Effects of engineered IL-18BP on attenuation of hepatic stellate cell activation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1173149 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Metabolic dysfunction-associated steatohepatitis (MASH) is a chronic liver disease associated with hepatic inflammation and fibrosis. Inflammasome-mediated IL-18 signaling is enhanced under MASH condition. IL-18 binding protein (IL-18BP) is a soluble protein that can block IL-18 actions and therapeutic potential of IL-18BP for MASH-induced fibrosis is largely unknown. We newly developed a human IL-18BP biologics (APB-R3) and injected it to mice to evaluate its pharmacologic efficacy. APB-R3 strikingly abolished hepatic fibrosis and reduced collagen markers. We further investigated whether APB-R3 could inhibit fibrotic activation of hepatic stellate cells (HSCs). This study proposes that abrogation of IL-18 signaling by boosting IL-18BP can strongly inhibit the development of MASH-induced fibrosis and our engineered IL-18BP biologics can become promising therapeutic candidate for curing MASH.
2024-10-18 | GSE279499 | GEO
Project description:Metabolic dysfunction-associated steatohepatitis (MASH) is a chronic liver disease associated with hepatic inflammation and fibrosis. Inflammasome-mediated IL-18 signaling is enhanced under MASH condition. IL-18 binding protein (IL-18BP) is a soluble protein that can block IL-18 actions and therapeutic potential of IL-18BP for MASH-induced fibrosis is largely unknown. We newly developed a human IL-18BP biologics (APB-R3) and injected it to mice to evaluate its pharmacologic efficacy. APB-R3 strikingly abolished hepatic fibrosis and reduced collagen markers. We further investigated whether APB-R3 could inhibit fibrotic activation of hepatic stellate cells (HSCs). This study proposes that abrogation of IL-18 signaling by boosting IL-18BP can strongly inhibit the development of MASH-induced fibrosis and our engineered IL-18BP biologics can become promising therapeutic candidate for curing MASH.
2024-10-18 | GSE279496 | GEO
Project description:Effects of engineered IL-18BP on attenuation of MASH liver
| PRJNA1173146 | ENA
Project description:Comparison of longitudinal transcriptomic profiles of activated human primary hepatic stellate cells to activated human primary hepatic stellate cells that are treated with anti-fibrotic inhibitor reveals inflammatory signaling as a key pathway that is modulated during pro-fibrotic activation and repressed during attenuation of fibrotic response.
2019-12-18 | GSE117329 | GEO
Project description:Recombinant cytokines were the first modern immunotherapies to produce durable cures in metastatic cancer, but their application has been hampered by only modest efficacy and limited tolerability. Next-generation cytokine therapies are therefore under development to overcome the biological limitations of native cytokines. By analyzing single-cell transcriptomic data from tumor infiltrating lymphocytes (TIL), we found that components of the Interleukin-18 (IL-18) pathway are upregulated on activated and dysfunctional TIL, suggesting that IL-18 therapy could potentially restore anti-tumor immunity by stimulating these key effector cells. However, recombinant IL-18 therapy has consistently failed to demonstrate anti-tumor efficacy in clinical trials. Here we show that the secreted, high-affinity decoy receptor IL-18BP is frequently upregulated in the tumor microenvironment of diverse human cancers and syngeneic murine tumor models. Using directed evolution, we engineered a ‘decoy-resistant’ IL-18 (DR-18), which maintains signaling potential, but is impervious to binding and inhibition by IL-18BP. In contrast to wild-type IL-18, DR-18 exhibits potent anti-tumor efficacy as monotherapy and in combination with anti-PD-1 checkpoint immunotherapy in multiple tumor models. Mechanistically, DR-18 drives the development of poly-functional effector CD8+ T cells, decreases the prevalence of exhausted CD8+ T cells expressing the transcription factor TOX, and expands the pool of TCF1+ precursor CD8+ T cells. DR-18 also enhances NK cell activity and maturation to effectively treat anti-PD-1 resistant tumors that have lost MHC class I surface expression. Together, these results highlight the IL-18 pathway as a powerful target for immunotherapeutic intervention and implicate the secreted immune checkpoint IL-18BP as an obstacle to effective IL-18 immunotherapy.
