Bystander IFN- γ activity promotes widespread and sustained cytokine signaling altering the tumor microenvironment
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE140191 | GEO | 2020/02/03
REPOSITORIES: GEO
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Project description:Bystander IFN- γ activity promotes widespread and sustained cytokine signaling altering the tumor microenvironment
| PRJNA588757 | ENA
Project description:The cytokine IFN-? produced by tumor-reactive T cells is a key effector molecule with pleiotropic effects during anti-tumor immune responses. While IFN-? production is targeted at the immunological synapse, its spatiotemporal activity within the tumor remains elusive. Here, we report that while IFN-? secretion requires local antigen recognition, IFN-? diffuses extensively to alter the tumor microenvironment in distant areas. Using intravital imaging and a reporter for STAT1 translocation, we provide evidence that T cells mediate sustained IFN-? signaling in remote tumor cells. Furthermore, tumor phenotypic alterations required several hours of exposure to IFN-?, a feature that disfavored local IFN-? activity over diffusion and bystander activity. Finally, single-cell RNA-seq data from melanoma patients also suggested bystander IFN-? activity in human tumors. Thus, tumor-reactive T cells act collectively to create large cytokine fields that profoundly modify the tumor microenvironment.
| S-EPMC7115926 | biostudies-literature
Project description:Background: In previous studies we showed that IL-27 shares several effects with IFN-γ in human cancer cells. To identify novel extracellular mediators, potentially involved in epithelial ovarian cancer (EOC) biology, we analyzed the effect of IL-27 or IFN-γ on the secretome of EOC cells in culture. Methods: The secretome of cytokine-treated or untreated SKOV3 cells was analyzed by nano-UHPLC-MS/MS and eluting peptides by an Orbitrap Fusion Tribrid mass spectrometer. Extracellular GBP1 was studied by ELISA, immunoprecipitation, GTP-agarose pull-down, and Western blotting. GBP and STAT proteins were analysed on cell lysates by Western blot. GBP1 was transfected using lipofectamine reagent and cell viability measured by MTT assay. Results: IL-27 and IFN-γ modulate the extracellular release of a limited fraction of proteins that were also induced in the whole cell. Among these proteins we focused our attention on GBP1, a guanylate-binding protein and GTPase, which is a mediator of several biological activities of IFNs. Interestingly GBP1, 2, and 5 were induced by cytokine treatment in EOC cells, but only GBP1 was secreted. ELISA and immuno-blotting analyses showed that cytokine-stimulated EOC cells release full-length GBP1 molecule in vitro, through non-classical pathways, not involving microvesicles. Moreover, soluble, full-length GBP1 accumulates in the ascites of most EOC patients, suggesting a potential role of extracellular GBP1 in the tumor environment. EOC cells enriched from ascites showed constitutive tyrosine-phosphorylated STAT1 and STAT3 proteins and GBP1 expression, supporting a role of STAT-activating cytokines in GBP1 induction in vivo. Data from the TCGA dataset of EOC indicate that high GBP1 gene expression correlates with a better overall survival. Accordingly GBP1 transfection reduced SKOV3 cell proliferation, suggesting a potential anti-tumor activity of GBP1. Conclusions: Our data show for the first time that soluble GBP1 is released by cytokine-stimulated EOC cells in vitro and accumulates in EOC patients’ ascites. GBP1 expression may have anti-tumor effects, in EOC, as suggested by TCGA dataset analysis and in vitro transfection experiments. Further studies to identify the biological role of soluble GBP1 in the tumor environment of EOC are warranted.
2020-05-27 | PXD016479 | Pride
Project description:<p>The purpose of this study is to discover in vivo cytokine expression quantitative trait locus (eQTL) interactions from a cohort of patients with systemic lupus erythematosus. 157 lupus patients were enrolled in a clinical trial to test the efficacy and safety of an anti-IL-6 monoclonal antibody. At three time points, we measured interferon (IFN) status, anti-IL-6 drug exposure and genome-wide gen expression. We identified 4,818 cis-eQTLs and then observed a statistically significant enrichment of in vivo eQTL interactions with IFN status and anti-IL-6 exposure.</p>
| phs001702 | dbGaP
Project description:This experiment was designed to study the cytokine gene expression profile of macrophage under 50uM DU exposure. the experiment was repeated three time, with duplicate spots for each gene on the array. Conclusion: DU exposure induces the expressions of IL-10, NF-kBP65, and Midkine and other cytokine genes, indicating the immunomodulation abilities of DU. (GSM43230-GSM43241) This experiment was designed to study the cytokine gene expression of splenic CD4+ T-cells under 100uM DU exposure in 24 hours. Conclusion: DU induces Th2 cytokine gene expression (eg. IL-5), and midkine, as well as other cytokine genes, indicating the abilities of DU in promoting Th2 shifting during differtiation. (GSM43242 to GSM43253)
2010-06-10 | E-GEOD-2333 | biostudies-arrayexpress
Project description:The transcription factor IRF8 is expressed in many types of blood cells and plays critical roles in cellular differentiation and function. However, the role of IRF8 in nonhematopoietic systems remains poorly understood. In this study, we examined the role of IRF8 in gastric epithelial cells (GECs) and provided evidence that IRF8 is a transcriptional modulator of the gastric mucosa necessary for limiting H. pylori colonization. H. pylori infection significantly upregulated expression of IRF8, which in turn promoted IFN-γ expression by GECs. Mice deficient of IRF8 exhibited increased H. pylori colonization and aborted induction of mucosal IFN-γ. Genome-wide analyses of IFN-γ-treated GECs by ChIP-seq and RNA-seq led to identification of IRF8 target genes with many belonging to the IFN regulated gene family that was previously observed in immune cells. Our results identify the IRF8- IFN-γ circuit as a previously unrecognized gastric innate immune mechanism in defense against infection of H. pylori.
