Inhibition of the IL-17A axis Protects against Immune-related Adverse Events while Supporting Checkpoint Inhibitor Anti-tumor Efficacy [RNA-seq (human)]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA792136 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17327527.fastq.gz | Fastqsanger.gz | |||
| SRR17327528_1.fastq.gz | Fastqsanger.gz | |||
| SRR17327528_2.fastq.gz | Fastqsanger.gz | |||
| SRR17327529_1.fastq.gz | Fastqsanger.gz | |||
| SRR17327529_2.fastq.gz | Fastqsanger.gz |
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Project description:Checkpoint inhibitor (ICI) immunotherapy leverages the body’s own immune system to attack cancer cells but leads to unwanted autoimmune side effects in up to 60% of patients. Such immune related adverse events (IrAE) lead to treatment interruption, permanent organ dysfunction, hospitalization and premature death. Thyroiditis is one of the most common IrAE, but the cause of thyroid IrAE remains unknown. Here we present a novel mouse model in which checkpoint inhibitor therapy leads to multi-organ autoimmune infiltrates and show that activation and infiltration of Type 3 immune cells including IL17A+ RORt+ CD4+ (T helper 17 or Th17) and gamma delta 17 (T17) T cells promote thyroid IrAE development. In parallel, Th17 and T17 cells were similarly expanded in cancer patients treated with ICI. Furthermore, antibody-based inhibition of IL-17A, a clinically available therapy, significantly reduced thyroid IrAE development in ICI-treated mice. Finally, combination of IL-17A neutralization with ICI treatment in a mouse tumor model did not reduce ICI anti-tumor efficacy and indeed showed a trend toward enhancement. These studies suggest that targeting Th17 and 17 function may reduce IrAE without impairing ICI anti-tumor efficacy and may be a generalizable strategy to address IL17-mediated IrAE.
2023-12-31 | GSE192580 | GEO
Project description:Checkpoint inhibitor (ICI) immunotherapy leverages the body’s own immune system to attack cancer cells but leads to unwanted autoimmune side effects in up to 60% of patients. Such immune related adverse events (IrAE) lead to treatment interruption, permanent organ dysfunction, hospitalization and premature death. Thyroiditis is one of the most common IrAE, but the cause of thyroid IrAE remains unknown. Here we present a novel mouse model in which checkpoint inhibitor therapy leads to multi-organ autoimmune infiltrates and show that activation and infiltration of Type 3 immune cells including IL17A+ RORgt+ CD4+ (T helper 17 or Th17) and gamma delta 17 (gdT17) T cells promote thyroid IrAE development. In parallel, Th17 and gdT17 cells were similarly expanded in cancer patients treated with ICI. Furthermore, antibody-based inhibition of IL-17A, a clinically available therapy, significantly reduced thyroid IrAE development in ICI-treated mice. Finally, combination of IL-17A neutralization with ICI treatment in a mouse tumor model did not reduce ICI anti-tumor efficacy and indeed showed a trend toward enhancement. These studies suggest that targeting Th17 and gd17 function may reduce IrAE without impairing ICI anti-tumor efficacy and may be a generalizable strategy to address IL17-mediated IrAE.
2022-11-21 | GSE176561 | GEO
Project description:Inhibition of IL-17A Protects against Thyroid Immune-related Adverse Events while Preserving Checkpoint Inhibitor Anti-tumor Efficacy [RNA-seq (murine)]
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Project description:Blood platelets destined for transfusion release panoply of molecules during preparation and storage. The leukoreduction process made the transfusion safer but did not completely abolish the adverse events. The rationale is to study the proteome profile of platelet components SDA-PC (platelet pellets) involved in transfusion adverse events.
2019-02-13 | PXD008886 | Pride
Project description:Blood platelets destined for transfusion release panoply of molecules during preparation and storage. The leukoreduction process made the transfusion safer but did not completely abolish the adverse events. The rationale is to study the proteome profile of platelet components PPC (platelet pellets) involved in transfusion adverse events.
