Endothelial cell activation driven by CD4+ memory T cells produced soluble factors
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ABSTRACT:
PROVIDER: PRJNA841366 | ENA |
REPOSITORIES: ENA
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Project description:In this project we analyzed whole transcriptome changes in endothelial cells (ECs) in response to stimulation with activated CD4+ memory T cells produced factors. Given the central role of NF-κB signaling in EC activation we treated cells with inhibitors for canonical NF-κB signaling (IKKβ inhibitor, iIKKβ) and non-canonical NF-κB signaling (NF-κB inducting kinase (NIK) inhibitor, iNIK). Cells were stimulated 72h with conditioned medium (hereafter called Tm sup = 50% culture supernatant from aCD3/aCD28 activated CD4+ memory T cells; 50% RMPI supplemented with 10% FCS) and treated with iIKKβ, iNIK or DMSO as a control. Other controls taken along were unstimulated DMSO treated ECs and unstimulated untreated ECs.
2022-05-29 | GSE203551 | GEO
Project description: Not available
| S-EPMC3277165 | biostudies-other
Project description:Angiogenesis and Lymphangiogenesis plays a key role in promoting tumor growth and breast cancer progression as well as metastasis. Active angiogenic process within the tumor tissue is known to promote cancer/tumor growth via nutrient supply, moreover, soluble molecules secreted by lymphatic endothelial cells (ECs) promotes tumor growth. Hence is feasible that paracrine factors generated by breast cancer cells play a role in regulating tumor neovascularization by lymphatic and vascular ECs. Here using cultured VECs and LECs assessed the paracrine impact of MCF-7 breast cancer derived soluble factors on LEC and VEC growth (cell number), gene expression (micro array) and angiogenic proteins (protein array). Moreover, we explored the modulatory actions of miR193 on LEC and VEC growth driven by MCF-7 derived conditioned medium (MCF7-CM). We demonstrate that MCF7-CM differentially modulates VEC and LEC growth, i.e. induces VEC growth and inhibits LEC growth. Moreover, the growth actions of MCF7-CM were accompanied with differential modulation VEC and LEC growth regulatory genes, that were further altered by miR193 a pretreatment of MCF7 cells. Our findings provide in-depth analysis of MCF7-CM altered genes relevant for angiogenesis and lymphogenesis. The fact that vascular capillaries support growth and lymphatic capillaries play a role counteracting cancer growth (kill cancer cells), together with our observation in VECs and LECs, suggests that MCF-7 breast cancer cells differentially modulate vascular and lymphatic growth to facilitate their survival and growth. Since miR193a abrogates the effects of MCF7-CM, it may be an effective therapeutic tool against breast cancer.
2022-07-13 | GSE189084 | GEO
Project description:Introduction: DCs sense and respond to a variety of pathogen-dependent and independent features. We found that DCs can directly sense the presence of immunological memory in the form of effector memory T cells. This activation by effector memory T cells led to a robust inflammatory signature in interacting DCs. Method: Bone marrow derived DCs (BMDCs) were differentiated in the presence of GMCSF for 7 days. WT naïve T cells were polarized to Th0 (platebound anti-CD3 and anti-CD28 and soluble IL-2) for 5 days, followed by 2 days of rest in low IL-2 containing media to mimic generation of effector memory T cells. CD11c+ BMDCs were sorted via AutoMacs and activated with LPS (100ng/mL) or effector memory T cells (ratio of 1:4) in the presence or absence of soluble anti-CD3 (200ng/mL) for 3 hours. Cells were blocked with FC block and stained with flourophores to distinguish DCs from T cells. DCs were FACS sorted and lysed in Trizol. Conclusion: BMDCs activated with LPS or effector memory T cells had a distict transcriptional response. When activated with effector memory T cells, BMDCs upregulated genes associated with TNFRSF signaling. BMDCs activated with LPS or effector memory T cells also shared certain transcriptional features of upregulated cytokine and chemokine expression.