2020-06-29 | GSE146609 | GEO
Project description:Recombinant cytokines have limited anti-cancer efficacy mostly due to narrow therapeutic window and systemic adverse effects. IL-18 is an inflammasome induced proinflammatory cytokine that enhances T and NK cell activity and stimulates IFNg production. The activity of IL-18 is naturally blocked by a high affinity endogenous binding protein (IL-18BP). IL-18BP is induced in the tumor microenvironment (TME) in response to IFNg upregulation in a negative feedback mechanism. In this study we found that IL-18 is upregulated in the TME compared to the periphery across multiple human tumors and most of it is bound to IL-18BP. Bound IL-18 levels were largely above the amount required for T cell activation in vitro, implying that releasing IL-18 in the TME could lead to potent T cell immune activation. To restore the activity of endogenous IL-18 we generated COM503, a high affinity anti-IL-18BP antibody (Ab), that blocks the IL-18BP:IL-18 interaction and displaces pre-complexed IL-18 to enhance T cell and NK cell activation. In vivo, administration of a surrogate anti-IL-18BP Ab, either alone or in combination with anti-PD-L1 Ab, resulted in significant tumor growth inhibition and increased survival across multiple mouse tumor models. Moreover, anti-IL-18BP Ab induced pronounced TME-localized immune modulation including an increase in polyfunctional non-exhausted T and NK cell numbers and activation. In contrast, no increase in inflammatory cytokines and lymphocyte numbers or activation state was observed in serum and spleen. Taken together, blocking IL-18BP using an Ab is a promising novel approach to harness cytokine biology for the treatment of cancer.
2024-03-15 | GSE239473 | GEO
Project description:Early during culture of primary mouse HSCs gene expression changes. These expression alterations can be affected by treating cells with histone deacetylase inhibitor, valproic acid Primary mouse Hepatic stellate cells were cultured for short periods of time (4-16-64h) in presence or absence of valproic acid. Gene expression analysis (mouse Gene 1.0 ST arrays according to manufacturerM-bM-^@M-^Ys manual 701880Rev4 (Affymetrix, Santa Clara, CA)), in vitro stellate cell activation and inhibition of the activation by valproic acid treatment.
2014-01-01 | E-GEOD-51882 | biostudies-arrayexpress
Project description:Gene expression of mouse hepatic stellate cells was characterized under the following conditions: Quiescent (isolated from normal mouse liver) and reverted (isolated from mouse liver treated with 4 injections of carbontetrachloride followed by 45 day rest period) Affymetrix Mouse 1.0ST gene expression measurements were used to characterize the transcriptomic basis in quiescent hepatic stellate cells, isolated from normal liver, and reverted hepatic stellate cells, isolated from liver treated with 4 injections of CCl4 followed by a 45 day rest period. Gene expression of mouse hepatic stellate cells was characterized under the following conditions: A. Quiescent control hepatic stellate cells (n=4). B. Reverted hepatic stellate cells (n=4).
2014-05-05 | E-GEOD-38648 | biostudies-arrayexpress
Project description:Transcriptomic analysis of primary human hepatic stellate cells undergoing TGFb mediated activation and JQ1 mediated attenuation of activation
| PRJNA481768 | ENA
Project description:Background & Aims: Rapid induction of beta-PDGF receptor (beta-PDGFR) is a core feature of hepatic stellate cell activation, the hallmark of liver fibrogenesis. However, biological consequences of the induction are not well characterized. We aimed to determine the involvement of beta-PDGFR-mediated molecular pathway activation on hepatic stellate cells in liver injury, fibrogenesis, and carcinogenesis in vivo. Methods: Loss and constitutive activation of beta-PDGFR were assessed in mouse models with either a stellate cell-specific beta-PDGFR knockout or the expression of an autoactivating mutation respectively. Liver injury and fibrosis were induced in two mechanistically distinct models: carbontetrachloride (CCl4) treatment and ligation of the common bile duct. Hepatocarcinogenesis with underlying liver injury/fibrosis was assessed by a single dose of diethylnitrosamine (DEN) followed by repeated injections of CCl4. Genome-wide expression profiling was performed isolated stellate cells from these models to determine deregulated pathways. Results: Depletion of beta-PDGFR in hepatic stellate cells led to decreased histological liver injury, serum transaminases, collagen alpha 1(I) and alpha smooth muscle actin expression, and collagen deposition. Stellate cell proliferation was significantly reduced after acute hepatic injury in vivo. In contrast, autoactivation of beta-PDGFR in stellate cells accelerated liver fibrosis, most prominently after 6 weeks of CCl4 induced injury. There was no difference in development of DEN-induced pre-neoplastic loci according to the status of beta-PDGFR. Conclusions: Depletion of beta-PDGFR in hepatic stellate cells attenuated the development of liver injury, fibrosis, and stellate cell proliferation in multiple animal models, whereas the constitutive activation of beta-PDGFR enhanced fibrosis. However, manipulation of beta-PDGFR alone did not reduce development of dysplastic nodules. These findings indicate that titration of receptor beta-PDGFR expression on stellate cells parallels fibrosis and injury, but may not impact the development of hepatic neoplasia alone. Hepatic stellate cells were isolated from liver of beta-PDGFR-wild-type or knockout mice, and treated with beta-PDGF ligand or vehicle control.
2015-02-19 | E-GEOD-52253 | biostudies-arrayexpress