Therapeutic activity of GARP:TGF-b1 blockade in murine primary myelofibrosis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA892617 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21986840_1.fastq.gz | Fastqsanger.gz | |||
| SRR21986840_2.fastq.gz | Fastqsanger.gz | |||
| SRR21986841_1.fastq.gz | Fastqsanger.gz | |||
| SRR21986841_2.fastq.gz | Fastqsanger.gz | |||
| SRR21986842_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 56 |
Similar Datasets
Project description:Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by clonal expansion of myeloid cells, notably megakaryocytes (MKs), and aberrant cytokine production leading to bone marrow (BM) fibrosis and insufficiency. Current treatment options are limited. TGF-b1, a profibrotic and immunosuppressive cytokine, is involved in PMF pathogenesis. While all cell types secrete inactive, latent TGF-b1, only a few activate the cytokine via cell type-specific mechanisms. The cellular source of the active TGF-b1 implicated in PMF is not known. Transmembrane protein GARP binds and activates latent TGF-b1 on the surface of regulatory T lymphocytes (Tregs) and MKs or platelets. Here, we found increased expression of GARP in BM and spleen of mice undergoing PMF and tested the therapeutic potential of a monoclonal antibody that blocks TGF-b1 activation by GARP-expressing cells. GARP:TGF-b1 blockade reduced not only fibrosis, but also clonal expansion of transformed cells. Using mice carrying a genetic deletion of Garp in either Tregs or MKs, we found that the therapeutic effects of GARP:TGF-b1 blockade in PMF imply targeting GARP on Tregs. These therapeutic effects, accompanied by increased IFN-g signals in the spleen, were lost upon CD8 T cell depletion. Our results suggest that selective blockade of TGF-b1 activation by GARP-expressing Tregs increase a CD8 T cell-mediated immune reaction that limits transformed cell expansion, providing a novel approach that could be tested to treat patients with myeloproliferative neoplasms.
2022-10-27 | GSE216221 | GEO
Project description:Immune checkpoint blockade (ICB) has revolutionized cancer immunotherapy. However, the majority of cancer patients fail to respond clinically. One potential reason is the accumulation of transforming growth factor-beta (TGFb) in the tumor microenvironment (TME). TGFb drives cancer immune evasion in part by inducing regulatory T cells (Tregs) and limiting CD8+ T cell function. Glycoprotein-A repetitions predominant (GARP) is a cell surface docking receptor for activating latent TGF1, TGFb2 and TGFb3, with its expression restricted in effector Tregs, cancer cells as well as platelets. Herein we demonstrate that GARP overexpression in human cancers correlates with unfavorable TME and poor clinical response to ICB, raising a possibility of GARP blockade to improve cancer immunotherapy. However, it is unclear if targeting GARP in the TME is feasible without affecting platelets. We report an anti-human GARP antibody (named PIIO-1) specific for its ligand-interacting domain, effectively blocking activation of latent TGFb1. PIIO-1 lacks recognition of GARP-TGF complex on platelets. Using human GARP knock-in mice, we demonstrate that PIIO-1 does not cause thrombocytopenia, and is preferentially distributed in the TME and effective for treating both GARP+ and GARP- cancers, alone or in combination with anti-PD-1 antibody. PIIO-1 treatment reduces canonical TGFb signaling in tumor-infiltrating immune cells, prevents T cell exhaustion, and enhances CD8+ T cell migration into the TME in a CXCR3-dependent manner. Collectively, we conclude that GARP contributes to multiple aspects of immune resistance in cancer; anti-GARP antibody PIIO-1 is an efficacious and safe strategy to overcome ICB resistance, therefore warranting clinical development.
2022-09-21 | GSE202153 | GEO
Project description:Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by the clonal expansion of myeloid cells, notably megakaryocytes (MKs), and an aberrant cytokine production leading to bone marrow (BM) fibrosis and insufficiency. Current treatment options are limited. TGF-β1, a profibrotic and immunosuppressive cytokine, is involved in PMF pathogenesis. While all cell types secrete inactive, latent TGF-β1, only a few activate the cytokine via cell type-specific mechanisms. The cellular source of the active TGF-β1 implicated in PMF is not known. Transmembrane protein GARP binds and activates latent TGF-β1 on the surface of regulatory T lymphocytes (Tregs) and MKs or platelets. Here, we found an increased expression of GARP in the BM and spleen of mice with PMF and tested the therapeutic potential of a monoclonal antibody (mAb) that blocks TGF-β1 activation by GARP-expressing cells. GARP:TGF-β1 blockade reduced not only fibrosis but also the clonal expansion of transformed cells. Using mice carrying a genetic deletion of Garp in either Tregs or MKs, we found that the therapeutic effects of GARP:TGF-β1 blockade in PMF imply targeting GARP on Tregs. These therapeutic effects, accompanied by increased IFN-γ signals in the spleen, were lost upon CD8 T-cell depletion. Our results suggest that the selective blockade of TGF-β1 activation by GARP-expressing Tregs increases a CD8 T-cell-mediated immune reaction that limits transformed cell expansion, providing a novel approach that could be tested to treat patients with myeloproliferative neoplasms.