2015-12-30 | GSE67476 | GEO
Project description:The cytokine environment and cellular infiltrate during an inflammatory response may contain prognostic features that could guide therapy or predict disease outcome. Here we analyzed the transcriptional responses of human monocytes, macrophages, dendritic cells and neutrophils to stimulation by type 1 cytokines (IFN-g, IFN-b and IFN-l) type 2 cytokines (IL-4 and IL-13) and the immunoregulatory cytokine IL-10. This generated a myeloid cell cytokine specific response matrix to infer representation of myeloid cells and the cytokine environment they may encounter during infection and in tumors. Neutrophils were surprisingly responsive to type 1 and type 2 cytokine stimulation but did not respond to IL-10. We identified transcripts specific to IFN-b stimulation, whereas other IFN signature genes were upregulated by both IFN-g and IFN-b. When used to deconvolute blood profiles from tuberculosis patients, the IFN-b specific neutrophil signature was surprisingly reduced in TB patients with active disease whereas the shared response to IFN-g and IFN-b in neutrophils was increased. When applied to glioma patients, transcripts of neutrophils exposed to IL-4 or IL-13 and monocyte responses to IFN-g or IFN-b emerged as opposing predictors of survival in samples from patients with glioma. This approach may help delineate biological roles for myeloid cells in different cytokine environments during disease processes.
2019-10-01 | GSE131990 | GEO
Project description:The cytokine environment and cellular infiltrate during an inflammatory response may contain prognostic features that could guide therapy or predict disease outcome. Here we analyzed the transcriptional responses of human monocytes, macrophages, dendritic cells and neutrophils to stimulation by type 1 cytokines (IFN-g, IFN-b and IFN-l) type 2 cytokines (IL-4 and IL-13) and the immunoregulatory cytokine IL-10. This generated a myeloid cell cytokine specific response matrix to infer representation of myeloid cells and the cytokine environment they may encounter during infection and in tumors. Neutrophils were surprisingly responsive to type 1 and type 2 cytokine stimulation but did not respond to IL-10. We identified transcripts specific to IFN-b stimulation, whereas other IFN signature genes were upregulated by both IFN-g and IFN-b. When used to deconvolute blood profiles from tuberculosis patients, the IFN-b specific neutrophil signature was surprisingly reduced in TB patients with active disease whereas the shared response to IFN-g and IFN-b in neutrophils was increased. When applied to glioma patients, transcripts of neutrophils exposed to IL-4 or IL-13 and monocyte responses to IFN-g or IFN-b emerged as opposing predictors of survival in samples from patients with glioma. This approach may help delineate biological roles for myeloid cells in different cytokine environments during disease processes.
2020-02-21 | GSE145647 | GEO
Project description:This experiment was designed to study the cytokine gene expression profile of macrophage under 50uM DU exposure. the experiment was repeated three time, with duplicate spots for each gene on the array. Conclusion: DU exposure induces the expressions of IL-10, NF-kBP65, and Midkine and other cytokine genes, indicating the immunomodulation abilities of DU. (GSM43230-GSM43241) This experiment was designed to study the cytokine gene expression of splenic CD4+ T-cells under 100uM DU exposure in 24 hours. Conclusion: DU induces Th2 cytokine gene expression (eg. IL-5), and midkine, as well as other cytokine genes, indicating the abilities of DU in promoting Th2 shifting during differtiation. (GSM43242 to GSM43253)
2005-02-25 | GSE2333 | GEO
Project description:Background: Cytokines are critical to human disease and are attractive therapeutic targets given their widespread influence on gene regulation and transcription. Defining the downstream regulatory mechanisms influenced by cytokines is central to defining drug and disease mechanisms. One promising strategy is to use interactions between expression quantitative trait loci (eQTLs) and cytokine levels to define target genes and mechanisms. Results: In a clinical trial for anti-IL-6 in patients with systemic lupus erythematosus we measured interferon (IFN) status, anti-IL-6 drug exposure and whole blood genome-wide gene expression at three time points (379 samples from 157 individuals). First, we show that repeat transcriptomic measurements increases the number of cis eQTLs identified compared to using a single time point by 64%. Then, after identifying 4,818 cis-eQTLs, we observed a statistically significant enrichment of in vivo eQTL interactions with IFN status (p<0.001 by permutation) and anti-IL-6 drug exposure (p<0.001). We observed 210 and 72 interactions for IFN and anti-IL-6 respectively (FDR<20%). Anti-IL-6 interactions have not yet been described while 99 of the IFN interactions are novel. Finally, we found transcription factor binding motifs interrupted by eQTL interaction SNPs, pointing to key regulatory mediators of these environmental stimuli and therefore potential therapeutic targets for autoimmune diseases. In particular, genes with IFN interactions are enriched for ISRE binding site motifs, while those with anti-IL-6 interactions are enriched for IRF4 motifs. Conclusion: This study highlights the potential to exploit clinical trial data to discover in vivo eQTL interactions with therapeutically relevant environmental variables.
2018-09-24 | GSE116006 | GEO