-19 patients, but classification was not successful in distinguishing those patients with early Lyme disease cases that would advance to develop post-treatment persistent symptoms.

scholarly journals Effects of Meglumine Antimoniate Treatment on Cytokine Production in a Patient with Mucosal Leishmaniasis and Chagas Diseases Co-Infection

2020 ◽  
Vol 5 (2) ◽  
pp. 69 ◽  
Author(s):  
Karine Rezende-Oliveira ◽  
Cesar Gómez-Hernández ◽  
Marcos Vinícius da Silva ◽  
Rafael Faria de Oliveira ◽  
Juliana Reis Machado ◽  
...  
Keyword(s):  
Chagas Disease ◽  
Mononuclear Cells ◽  
Interleukin 10 ◽  
Treg Cells ◽  
Interleukin 12 ◽  
Leishmania Braziliensis ◽  
T Regulatory Cell ◽  
Peripheral Blood Mononuclear ◽  
Tnf Α ◽  
Mucosal Leishmaniasis

The influence of antimoniate treatment on specific anti-protozoan T-cell responses was evaluated in a 48-year-old male patient diagnosed with mucosal leishmaniasis and Chagas disease infection. Before and after treatment, PBMC (peripheral blood mononuclear cells) were cultured in the absence or presence of Leishmania braziliensis or Trypanosoma cruzi live parasites, their soluble antigens, or PHA (phytohaemagglutinin). Cytokines were measured and Treg (T regulatory) cell percentages were quantified. Before treatment, PBMC were able to produce higher amounts of TNF-α, IL-6 (Interleukin-6), and IL-10 (Interleukin-10) but lower amounts of IL-12 (Interleukin-12) in response to culture stimulation. However, after treatment, there was a down-modulation of TNF-α, IL-6, and IL-10 cytokines but an up-modulation in IL-12 production. PBMC had the ability to produce TNF-α only against live parasites or PHA. There was an overall decrease of circulating Treg cells after treatment. In mixed Leishmaniasis and Chagas disease infection, treatment with antimoniate could modulate immune responses toward a more protective profile to both diseases.

scholarly journals Daclizumab reduces CD25 levels on T cells through monocyte-mediated trogocytosis

2013 ◽  
Vol 20 (2) ◽  
pp. 156-164 ◽  
Author(s):  
Y Zhang ◽  
M McClellan ◽  
L Efros ◽  
D Shi ◽  
B Bielekova ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mononuclear Cells ◽  
Interleukin 2 ◽  
Treg Cells ◽  
Activated T Cells ◽  
Peripheral Blood Mononuclear ◽  
Dependent Relationship ◽  
Cell Counts ◽  
Humanized Monoclonal Antibody

Daclizumab is a humanized monoclonal antibody that prevents interleukin-2 (IL-2) binding to CD25, blocking IL-2 signaling by cells that require high-affinity IL-2 receptors to mediate IL-2 signaling. The phase 2a CHOICE study evaluating daclizumab as a treatment for multiple sclerosis (MS) included longitudinal analysis of activated T cell counts. Whereas an exposure-dependent relationship was observed between daclizumab and reductions in HLA-DR+-activated T cells, a similar relationship was not observed for reductions in CD25 levels. The objective of this report is to determine the mechanism by which daclizumab reduces CD25 levels on peripheral blood mononuclear cells (PBMCs) using cytometric techniques. Daclizumab reduced T cell CD25 levels through a mechanism that required the daclizumab-Fc domain interaction with Fc receptors (FcR) on monocytes, but not on natural killer (NK) cells, and was unrelated to internalization or cell killing. Activated CD4+ T cells and FoxP3+ Treg cells showed evidence of trogocytosis of the CD25 antigen in the presence of monocytes. A daclizumab variant that retained affinity for CD25 but lacked FcR binding did not induce trogocytosis and was significantly less potent as an inhibitor of IL-2-induced proliferation of PBMCs. In conclusion, Daclizumab-induced monocyte-mediated trogocytosis of CD25 from T cells appears to be an additional mechanism contributing to daclizumab inhibition of IL-2 signaling.

scholarly journals In Silico Discovery of Candidate Drugs against Covid-19

Viruses ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 404 ◽  
Author(s):  
Claudia Cava ◽  
Gloria Bertoli ◽  
Isabella Castiglioni
Keyword(s):  
Gene Expression ◽  
In Silico ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Interaction Network ◽  
Enrichment Analysis ◽  
Basic Mechanism ◽  
Cell Receptor ◽  
The Cancer Genome Atlas ◽  
Pathway Enrichment Analysis

Previous studies reported that Angiotensin converting enzyme 2 (ACE2) is the main cell receptor of SARS-CoV and SARS-CoV-2. It plays a key role in the access of the virus into the cell to produce the final infection. In the present study we investigated in silico the basic mechanism of ACE2 in the lung and provided evidences for new potentially effective drugs for Covid-19. Specifically, we used the gene expression profiles from public datasets including The Cancer Genome Atlas, Gene Expression Omnibus and Genotype-Tissue Expression, Gene Ontology and pathway enrichment analysis to investigate the main functions of ACE2-correlated genes. We constructed a protein-protein interaction network containing the genes co-expressed with ACE2. Finally, we focused on the genes in the network that are already associated with known drugs and evaluated their role for a potential treatment of Covid-19. Our results demonstrate that the genes correlated with ACE2 are mainly enriched in the sterol biosynthetic process, Aryldialkylphosphatase activity, adenosylhomocysteinase activity, trialkylsulfonium hydrolase activity, acetate-CoA and CoA ligase activity. We identified a network of 193 genes, 222 interactions and 36 potential drugs that could have a crucial role. Among possible interesting drugs for Covid-19 treatment, we found Nimesulide, Fluticasone Propionate, Thiabendazole, Photofrin, Didanosine and Flutamide.

scholarly journals Mesenchymal Stem Cells from Patients with Rheumatoid Arthritis Display Impaired Function in Inhibiting Th17 Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Yue Sun ◽  
Wei Deng ◽  
Linyu Geng ◽  
Lu Zhang ◽  
Rui Liu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Th17 Cell ◽  
Mononuclear Cells ◽  
Biological Activities ◽  
Treg Cells ◽  
Cell Polarization ◽  
Peripheral Blood Mononuclear ◽  
Tfh Cells

Mesenchymal stem cells (MSCs) possess multipotent and immunomodulatory properties and are suggested to be involved in the pathogenesis of immune-related diseases. This study explored the function of bone marrow MSCs from rheumatoid arthritis (RA) patients, focusing on immunomodulatory effects. RA MSCs showed decreased proliferative activity and aberrant migration capacity. No significant differences were observed in cytokine profiles between RA and control MSCs. The effects of RA MSCs on proliferation of peripheral blood mononuclear cells (PBMCs) and distribution of specific CD4+T cell subtypes (Th17, Treg, and Tfh cells) were investigated. RA MSCs appeared to be indistinguishable from controls in suppressing PBMC proliferation, decreasing the proportion of Tfh cells, and inducing the polarization of Treg cells. However, the capacity to inhibit Th17 cell polarization was impaired in RA MSCs, which was related to the low expression of CCL2 in RA MSCs after coculture with CD4+T cells. These findings indicated that RA MSCs display defects in several important biological activities, especially the capacity to inhibit Th17 cell polarization. These functionally impaired MSCs may contribute to the development of RA disease.

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