2021-11-30 | GSE184607 | GEO
Project description:Introduction: DCs sense and respond to a variety of pathogen-dependent and independent features. We found that DCs can directly sense the presence of immunological memory in the form of effector memory T cells via TNFRSF signaling. Expression of CD40L and TNF by effector memory T cells specifically led to a robust inflammatory signature in interacting DCs. Method: Bone marrow derived DCs (BMDCs) were differentiated in the presence of GMCSF for 7 days. WT naïve T cells were polarized to Th0 (platebound anti-CD3 and anti-CD28 and soluble IL-2) for 5 days, followed by 2 days of rest in low IL-2 containing media to mimic generation of effector memory T cells. CD11c+ BMDCs were sorted via AutoMacs and activated with effector memory T cells (ratio of 1:4) in the presence or absence of soluble anti-CD3 (200ng/mL) for 3 hours. Cells were pretreated with blocking and neutralizing antibodies for CD40L and TNF (20ug/mL for 30 minutes) when indicated. Cells were blocked with FC block and stained with flourophores to distinguish DCs from T cells. DCs were FACS sorted and lysed in Trizol. Conclusion: Effector memory T cells activate interacting BMDCs via CD40 and TNF signaling. When these pathways are blocked, BMDCs fail to upregulate the transcriptional program associated with effector memory T cell induced activation.
2021-11-30 | GSE184608 | GEO
Project description:BACKGROUND. Precise stratification of patients with non–small cell lung cancer (NSCLC) is needed for appropriate application of PD-1/PD-L1 blockade therapy. METHODS. We measured soluble (s) forms of the PD-L1, PD-1, and CTLA-4 in plasma of patients with advanced NSCLC before PD-1/PD-L1 blockade. Prospective biomarker finding trial (cohort A), 50 patients with pretreated NSCLC received nivolumab. In cohort B to E, retrospective observational study, soluble immune checkpoint molecules were evaluated for patients with advanced NSCLC treated with any PD-1/PD-L1 blockade (cohort B and C), cytotoxic chemotherapy (D) or targeted therapy (E). Blood samples were obtained from all patients and soluble immune checkpoint molecules were evaluated using a highly sensitive chemiluminescence-based assay. RESULTS. Nonresponsiveness to PD-1/PD-L1 blockade therapy was associated with higher concentrations of these soluble immune factors among patients with immune-reactive (hot) tumors. Such correlation was not observed in patients treated with cytotoxic chemotherapy or targeted therapies. Integrative analysis of tumor size, PD-L1 expression in tumor tissue (tPD-L1), and gene expression in tumor tissue and peripheral CD8+ T cells revealed that high concentrations of the three soluble immune factors were associated with hyper or terminal exhaustion of antitumor immunity. The combination of sPD-L1 and sCTLA-4 efficiently discriminated responsiveness among patients with immune-reactive tumors. CONCLUSION. Combinations of soluble immune factors might be able to identify patients unlikely to respond to PD-1/PD-L1 blockade as a result of terminal exhaustion of antitumor immunity. Our data suggest such a combination might provide a biomarker complementary to tPD-L1 for NSCLC patients.