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Project description:Immune checkpoint inhibitors (ICIs) are a standard-of-care for the treatment of advanced melanoma, but their use is limited by immune-related adverse events (irAEs). Proteomic analysis and multiplex cytokine/chemokine assay from serum at baseline and at irAEs onset in 82 patients indicated aberrant T-cell activity with differential expression of Type I and III immune signatures. This was in line with an increase in the proportions of monocytes and decrease of IL-17A producing CD4+ T-cells in the peripheral blood in single cell RNA sequencing. Multiplex immunohistochemistry on ICI-induced skin rash and inflamed colon showed increase in the proportion of CD4+ T-cells with IL-17A expression. Anti-IL17A antagonistic mAbs were administered in two patients with severe myocarditis, colitis and skin rash with resolution of the irAE. This study demonstrates the potential role of Type III CD4+ T-cells in the irAEs development and provides proof-of-principle evidence to support a clinical trial examining anti-IL17A in their management.
2023-12-01 | GSE227001 | GEO
Project description:Immune checkpoint inhibitor (ICI) immunotherapy leverages the body's own immune system to attack cancer cells but leads to unwanted autoimmune side effects in up to 60% of patients. Such immune-related adverse events (IrAEs) may lead to treatment interruption, permanent organ dysfunction, hospitalization, and premature death. Thyroiditis is one of the most common IrAEs, but the cause of thyroid IrAEs remains unknown. In this study, we use a new, physiologically relevant mouse model of ICI-associated autoimmunity to identify a key role for type 3 immune cells in the development of thyroid IrAEs. Multiple lineages of IL-17A-producing T cells expand in thyroid tissue with ICI treatment. Intrathyroidal IL-17A-producing innate-like γδT17 cells were increased in tumor-free mice, whereas adaptive Th17 cells were also prominent in tumor-bearing mice, following ICI treatment. Furthermore, Ab-based inhibition of IL-17A, a clinically available therapy, significantly reduced thyroid IrAE development in ICI-treated mice with and without tumor challenge. Finally, combination of IL-17A neutralization with ICI treatment in multiple tumor models did not reduce ICI antitumor efficacy. These studies suggest that targeting Th17 and γδT17 cell function via the IL-17A axis may reduce IrAEs without impairing ICI antitumor efficacy and may be a generalizable strategy to address type 3 immune-mediated IrAEs.
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Project description:Transcriptomic-based functional characterization of adverse events following lymphatic filariasis treatment
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Project description:IL-17A is a pro-inflammatory cytokine that promotes host defense against infections and contributes to the pathogenesis of chronic inflammatory diseases. Dendritic cells (DC) are antigen-presenting cells responsible for adaptive immune responses. Here, we report that IL-17A induces intense remodeling of lipid metabolism in human monocyte-derived DC, as revealed by microarrays analysis. In particular NR1H3/LXR-a and its target genes were significantly upregulated in response to IL-17A. IL-17A induced accumulation of Oil Red O-positive lipid droplets in DC leading to the generation of lipid-laden DC. A lipidomic study established that all the analyzed lipid species, i.e phospholipids, cholesterol, triglycerides, cholesteryl esters were elevated in IL-17A-treated DC. The increased expression of membrane lipid transporters in IL-17A-treated DC as well as their enhanced ability to uptake the fatty acid Bodipy-FL-C16 suggested that lipid uptake was the main mechanism responsible for lipid accumulation in response to IL-17A. IL-17A-induced lipid laden DC were able to stimulate allogeneic T cell proliferation in vitro as efficiently as untreated DC, indicating that IL-17A-treated DC are potently immunogenic. This study, encompassed in the field of immunometabolism, points out for the first time IL-17A as a modulator of lipid metabolism in DC and provides a rationale to delineate the importance of lipid-laden DC in IL-17A-related inflammatory diseases. We used microarrays analysis to understand the impact of IL-17A on human