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Exosome mediated genetic reprogramming of tumor associated macrophages by exoASO-STAT6 leads to potent monotherapy anti-tumor activity

ABSTRACT: The M2 phenotype is controlled by key transcription factors such as STAT6. We describe an engineered exosome therapeutic candidate delivering an antisense oligonucleotide (ASO) targeting STAT6 (exoASO-STAT6), which preferentially silences STAT6 expression in tumor-associated macrophages (TAMs). We demonstrate that administration of exoASO-STAT6 reprograms TAMs to an M1 phenotype, leading to the induction of nitric oxide synthase 2 (NOS2) and remodeling of the TAMs.

ORGANISM(S): Mus musculus

PROVIDER: GSE174068 | GEO | 2021/12/31

REPOSITORIES: GEO

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TH2 cytokines promote tumor progression via regulating cathepsin secretion in tumor-associated macrophages

Project description:Tumor-associated macrophages (TAMs) have emerged as prominent cells within the tumor microenvironment playing critical roles in extracellular matrix remodeling, tumor cell proliferation and invasion, angiogenesis, and metastasis. Cathepsin proteases, produced by tumor cells and TAMs, have been demonstrated to mediate these processes, but it still remains unclear how these typically lysosomal enzymes are capable of executing their functions in the extracellular space. Here we identify a novel interaction between STAT6 and STAT3 that potently upregulates cathepsin secretion in macrophages in response to TH2 cytokine stimulation. Systematic gene expression analyses reveal that the TH2 cytokine IL-4 synergizes with IL-6 or IL-10 to activate the IRE1α/ XBP1 axis of the unfolded protein response. Pharmacological inhibition of the IRE1α axis blunts cathepsin secretion in macrophages and blocks macrophage-mediated tumor cell invasion. Finally, we show that genetic ablation of either STAT6 or STAT3 signaling impairs tumor development and invasion. Thus, these findings demonstrate that TH2 cytokine-mediated STAT6 and STAT3 activation in macrophages promotes a professional secretory phenotype capable of enhancing tumor cell invasion in a cathepsin-dependent manner.

2016-08-17 | GSE70626 | GEO

Identification of novel STAT6-regulated proteins in mouse B cells by comparative transcriptome and proteome analysis

Project description:IL-4/STAT6-regulated transcriptome and proteome were compared in primary B cells isolated from wild-type and STAT6-deficient mice. B cells were purified from the spleen and stimulated in vitro with anti-CD40 and LPS or anti-IgM-F(ab)2 in the presence or absence of IL-4. Transcriptome analysis was performed with oligonucleotide microarrays. Global relative quantification of proteins was achieved by gel-enhanced label-free liquid chromatography/mass spectrometry (LC/MS). Hierarchical clustering and principal component analysis revealed that IL-4-induced changes of the transcriptome were almost completely dependent on STAT6. In contrast, the quantitative proteome analysis revealed that the expression of many IL-4-regulated proteins changes even in the absence of STAT6. The top 75 proteins with changes in abundance levels induced by IL-4 in a STAT6-dependent manner were also found to be regulated at the transcriptional level. Most of these proteins were not previously known to be regulated by STAT6 in B cells. We confirmed the MS-based quantitative proteome data by flow cytometric and Western blot analysis of selected proteins. This study provides a framework for further functional characterization of STAT6-regulated proteins in B cells that might be involved in germinal center formation and class switch recombination.

2017-03-06 | PXD005224 | Pride

T-bet and STAT6 Coordinately Suppress the Development of IL-9-mediated Atopic Dermatitis-like Skin Inflammation in Mice

Project description:T-bet and STAT6 are critical factors for helper T cell differentiation in humans and mice. Additionally, polymorphisms in TBX21 (T-bet) and STAT6 are associated with the susceptibility of allergic diseases. However, precise mechanisms of the reciprocal regulation between T-bet and STAT6 in allergy remain unclear. To determine the reciprocal regulation in vivo, we investigated the phenotype of T-bet/STAT6 double-deficient (T-bet-/- STAT6-/-) mice. Unexpectedly, T-bet-/- STAT6-/- mice but not T-bet-/- mice or STAT6-/- mice spontaneously developed severe dermatitis. Not only eosinophils and mast cells but also CD4+ T cells infiltrated into the skin of T-bet-/- STAT6-/- mice. Adoptive transfer of CD4+ T cells of T-bet-/- STAT6-/- mice into SCID mice induced the accumulation of eosinophils and mast cells in the skin, while depletion of CD4+ T cells ameliorated the dermatitis in T-bet-/- STAT6-/- mice. Comprehensive transcriptome analyses revealed that IL-9 expression was enhanced in T-bet-/- STAT6-/- CD4+ T cells. Indeed, IL-9 neutralization ameliorated the dermatitis in T-bet-/- STAT6-/- mice. Importantly, T-bet-/- STAT6-/- CD4+ T cells expressed functional TSLP receptor and produced large amounts of IL-9 upon TSLP stimulation. These results indicate that T-bet and STAT6 suppress atopic dermatitis-like skin inflammation, possibly by inhibiting TSLP-dependent IL-9 production in CD4+ T cells.

