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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Effect of TLR Ligation on the Differentiation and Function of Human mMDSC

ABSTRACT: Immunosuppressive microenvironments block the activity of tumoricidal T and NK cells, allowing cancers to avoid immune elimination. Monocytic myeloid-derived suppressor cells (mMDSC) are an important component of these immunosuppressive milieus. Human mMDSC respond to stimulation via their Toll-like receptors by differentiating into macrophage. Agonists targeting TLRs 1/2 (such as PAM3) induce mMDSC to mature into immumosuppressive M2-like macrophage through a process that involves TNF and IL6. Agonists targeting TLRs 7/8 (such as R848) cause the same precursors to mature into tumoricidal M1-like macrophages, a process in which IL12 plays a central role. The immune suppression mediated by mMDSC is reversed by exposure to TLR 7/8 agonists which thus might be useful adjuncts for tumor immunotherapy. In this study we looked at several time points. hMDSC from four different donors were sorted from PBMC then cultured in the presence of R848, Pam 3 or left unstimulated for 30, 75 and 225 minutes. Late time points included samples from seven donors after 3 days in culture with the same TLR ligands. For microarray experiments total RNA was extracted, amplified into aRNA and coupled to Cy5. Similarly amplified RNA from universal RNA was coupled to Cy3 and used as a reference for each array.

ORGANISM(S): Homo sapiens

SUBMITTER: Dennis Klinman

PROVIDER: E-GEOD-57032 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Effect of TLR Ligation on the Differentiation and Function of Human mMDSC

Project description:Immunosuppressive microenvironments block the activity of tumoricidal T and NK cells, allowing cancers to avoid immune elimination. Monocytic myeloid-derived suppressor cells (mMDSC) are an important component of these immunosuppressive milieus. Human mMDSC respond to stimulation via their Toll-like receptors by differentiating into macrophage. Agonists targeting TLRs 1/2 (such as PAM3) induce mMDSC to mature into immumosuppressive M2-like macrophage through a process that involves TNF and IL6. Agonists targeting TLRs 7/8 (such as R848) cause the same precursors to mature into tumoricidal M1-like macrophages, a process in which IL12 plays a central role. The immune suppression mediated by mMDSC is reversed by exposure to TLR 7/8 agonists which thus might be useful adjuncts for tumor immunotherapy.

2014-07-21 | GSE57032 | GEO

Transcription profiling of human dendritic cells to identify a combinatorial code by which DCs discriminate pathogens and provide (suggest) a rationale to design adjuvants for TH1 responses.

Project description:Toll like receptors (TLRs) sense microbial products and initiate adaptive immune responses by activating dendritic cells (DCs). Since pathogens may contain several agonists we asked whether different TLRs may synergize in DC activation. We report that in human and mouse DC TLR3 or TLR4 potently synergize with TLR7, TLR8 or TLR9 in the induction of selected cytokine genes. Upon synergistic stimulation, IL-12, IL-23 and Delta-4 are induced at levels 50-100 fold higher than those induced by optimal concentrations of single agonists, leading to enhanced and sustained TH1 polarizing capacity. Using microarray analysis we show that only 1.5% of the transcripts induced by single TLR agonists are synergistically regulated by combinations of TLR4 and TLR8 agonists.. These results identify a combinatorial code by which DCs discriminate pathogens and provide (suggest) a rationale to design adjuvants for TH1 responses. Series_overall_design: 3 untreated, 3 treated with LPS at 2h, 3 treated with LPS at 8h, 3 treated with R848 at 2h, 3 treated with R848 at 8h, 3 treated with LPS + R848 at 2h, 3 treated with LPS + R848 at 8h

2007-09-14 | E-GEOD-2706 | biostudies-arrayexpress

TLR agonists on human dendritic cells

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Intra-tumoral activation of endosomal TLR pathways reveals a distinct role for TLR3 agonist dependent type-1 interferons in shaping the tumor immune microenvironment

Project description:Toll-like receptor (TLR) agonists have received considerable attention as therapeutic targets for cancer immunotherapy owing to their ability to convert immunosuppressive tumor microenvironments towards a more T-cell inflamed phenotype. However, TLRs differ in their cell expression profiles and intracellular signaling pathways, raising the possibility that distinct TLRs differentially influence the tumor immune microenvironment.

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Microarray analyses using bone marrow-derived macrophages from Batf2−/− and wildtype mice that had been stimulated with R848

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Project description:RNA-seq analysis of Macrophage activated with TLR agonists

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Transcriptome analysis of BMDM from wild type and Rasgef1b_fl/fl_vav-icre mice treated or not for four hours with R848

Project description:Despite much progress, the specific role of some the putative intracellular signaling players upstream to inflammatory gene expression activated by Toll-like receptor (TLRs) in the immune response remains unknown. For instance, the TLR-inducible Ras guanine exchange factor member 1b (RasGEF1b) was previously shown to be expressed in activated macrophages, but its specific function is still obscure. To investigate the role of RasGEF1b in TLR-mediated innate immune response, we generated Rasgef1bfl/fl mice for tissue conditional gene deletion . We found that the expression and production of the neutrophil chemoattractant chemokine KC/Cxcl1 was impaired in response to TLRs stimulation of bone marrow derived macrophages (BMDMs) devoid of RasGEF1b. The production of KC/Cxcl1 was also impaired in in vivo models of LPS-induced peritonitis, and R848-induced acute lung injury inflammation. RasGEF1b was not required or sufficient to neither induce nor increase the transcriptional activation of Cxcl1 promoter. In addition, TLR-triggered inflammatory activation of NF-ΚB signaling pathway was unimpaired in macrophages lacking RasGEF1b suggesting a mechanism independent of the NF-B transcription factor. Our data presented herein revealed an important role of RasGEF1b in innate immunity by regulating gene expression, following TLR stimulation.

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Identification of the networks that regulate human monocytic myeloid-derived suppressor cell differentiation into inflammatory macrophages

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2017-10-19 | GSE105142 | GEO

Peripheral blood transcriptomics following immunization with TLR-adjuvanted nanoparticle vaccine in rhesus macaques

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Sustained R848 treatment of Mice

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2008-09-30 | GSE12957 | GEO

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