monocyte-derived human dendritic cells. We found overexpression of many genes involved in lipid metabolism in IL-17A-treated dendritic cells compared to untreated dendritic cells. In particular NR1H3/LXR-a and its target genes were significantly upregulated in response to IL-17A. IL-17A induced accumulation of Oil Red O-positive lipid droplets in DC leading to the generation of lipid-laden DC. A lipidomic study established that all the analyzed lipid species, i.e phospholipids, cholesterol, triglycerides, cholesteryl esters were elevated in IL-17A-treated DC. The increased expression of membrane lipid transporters in IL-17A-treated DC as well as their enhanced ability to uptake the fatty acid Bodipy-FL-C16 suggested that lipid uptake was the main mechanism responsible for lipid accumulation in response to IL-17A. IL-17A-induced lipid laden DC were able to stimulate allogeneic T cell proliferation in vitro as efficiently as untreated DC, indicating that IL-17A-treated DC are potently immunogenic. This study, encompassed in the field of immunometabolism, points out for the first time IL-17A as a modulator of lipid metabolism in DC and provides a rationale to delineate the importance of lipid-laden DC in IL-17A-related inflammatory diseases. RNA was extracted from untreated in vitro-generated DC at day 0 (DC, 4 biological replicates ) or DC cultured for 12 days with IL-17A, in the absence or presence of IFN-g (DC-17 and DC-G17, 5 biological replicates)
2015-03-31 | E-GEOD-53163 | biostudies-arrayexpress
Project description:IL-17A is a pro-inflammatory cytokine that promotes host defense against infections and contributes to the pathogenesis of chronic inflammatory diseases. Dendritic cells (DC) are antigen-presenting cells responsible for adaptive immune responses. Here, we report that IL-17A induces intense remodeling of lipid metabolism in human monocyte-derived DC, as revealed by microarrays analysis. In particular NR1H3/LXR-a and its target genes were significantly upregulated in response to IL-17A. IL-17A induced accumulation of Oil Red O-positive lipid droplets in DC leading to the generation of lipid-laden DC. A lipidomic study established that all the analyzed lipid species, i.e phospholipids, cholesterol, triglycerides, cholesteryl esters were elevated in IL-17A-treated DC. The increased expression of membrane lipid transporters in IL-17A-treated DC as well as their enhanced ability to uptake the fatty acid Bodipy-FL-C16 suggested that lipid uptake was the main mechanism responsible for lipid accumulation in response to IL-17A. IL-17A-induced lipid laden DC were able to stimulate allogeneic T cell proliferation in vitro as efficiently as untreated DC, indicating that IL-17A-treated DC are potently immunogenic. This study, encompassed in the field of immunometabolism, points out for the first time IL-17A as a modulator of lipid metabolism in DC and provides a rationale to delineate the importance of lipid-laden DC in IL-17A-related inflammatory diseases. We used microarrays analysis to understand the impact of IL-17A on human monocyte-derived human dendritic cells. We found overexpression of many genes involved in lipid metabolism in IL-17A-treated dendritic cells compared to untreated dendritic cells. In particular NR1H3/LXR-a and its target genes were significantly upregulated in response to IL-17A. IL-17A induced accumulation of Oil Red O-positive lipid droplets in DC leading to the generation of lipid-laden DC. A lipidomic study established that all the analyzed lipid species, i.e phospholipids, cholesterol, triglycerides, cholesteryl esters were elevated in IL-17A-treated DC. The increased expression of membrane lipid transporters in IL-17A-treated DC as well as their enhanced ability to uptake the fatty acid Bodipy-FL-C16 suggested that lipid uptake was the main mechanism responsible for lipid accumulation in response to IL-17A. IL-17A-induced lipid laden DC were able to stimulate allogeneic T cell proliferation in vitro as efficiently as untreated DC, indicating that IL-17A-treated DC are potently immunogenic. This study, encompassed in the field of immunometabolism, points out for the first time IL-17A as a modulator of lipid metabolism in DC and provides a rationale to delineate the importance of lipid-laden DC in IL-17A-related inflammatory diseases.
2015-03-31 | GSE53163 | GEO