| S-EPMC10651781 | biostudies-literature
Project description:Imbalances in glucose and energy homeostasis are at the core of the worldwide epidemic of obesity and diabetes. Here, we illustrate an important role of the TGF-beta/Smad3 signaling pathway in regulating glucose and energy homeostasis. Smad3 deficient mice are protected from diet-induced obesity and diabetes. Interestingly, the metabolic protection is accompanied by Smad3-/- white adipose tissue acquiring the bioenergetic and gene expression profile of brown fat/skeletal muscle. Smad3-/- adipocytes demonstrate a marked increase in mitochondrial biogenesis, with a corresponding increase in basal respiration, and Smad3 acts as a repressor of PGC-alpha1 expression. We observe significant correlation between TGF-beta1 levels and adiposity in rodents and humans. Further, systemic blockade of TGF-beta1 signaling protects mice from obesity, diabetes and hepatic steatosis. Together, these results demonstrate that TGF-beta signaling regulates glucose tolerance and energy homeostasis and suggest that modulation of TGF-beta1 activity might be an effective treatment strategy for obesity and diabetes. Smad3-/- and WT mice were fed with regular diet (RD) and high fat diet (HFD), and diet induced obese (DIO) mice were treated with IgG and anti-TGF-b1 antibody
2011-07-12 | E-GEOD-28598 | biostudies-arrayexpress
Project description:Proteins secreted from TGF-B1-stimulated IMR-90 cells with and without sanglifehrin A were profiled.
2024-10-17 | PXD029541 | Pride
Project description:Response of mouse mammary epithelial cells NMuMG to TGF-b1 - time course experiment. Identification of novel gene targets involved in TGF-b1-driven regulation of epithelial-mesenchymal transition (EMT).
2004-10-01 | E-MEXP-139 | biostudies-arrayexpress
Project description:Regulation of organismal homeostasis in response to nutrient availability is a vital physiological process that involves inter-organ communication. Understanding the mechanisms controlling systemic cross talk for maintenance of metabolic health is critical to counteract diet-induced obesity. Here, we show that cardiac-derived transforming growth factor beta 1 (TGF-b1) protects against weight gain and glucose intolerance in mice subjected to high-fat diet. Secretion of TGF-b1 by cardiomyocytes correlates with bioavailability of this factor in circulation. TGF-b1 prevents adipose tissue inflammation independent of body weight and glucose metabolism phenotypes, suggesting protection from adipocyte dysfunction-driven immune cell recruitment. TGF-b1 alters gene expression programs in white adipocytes, favoring their thermogenic fate and consequently increasing their mitochondrial oxygen consumption rates. Ultimately, subcutaneous and visceral white adipose tissue from heart-specific TGF-b1 transgenic mice fail to undergo cellular hypertrophy, leading to reduced overall adiposity during high-fat feeding. Thus, TGF-b1 is a critical mediator of heart-fat communication for regulation of systemic metabolism.
2021-11-03 | GSE179102 | GEO
Project description:Long-term peritoneal dialysis is associated with progressive fibrosis of the peritoneum. Epithelial-mesenchymal transition (EMT) of mesothelial cells is an important mechanism involved in peritoneal fibrosis, and TGF-b1 is considered central in this process. We conducted network-based integrated analysis of transcriptomic data to systemically characterize the molecular signature of TGF-b1-stimulated human peritoneal mesothelial cells (HPMCs).
2018-10-18 | GSE121372 | GEO
Project description:To understand the transcriptional responses induced by LIGHT in esophageal fibroblasts and compare them to the pro-fibrotic TGF-B1
2020-08-03 | GSE143482 | GEO
Project description:Multipotent mesenchymal stromal cells (MSCs) have been shown to promote tissue repair and inhibit inflammatory/autoimmune responses in preclinical and human clinical trials A major problem for MSC-based therapies is the need to expand MSCs in vitro due to the low frequency of MSCs in tissues and the large numbers of cells needed/patient (1-10 x 10^6 cells/kg). The expansion of MSCs is associated with several problems including loss of homing capacity, onset of cellular senescence, decrease in differentiation capacityand susceptibility to genomic instability and malignant transformation, limiting the utility of MSCs as a cell-based therapy. We have recently reported that murine adipose tissue-derived MSCs (mASCs) and human ASCs (hASCs) express glycoprotein A repetitions predominant (GARP)/leucine-rich repeat-containing 32 (LRRC32). GARP binds LAP/TGF-β1 to the surface of mASCs and hASCs, regulating their secretion and activation of TGF-β1 and promoting their immunomodulatory capacity. Interestingly, silencing of GARP in ASCs significantly decreased their proliferative capacity but the mechanisms remain unknown. As the proliferative capacity of MSCs is fundamental for their success in therapy, we have aimed at understanding how GARP modulates the expansion of MSC.
2019-06-05 | GSE104254 | GEO