IL-18BP is a secreted immune checkpoint and barrier to effective IL-18 immunotherapy
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA611084 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11266557_1.fastq.gz | Fastqsanger.gz | |||
| SRR11266557_2.fastq.gz | Fastqsanger.gz | |||
| SRR11266558_1.fastq.gz | Fastqsanger.gz | |||
| SRR11266558_2.fastq.gz | Fastqsanger.gz | |||
| SRR11266559_1.fastq.gz | Fastqsanger.gz |
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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:Cytokines were the first modern immunotherapies to produce durable responses in patients with advanced cancer, but they have only modest efficacy and limited tolerability1,2. In an effort to identify alternative cytokine pathways for immunotherapy, we found that components of the interleukin-18 (IL-18) pathway are upregulated on tumour-infiltrating lymphocytes, suggesting that IL-18 therapy could enhance anti-tumour immunity. However, recombinant IL-18 previously did not demonstrate efficacy in clinical trials3. Here we show that IL-18BP, a high-affinity IL-18 decoy receptor, is frequently upregulated in diverse human and mouse tumours and limits the anti-tumour activity of IL-18 in mice. Using directed evolution, we engineered a 'decoy-resistant' IL-18 (DR-18) that maintains signalling potential but is impervious to inhibition by IL-18BP. Unlike wild-type IL-18, DR-18 exerted potent anti-tumour effects in mouse tumour models by promoting the development of poly-functional effector CD8+ T cells, decreasing the prevalence of exhausted CD8+ T cells that express the transcriptional regulator of exhaustion TOX, and expanding the pool of stem-like TCF1+ precursor CD8+ T cells. DR-18 also enhanced the activity and maturation of natural killer cells to effectively treat anti-PD-1 resistant tumours that have lost surface expression of major histocompatibility complex class I molecules. These results highlight the potential of the IL-18 pathway for immunotherapeutic intervention and implicate IL-18BP as a major therapeutic barrier.
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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: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: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
Project description:Effects of engineered IL-18BP on attenuation of MASH liver
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Project description:Unleashing natural IL-18 activity using an anti-IL-18BP blocker antibody induces potent immune stimulation and anti-tumor effects
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Project description:IL-18 has been found to be associated with eczema. However, little is known of the role of IL-18 binding protein (BP) and IL-18 receptor (R) in eczema. We therefore investigated the expression of IL-18, IL-18BP, and IL-18R on mast cells by using flow cytometry analysis and mouse eczema model. The results showed that plasma free IL-18 and free IL-18BP levels in eczema patients were higher than those in healthy controls. IL-18 provoked up to 3.1-fold increase in skin mast cells. IL-18 induced also an increase in IL-18BP+ mast cells, but a reduction of IL-18R+ mast cells in mouse eczema skin. It was found that house dust mite allergen Der p1 and egg allergen OVA induced upregulation of the expression of IL-18, IL-18BP, and IL-18R mRNAs in HMC-1 cells following 2 and 16 h incubation. In conclusion, correlation of IL-18 and IL-18BP in eczema plasma suggests an important balance between IL-18 and IL-18BP in eczema. The decrease in molar concentration ratio of plasma IL-18BP/IL-18 and allergen-induced upregulated expression of IL-18 and IL-18R in skin mast cells of the patients with eczema suggests that anti-IL-18 including IL-18BP therapy may be useful for the treatment of eczema.
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Project description:Effects of engineered IL-18BP on attenuation of hepatic stellate cell activation
| PRJNA1173149 | ENA