2020-08-15 | GSE156288 | GEO

Gene expression in WT and Stat6 KO intestinal stem cells

Project description:Purpose: To examine the expression profile of WT and Stat6 KO intestinal stem cells. Methods: We isolated Lgr5+ ISCs from the intestine tissue, and generated Stat6 KO ISCs through CRISPR/Cas9 approach. Results: Many genes are changed upon Stat6 KO cells. We pay special attention on Wnt/β-catenin signaling that is the most critical pathway in ISCs, and discovered Stat6 drove the expression of Wnt target genes. Conclusions: Stat6 crosstalks with Wnt signaling to drive ISC self-renewal.

2018-12-05 | GSE123353 | GEO

Activation of STAT6 by STING Is Critical for Antiviral Innate Immunity

Project description:Analysis of the transcriptional response of HEK293 or HEK293-STAT6 stable cell lines to poly(I:C) transfection. The hypothesis tested was that poly(I:C) transfection is capable of inducing the expression of STAT6-dependent antiviral genes. mRNA isolated from HEK293 or HEK293-STAT6 stable cell lines with control treatment or poly(I:C) transfection for 16 hours.

2011-11-21 | E-GEOD-26435 | biostudies-arrayexpress

PARP14 is a Novel Target in STAT6 Mutant Follicular Lymphoma

Project description:The variable clinical course of follicular lymphoma (FL) is determined by the molecular heterogeneity of tumor cells and complex interactions within the tumor microenvironment (TME). IL-4 producing follicular helper T cells (TFH) are critical components of the FL TME. Binding of IL-4 to IL-4R on FL cells activates JAK/STAT signaling. We identified STAT6 mutations (STAT6MUT) in 13% of FL (N = 33/258), all clustered within the DNA binding domain. Gene expression data and immunohistochemistry showed upregulation of IL-4/STAT6 target genes in STAT6MUT FL, including CCL17, CCL22, and FCER2 (CD23). Functionally, STAT6MUT was gain-of-function by serial replating phenotype in pre-B CFU assays. Expression of STAT6MUT enhanced IL-4 induced FCER2/CD23, CCL17 and CCL22 expression and was associated with nuclear accumulation of pSTAT6. RNA sequencing identified PARP14 -a transcriptional switch and co-activator of STAT6- among the top differentially upregulated genes in IL-4 stimulated STAT6MUT lymphoma cells and in STAT6MUT primary FL cells. Quantitative chromatin immunoprecipitation (qChIP) demonstrated binding of STAT6MUT but not STAT6WT to the PARP14 promotor. Reporter assays showed increased IL-4 induced transactivation activity of STAT6MUT at the PARP14 promotor, suggesting a self-reinforcing regulatory circuit. Knock-down of PARP14 or PARP-inhibition abrogated the STAT6MUT gain-of-function phenotype. Thus, our results identify PARP14 as a novel therapeutic target in STAT6MUT FL.

2022-07-17 | GSE208031 | GEO

Discrete Roles of STAT4 and STAT6 Transcription Factors in Tuning Epigenetic Modifications and Transcription during Helper T Cell Differentiation (ChIP-Seq)

Project description:Signal transducer and activator of transcription 4 (STAT4) and STAT6 are key factors in the specification of helper T cells; however, their direct roles in driving differentiation are not well understood. Using chromatin immunoprecipitation and massive parallel sequencing, we quantitated the full complement of STAT-bound genes, concurrently assessing global STAT-dependent epigenetic modifications and gene transcription using cells from cognate STAT-deficient mice. STAT4 and STAT6 each bound over 4000 genes with distinct binding motifs. Both played critical roles in maintaining chromatin configuration and transcription of a core subset of genes through the combination of different epigenetic patterns. Globally, STAT4 had a more dominant role in promoting active epigenetic marks, whereas STAT6 had a more prominent role in antagonizing repressive marks. Clusters of genes negatively regulated by STATs were also identified, highlighting previously unappreciated repressive roles. Therefore, STAT4 and STAT6 play wide regulatory roles in T helper specification. The roles of STAT proteins to shape T helper cell phenotype was investigated by comparing DNA binding profiles of STAT4 and STAT6 in Th1 and Th2 conditions. The functional outcome of STAT bindings was further evaluated by profiling histone epigenetic marks and gene expression changes between WT and STAT-deficient T cells in Th1 and Th2 conditions.

2010-06-18 | E-GEOD-22104 | biostudies-arrayexpress

Exosome mediated genetic reprogramming of tumor associated macrophages by exoASO-STAT6 leads to potent monotherapy anti-tumor activity

Project description:Exosome mediated genetic reprogramming of tumor associated macrophages by exoASO-STAT6 leads to potent monotherapy anti-tumor activity

| PRJNA728095 | ENA

Discrete Roles of STAT4 and STAT6 Transcription Factors in Tuning Epigenetic Modifications and Transcription during Helper T Cell Differentiation (gene expression)

2010-07-07 | E-GEOD-22081 | biostudies-arrayexpress

Expression analysis of tumor-associated macrophages from primary tumor and metastatic lung

Project description:In tumor microenvironment, tumor-associated macrophages (TAMs) have been characterized as M1-like or M2-like phenotype. In this study, we investigated the characteristics and functional roles of different TAMs on cancer metastasis. We isolated TAMs from primary tumor and metastatic lung and performed microarrays to identify the gene expression in distinct TAMs populations.

2018-07-26 | GSE96944 | GEO

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