Dual blockade of IL-4 and IL-13 with dupilumab, an IL-4Ra antibody, is required to broadly inhibit type 2 inflammation
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ABSTRACT:
PROVIDER: PRJNA591357 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| SRR10523200.fastq.gz | Fastqsanger.gz | |||
| SRR10523201.fastq.gz | Fastqsanger.gz | |||
| SRR10523202.fastq.gz | Fastqsanger.gz | |||
| SRR10523203.fastq.gz | Fastqsanger.gz | |||
| SRR10523204.fastq.gz | Fastqsanger.gz |
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Project description:Background: Dupilumab, a fully human monoclonal antibody that binds IL-4Ra and inhibits signaling of both IL-4 and IL-13, has shown efficacy across multiple diseases with underlying type 2 signatures and is approved for treatment of asthma, atopic dermatitis and chronic sinusitis with nasal polyposis. We sought to provide a comprehensive analysis of the redundant and distinct roles of IL-4 and IL-13 in type 2 inflammation and report dupilumab mechanisms of action. Methods: Using primary cell assays and a mouse model of house dust mite induced asthma, we compared IL-4 versus IL-13 versus IL-4Ra blockers. Results: Intranasal administration of either IL-4 or IL-13 confers an asthma-like phenotype in mice by inducing immune cell lung infiltration, including eosinophils, increasing cytokine/chemokine expression and mucus production, thus demonstrating redundant functions of these cytokines. We further teased out their respective contributions using human in vitro culture systems. Then, in a mouse asthma model by comparing in head to head studies, either IL-4 or IL-13 inhibition to dual IL-4/IL-13 inhibition, we demonstrate that blockade of both IL-4 and IL-13 is required to broadly block type 2 inflammation, which translates to protection from allergen-induced lung function impairment. Notably, only dual IL-4/IL-13 blockade prevented eosinophil infiltration into lung tissue without affecting circulating eosinophils, demonstrating that tissue, but not circulating eosinophils contribute to disease pathology. Conclusions: Overall, these data support IL-4 and IL-13 as key drivers of type 2 inflammation, and help provide insight into the therapeutic mechanism of dupilumab, a dual IL-4/IL-13 blocker, in multiple type 2 diseases.
2019-11-25 | GSE140900 | GEO
Project description:BackgroundDupilumab, a fully human monoclonal antibody that binds IL-4Rα and inhibits signaling of both IL-4 and IL-13, has shown efficacy across multiple diseases with underlying type 2 signatures and is approved for treatment of asthma, atopic dermatitis, and chronic sinusitis with nasal polyposis. We sought to provide a comprehensive analysis of the redundant and distinct roles of IL-4 and IL-13 in type 2 inflammation and report dupilumab mechanisms of action.MethodsUsing primary cell assays and a mouse model of house dust mite-induced asthma, we compared IL-4 vs IL-13 vs IL-4Rα blockers.ResultsIntranasal administration of either IL-4 or IL-13 confers an asthma-like phenotype in mice by inducing immune cell lung infiltration, including eosinophils, increasing cytokine/chemokine expression and mucus production, thus demonstrating redundant functions of these cytokines. We further teased out their respective contributions using human in vitro culture systems. Then, in a mouse asthma model by comparing in head-to-head studies, either IL-4 or IL-13 inhibition to dual IL-4/IL-13 inhibition, we demonstrate that blockade of both IL-4 and IL-13 is required to broadly block type 2 inflammation, which translates to protection from allergen-induced lung function impairment. Notably, only dual IL-4/IL-13 blockade prevented eosinophil infiltration into lung tissue without affecting circulating eosinophils, demonstrating that tissue, but not circulating eosinophils, contributes to disease pathology.ConclusionsOverall, these data support IL-4 and IL-13 as key drivers of type 2 inflammation and help provide insight into the therapeutic mechanism of dupilumab, a dual IL-4/IL-13 blocker, in multiple type 2 diseases.
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Project description:Here, we report a case of atopic dermatitis (AD) in a patient who received biweekly doses of dupilumab, an antibody against the IL-4 receptor α chain (IL-4Rα). Single cell RNA-sequencing showed that naïve B cells expressed the highest levels of IL4R compared to other B cell subpopulations. Compared to controls, the dupilumab-treated patient exhibited diminished percentages of IL4R+IGHD+ naïve B cells and down-regulation of IL4R, FCER2 (CD23), and IGHD. Dupilumab treatment resulted in upregulation of genes associated with apoptosis and inhibition of B cell receptor signaling and down-regulation of class-switch and memory B cell development genes. The dupilumab-treated patient exhibited a rapid decline in COVID-19 anti-spike and anti-receptor binding domain antibodies between 4 and 8 and 11 months post COVID-19 vaccination. Our data suggest that intact and persistent IL-4 signaling is necessary for maintaining robust survival and development of naïve B cells, and maintaining a long term vaccine response.
