Remodeling of the tumor microenvironment via blockade of LAIR-1 and TGF-β signaling [single cell RNA-seq]
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PROVIDER: PRJNA800465 | ENA |
REPOSITORIES: ENA
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Project description:Remodeling of the tumor microenvironment via blockade of LAIR-1 and TGF-β signaling
| PRJNA801708 | ENA
Project description:Collagens in the extracellular matrix (ECM) provide a physical barrier to tumor immune infiltration, while also acting as a ligand for immune inhibitory receptors. Transforming growth factor-β (TGF-β) is a key contributor to shaping the ECM by stimulating the production and remodeling of collagens. TGF-β-activation signatures and collagen-rich environments have both been associated with T-cell exclusion and lack of responses to immunotherapy. Here we describe the effect of targeting collagens that signal through the LAIR-1 inhibitory receptor in combination with blockade of TGF-β and programmed cell death ligand 1 (PD-L1). This approach remodeled the tumor collagenous matrix, enhanced tumor infiltration and activation of CD8+ T cells, and repolarized suppressive macrophage populations resulting in high cure rates and long-term tumor-specific protection across murine models of colon and mammary carcinoma. The results highlight the advantage of direct targeting of ECM components in combination with immune checkpoint blockade therapy.
2022-03-09 | GSE195685 | GEO
Project description:Collagens in the extracellular matrix (ECM) provide a physical barrier to tumor immune infiltration, while also acting as a ligand for immune inhibitory receptors. Transforming growth factor-β (TGF-β) is a key contributor to shaping the ECM by stimulating the production and remodeling of collagens. TGF-β-activation signatures and collagen-rich environments have both been associated with T-cell exclusion and lack of responses to immunotherapy. Here we describe the effect of targeting collagens that signal through the LAIR-1 inhibitory receptor in combination with blockade of TGF-β and programmed cell death ligand 1 (PD-L1). This approach remodeled the tumor collagenous matrix, enhanced tumor infiltration and activation of CD8+ T cells, and repolarized suppressive macrophage populations resulting in high cure rates and long-term tumor-specific protection across murine models of colon and mammary carcinoma. The results highlight the advantage of direct targeting of ECM components in combination with immune checkpoint blockade therapy.
2022-03-09 | GSE194421 | GEO
Project description:Remodeling of the tumor microenvironment via blockade of LAIR-1 and TGF-β signaling [bulk RNA-seq]
| PRJNA801710 | ENA
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:Tumor immunogenicity enhanced by radiotherapy (RT), is often counterbalanced by immune evasive mechanisms and tissue remodeling effects via upregulation of transforming growth factor-β (TGF-β) and programmed cell death-ligand 1 (PD-L1). We report that bintrafusp alfa (BA), a bifunctional fusion protein that simultaneously inhibits TGF-β and PD-L1, is a favorable combination partner for RT in eradicating multiple treatment-resistant tumor models. Beneficial effects of BA+RT (BART) are partly attributed to counterbalancing undesired RT effects and local tumor microenvironment reprograming, leading to reconstitution of tumor immunity and regression of spontaneous lung metastases. Intriguingly, BA, but neither TGF-β trap nor anti–PD-L1 alone, attenuates late-stage RT-induced lung fibrosis. Single cell transcriptome show TGF-β expression is confined to PD-L1+ endothelium and M2/lipofibroblast-like cells. Hence, superior effects of BA could be attributed to its ability to trap TGF-β to relevant PD-L1+ compartments. Here, we provide rationales that BART resensitizes tumors and broadens the therapeutic window.
2021-08-16 | GSE182004 | GEO
Project description:Collagens in the extracellular matrix (ECM) provide a physical barrier to tumor immune infiltration, while also acting as a ligand for immune inhibitory receptors. Transforming growth factor-β (TGF-β) is a key contributor to shaping the ECM by stimulating the production and remodeling of collagens. TGF-β activation signatures and collagen-rich environments have both been associated with T cell exclusion and lack of responses to immunotherapy. Here, we describe the effect of targeting collagens that signal through the inhibitory leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) in combination with blockade of TGF-β and programmed cell death ligand 1 (PD-L1). This approach remodeled the tumor collagenous matrix, enhanced tumor infiltration and activation of CD8+ T cells, and repolarized suppressive macrophage populations, resulting in high cure rates and long-term tumor-specific protection across murine models of colon and mammary carcinoma. The results highlight the advantage of direct targeting of ECM components in combination with immune checkpoint blockade therapy.
| S-EPMC9012291 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-03-09 | GSE195686 | GEO
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.
2011-07-13 | GSE28598 | GEO
Project description:Extracellular pH (pHe) is lower in many tumors than in the corresponding normal tissue. Acidic tumor microenvironment has been shown to facilitate epithelial mesenchymal transition (EMT) and tumor metastasis, while the mechanisms underlying tumor acidic microenvironment-induced tumor cell metastasis remain undefined. Here, we aimed to investigate the tumor metastasis and the EMT by acidic microenvironment and to explore their mechanisms and clinical significance in lung cancer. Results showed that acidic pHe remarkably enhanced invasion ability of lung cells accompanying with increased mesenchymal and decreased epithelial markers. Moreover, acidic pHe triggered the inhibition of microRNA-7 (miR-7) expression and activation of TGF-β2/SMAD signaling. Mechanistic studies showed that TGF-β2 is a direct potential target gene of miR-7, and acidity-induced metastasis could be abolished by treatment with a TGFβRI inhibitor, anti-TGF-β2 antibody and miR-7 mimic, respectively. The clinical samples further revealed that miR-7 was decreased in lung tissues and antagonistically correlated with TGF-β2 expression, associating with overall survival and metastasis. In conclusion, our study indicated that acidic pHe showed enhanced invasive potential, and enhanced potential to develop experimental metastases by a novel mechanism involving tumor acidic microenvironment-induced regulation of miR-7/TGF-β2/SMAD axis. Our findings suggest that the possibility that pHe of the primary tumor may be an important prognostic parameter for lung cancer patients merit clinical investigation. Moreover, miR-7 may serve as prognostic molecular marker and a novel therapeutic target for lung cancer.
2022-04-01 | PXD016524 | Pride