2024-03-30 | GSE242860 | GEO
Project description:Introduction: Tobacco smoking generates airway inflammation in chronic obstructive pulmonary disease (COPD), and its involvement in the development of lung cancer is still among the leading causes of early death. Therefore, we aimed to have a better understanding of the disbalance in immunoregulation in chronic inflammatory conditions in smoker subjects with stable COPD (stCOPD), exacerbating COPD (exCOPD), or non-small cell lung cancer (NSCLC). Methods: Smoker controls without chronic illness were recruited as controls. Through extensive mapping of single cells, surface receptor quantification was achieved by single-cell mass cytometry (CyTOF) with 29 antibodies. The CyTOF characterized 14 main immune subsets such as CD4+, CD8+, CD4+/CD8+, CD4 −/CD8−, and g/d T cells and other subsets such as CD4+ or CD8+ NKT cells, NK cells, B cells, plasmablasts, monocytes, CD11cdim, mDCs, and pDCs. The CD4+ central memory (CM) T cells (CD4+/CD45RA−/CD45RO+/CD197+) and CD4+ effector memory (EM) T cells (CD4+/CD45RA−/CD45RO+/CD197−) were FACSsorted for RNA-Seq analysis. Plasma samples were assayed by Luminex MAGPIX® for the quantitative measurement of 17 soluble immuno-oncology mediators (BTLA, CD28, CD80, CD27, CD40, CD86, CTLA-4, GITR, GITRL, HVEM, ICOS, LAG-3, PD-1, PD-L1, PD-L2, TIM-3, TLR-2) in the four studied groups. Results: Our focus was on T-cell-dependent differences in COPD and NSCLC, where peripheral CD4+ central memory and CD4+ effector memory cells showed a significant reduction in exCOPD and CD4+ CM showed elevation in NSCLC. The transcriptome analysis delineated a perfect correlation of differentially expressed genes between exacerbating COPD and NSCLCderived peripheral CD4+ CM or CD4+ EM cells. The measurement of 17 immuno-oncology soluble mediators revealed a disease-associated phenotype in the peripheral blood of stCOPD, exCOPD, and NSCLC patients. Discussion: The applied single-cell mass cytometry, the whole transcriptome profiling of peripheral CD4+ memory cells, and the quantification of 17 plasma mediators provided complex data that may contribute to the understanding of the disbalance in immune homeostasis generated or sustained by tobacco smoking in COPD and NSCLC.
2023-12-17 | GSE250254 | GEO
Project description:Hobit- and Blimp-1-driven CD4+ P2X7+ tissue resident memory T cells critically control chronic intestinal inflammation
| PRJNA506785 | ENA
Project description:A growing amount of reports has consistently evidenced that a sustained inhibition of the angiogenesis is an effective therapeutic strategy, able to improve the outcome of metastatic colorectal cancer (mCRC) patients.
In the last decade different biologic agents targeting angiogenesis have been approved for the treatment of mCRC, such as bevacizumab, aflibercept and regorafenib, and, more recently, solid evidences have demonstrated the efficacy of a sustained antiangiogenic approach even beyond the first progression to a bevacizumab-containing regimen. In particular, two phase III randomized trials proved the effectiveness of prosecuting bevacizumab in second-line switching the chemotherapeutic regimen in patients already treated with bevacizumab in first-line. Preliminary experiences evidenced that circulating levels of angiogenesis-related markers are significantly modulated during first-line chemotherapy plus bevacizumab. In particular, a wide variability of plasma soluble Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) levels is observed at the time of disease progression and retrospective data suggest that benefit from the continuation of bevacizumab may be restricted to patients with high levels of soluble VEGFR-2 at the first evidence of disease progression. This study aims at prospectively validating those retrospective data.
| 2203761 | ecrin-mdr-crc
Project description:Malaria infection elicits both protective and pathogenic immune responses, and IL-27 is a critical cytokine that regulate effector responses during infection. Here, we identified a critical window of CD4+ T cell responses that is targeted by IL-27. Neutralization of IL-27 during acute infection with Plasmodium chabaudi expanded specific CD4+ T cells, which were maintained at high levels thereafter. In the chronic phase, Plasmodium-specific CD4+ T cells in IL-27-neutralized mice consisted mainly of CD127+KLRG1- and CD127-KLRG1+ subpopulations that displayed distinct cytokine production, proliferative capacity and are maintained in a manner independent of active infection. Single cell RNA-seq analysis revealed that these CD4+ T cell subsets formed independent clusters that express unique Th1-type genes. These IL-27-neutralized mice exhibited enhanced cellular and humoral immune responses and protection. These findings demonstrate that IL-27, which is produced during the acute phase of malaria infection, inhibits the development of unique Th1 memory precursor CD4+ T cells, suggesting potential implications for the development of vaccines and other strategic interventions.
2023-10-19 | GSE225556 | GEO