Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Effects of engineered IL-18BP on attenuation of MASH liver

ABSTRACT: Effects of engineered IL-18BP on attenuation of MASH liver

PROVIDER: PRJNA1173146 | ENA |

REPOSITORIES: ENA

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	SRR31002258_1.fastq.gz	Fastqsanger.gz
	SRR31002258_2.fastq.gz	Fastqsanger.gz
	SRR31002259_1.fastq.gz	Fastqsanger.gz
	SRR31002259_2.fastq.gz	Fastqsanger.gz
	SRR31002260_1.fastq.gz	Fastqsanger.gz

Items per page:

1 - 5 of 16

Similar Datasets

Effects of engineered IL-18BP on attenuation of MASH liver

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

Effects of engineered IL-18BP on attenuation of hepatic stellate cell activation

2024-10-18 | GSE279499 | GEO

Effects of engineered IL-18BP on attenuation of hepatic stellate cell activation

Project description:Effects of engineered IL-18BP on attenuation of hepatic stellate cell activation

| PRJNA1173149 | ENA

Unleashing natural IL-18 activity using an anti-IL-18BP blocker antibody induces potent immune stimulation and anti-tumor effects

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

IL-18BP is a secreted immune checkpoint and barrier to effective IL-18 immunotherapy

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

IL-18BP is a secreted immune checkpoint and barrier to effective IL-18 immunotherapy

Project description:IL-18BP is a secreted immune checkpoint and barrier to effective IL-18 immunotherapy

| PRJNA611084 | ENA

Chicken IL-18BP

Project description:Molecular cloning and characterisation of chicken IL-18 binding protein

| PRJEB38516 | ENA

IL-18 engineered to avoid decoy-receptor binding enhances tumor rejection by anti-CTLA-4 in kidney cancer models through immune microenvironment remodeling.

Project description:The cytokine interleukin-18 (IL-18) has immunostimulatory effects but is negatively regulated by a secreted binding protein, IL-18BP, that limits IL-18’s anti-cancer efficacy. A “decoy-resistant” form of IL-18 (DR-18), that avoids sequestration by IL-18BP while maintaining its immunostimulatory potential has recently been developed. Here, we investigate the therapeutic potential of DR-18 in renal cell carcinoma (RCC). We used immunocompetent RCC murine models to assess the efficacy of DR-18 in combination with single- and dual-agent anti-PD-1 and anti-CTLA-4. In contrast to preclinical models of other tumor types, in RCC models DR-18 enhanced the activity of anti-CTLA-4 but not anti-PD-1 treatment. This activity correlated with intra-tumoral enrichment and clonal expansion of effector CD8+ T cells, decreased regulatory T cell levels, and enrichment of pro-inflammatory, anti-tumor myeloid cell populations, as assessed by scRNA- and scTCR-seq.

2024-11-01 | GSE279662 | GEO

Unleashing natural IL-18 activity using an anti-IL-18BP blocker antibody induces potent immune stimulation and anti-tumor effects

Project description:Unleashing natural IL-18 activity using an anti-IL-18BP blocker antibody induces potent immune stimulation and anti-tumor effects

| PRJNA999351 | ENA

RNA-seq of mouse colon tissue treated with engineered IL-22 variants

Project description:RNA-seq analysis of colon tissue from mice treated with PBS, WT IL-22, or engineered IL-22 variant 22-B3.

2021-10-26 | GSE160217 | GEO