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Project description:Atopic dermatitis (AD) is the most common inflammatory skin disease, with high unmet need for new therapies that are safe for chronic use. Emerging data suggest that TH2-cytokines play important roles in a variety of allergic and atopic conditions, including asthma and AD. In early phase clinical trials, dupilumab (a fully human monoclonal antibody against IL-4R? that potently blocks IL-4 and IL-13 signaling) rapidly and markedly improved clinical measures in adults with either asthma (with elevated eosinophil counts) or moderate-to-severe AD. The pathomechanisms that may be impacted by IL-4/13 blockade in these disease settings have not yet been characterized in detail. Transcriptome analyses in pre- and post-treatment skin biopsies from patients with moderate-to-severe AD treated with dupilumab or placebo in two completed clinical trials 18 Patients with AD treated with dupilumab or placebo. 28 biopsies in lesional (LS) Skin (16 pre-treatment and 12 post-treatment). 12 biopsies in non-lesional (NL) Skin (7 pre-treatment and 5 post treatment)
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Project description:Atopic dermatitis (AD) is the most common inflammatory skin disease, with high unmet need for new therapies that are safe for chronic use. Emerging data suggest that TH2-cytokines play important roles in a variety of allergic and atopic conditions, including asthma and AD. In early phase clinical trials, dupilumab (a fully human monoclonal antibody against IL-4Rα that potently blocks IL-4 and IL-13 signaling) rapidly and markedly improved clinical measures in adults with either asthma (with elevated eosinophil counts) or moderate-to-severe AD. The pathomechanisms that may be impacted by IL-4/13 blockade in these disease settings have not yet been characterized in detail. Transcriptome analyses in pre- and post-treatment skin biopsies from patients with moderate-to-severe AD treated with dupilumab or placebo in two completed clinical trials
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Project description:Regulatory T cells (Treg) can impede anti-tumor immunity and currently represent a major obstacle to effective cancer immunotherapy. Targeting tumor-infiltrating regulatory Treg while sparing systemic Treg represent optimal approaches to this problem. Here, we provide evidence that the interleukin 23 receptor (IL23R) expressed by tumor-infiltrating Treg promotes suppressive activity. Disruption of the IL23R results in increased responsiveness of destabilized Treg to the IL-12 cytokine, production of g-interferon (IFNg) and recruitment of CD8 T cells that inhibit tumor growth. Since the Treg destabilization pathway that is initiated by IL23R blockade is distinct and independent from the destabilization pathway coupled to Glucocorticoid-Induced TNFR-Related protein (GITR) activation, we examined the impact of coordinate induction of the two destabilization pathways on anti-tumor immune responses. Combined GITR and IL23R antibody treatment of mice inoculated with MC38 tumors resulted in robust and synergistic anti-tumor responses. These findings indicate that delineation of independent Treg destabilization pathways may allow improved approaches to the development of combination immunotherapy for cancers.
2022-05-02 | GSE197287 | GEO
Project description:Myeloid cells, in particular monocytes and macrophages, are well-described to suppress the antitumor immune response. However, the molecular mechanisms controlling immunosuppressive myeloid cell states are ill- defined, hampering the development of myeloid-targeted therapies for cancer1,2. Here, we transcriptionally profiled over 500,000 tumor infiltrating leukocytes in non-small cell lung cancer (NSCLC) patients and in the KrasG12DTp53-/- (KP) murine lung adenocarcinoma model. In both species, the Type 2 cytokine IL-4 was predicted to be the primary driver of tumor infiltrating monocyte-derived macrophage (mo-mac) phenotype, despite the fact that lung tumors were largely devoid of IL-4 producing cells. Using a panel of conditional knockout mice, we found that only deletion of IL-4Ra within early myeloid progenitors in bone marrow (BM) reduced lung tumor burden, while deletion of this receptor in downstream mature myeloid cells had no effect. Detailed transcriptional analysis followed by mechanistic studies in vivo revealed an essential role for local BM IL-4 signaling in reprograming myelopoiesis in cancer. Mechanistically, basophils and eosinophils within BM upregulated IL4 production upon sensing distal tumor cues; local BM IL-4 acted on granulocyte-monocyte progenitors to transcriptionally program the development of immunosuppressive myeloid cells, which then homed to the tumor and promoted tumor growth. Consequentially, specific depletion of basophils, which were enriched in BM but absent from the tumor, profoundly reduced tumor burden and normalized myelopoiesis in experimental lung tumors. Prompted by these results, we designed and initiated the first clinical trial of dupilumab, a humanized IL- 4Ra blocking antibody commonly used for atopic disease, given in conjunction with PD-(L)1 blockade in relapsed/refractory NSCLC patients who had progressed on standard chemoimmunotherapy combinations. Consistent with our preclinical mouse data, dupilumab drove a reduction in circulating monocytes. This was coupled with an expansion of circulating and tumor-infiltrating CD8 T cells. Notably, one out of the six patients who enrolled in Phase 1b of this trial exhibited significant decrease in his tumor burden after two months of dupilumab treatment, and the clinical response deepened further to a near complete response even after cessation of dupilumab, suggestive of successful reprogramming of the antitumor response. Collectively, our study defines a role for IL-4 signaling in lung tumor progression, identifies a central axis controlling immunosuppressive myelopoiesis in cancer, and highlights a novel combination therapy for immune checkpoint blockade in humans.
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