Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Inhibition of the IL-17A axis Protects against Immune-related Adverse Events while Supporting Checkpoint Inhibitor Anti-tumor Efficacy [RNA-seq (human)]

ABSTRACT: 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+ RORt+ 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE192580 | GEO | 2023/12/31

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Inhibition of IL-17A Protects against Thyroid Immune-related Adverse Events while Preserving Checkpoint Inhibitor Anti-tumor Efficacy [RNA-seq (murine)]

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

Interleukin 21 drives CXCR6+ CD8+ T cell mediators in Autoimmune Checkpoint Inhibitor Thyroiditis

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. To delineate human IRAE pathogenesis, we sampled thyroid tissue from subjects with ICI-thyroiditis and HT. Using single cell RNA sequencing of human thyroid fine needle aspiration (FNA) specimens, we identify CXCR6+ interferon gamma (IFN)+ cytotoxic CD8+ T cells as key contributors to ICI-thyroiditis (IRAE). This is in contrast to the primary role for CD4+ Th17 cells in the pathogenesis of HT (14, 15). Interestingly, we also found a supporting role for IL21-producing CD4+ T follicular (Tfh) and peripheral helper (Tph) cells via the upregulation of CXCR6 and cytotoxic function in CD8+ T cells.

2023-05-17 | GSE218743 | GEO

The cytokine IL-17A limits Th17 pathogenicity via a negative feedback loop driven by autocrine induction of IL-24

Project description:Dysregulated Th17 cell responses underlie multiple inflammatory and autoimmune diseases, including autoimmune uveitis and its animal model, EAU. However, clinical trials targeting IL-17A in uveitis were not successful. Here, we found that Th17 cells were regulated by their own signature cytokine, IL-17A. Loss of IL-17A in autopathogenic Th17 cells did not reduce their pathogenicity and instead elevated their expression of the Th17 cell cytokines GM-CSF and IL-17F. Mechanistic in vitro studies revealed a Th17 cell-intrinsic autocrine loop triggered by binding of IL-17A to its receptor, leading to activation of transcription factor NFκB and induction of IL 24, which repressed the Th17 cytokine program. In vivo, IL-24 treatment ameliorated Th17-induced EAU, whereas silencing of IL-24 in Th17 cells enhanced disease. This regulatory pathway also operated in human Th17 cells. Thus, IL-17A limits pathogenicity of Th17 cells by inducing IL-24. These findings may explain the disappointing therapeutic effect in targeting IL-17A in uveitis.

2020-07-22 | GSE152534 | GEO

Single-cell genomics segregate different transcriptomic impacts of anti-IL-17A blockade on type 17 T-cells and regulatory immune cells in psoriasis skin

Project description:Durable psoriasis improvement has been reported in a subset of psoriasis patients after treatment withdrawal of biologics blocking IL-23/Type 17 T-cell (T17) autoimmune axis. However, it is not well understood if systemic blockade of the IL-23/T17 axis promotes immune tolerance in psoriasis skin. The purpose of the study was to find translational evidence that systemic IL-17A blockade promotes regulatory transcriptome modification in human psoriasis skin immune cell subsets. We analyzed human psoriasis lesional skin 6 mm punch biopsy tissues before and after systemic IL-17A blockade using the muti-genomics approach integrating immune cell-enriched scRNA-seq (n = 18), microarray (n = 61), and immunohistochemistry (n = 61) with repository normal control skin immune cell-enriched scRNA-seq (n = 10) and microarray (n = 8) data. For the T17 axis transcriptome, systemic IL-17A blockade depleted 100% of IL17A + T-cells and 95% of IL17F + T-cells in psoriasis skin. The expression of IL23A in DC subsets was also downregulated by IL-17A blockade. The expression of IL-17-driven inflammatory mediators (IL36G, S100A8, DEFB4A, and DEFB4B) in suprabasal keratinocytes was correlated with psoriasis severity and was downregulated by IL-17A blockade. For the regulatory DC transcriptome, the proportion of regulatory semimature DCs expressing regulatory DC markers of BDCA-3 (THBD) and DCIR (CLEC4A) was increased in posttreatment psoriasis lesional skin compared to pretreatment psoriasis lesional skin. In addition, IL-17A blockade induced higher expression of CD1C and CD14, which are markers of CD1c+ CD14+ dendritic cell (DC) subset that suppresses antigen-specific T-cell responses, in posttreatment regulatory semimature DCs compared to pretreatment regulatory semimature DCs. In conclusion, systemic IL-17A inhibition not only blocks the entire IL-23/T17 cell axis but also promotes regulatory gene expression in regulatory DCs in human psoriasis skin.

2023-09-04 | GSE183047 | GEO

Gene Expression Profiling of IL-17A-treated Synovial Fibroblasts from the Human Temporomandibular Joint

Project description:Synovial fibroblasts contribute to the inflammatory temporomandibular joint under pathogenic stimuli. Synovial fibroblasts and T cells participate in the perpetuation of joint inflammation in a mutual activation feedback, via secretion of cytokines and chemokines that stimulate each other. IL-17 is an inflammatory cytokine produced primarily by Th17 cells that plays critical roles in the pathogenesis of numerous autoimmune and inflammatory diseases. Here, we investigated the roles of IL-17A in temporomandibular joint disorders (TMD) by using genome-wide analysis of synovial fibroblasts isolated from patients with TMD. We analyzed the gene expression profiles of synovial fibroblasts that were treated with or without IL-17A. IL-17 induced gene expression in synovial fibroblasts from human temporomandibular joint was measured at 4 hours after treated with IL-17A (10 ng/ml) and untreated control samples. This experiment used one donor sample.

2015-11-05 | E-GEOD-74668 | biostudies-arrayexpress

CMTM4 is a subunit of the IL-17 receptor and mediates autoimmune pathology

Project description:Interleukin-17A (IL-17A) is a key mediator of protective immunity to yeast and bacterial infections but also drives the pathogenesis of several autoimmune diseases, such as psoriasis or psoriatic arthritis. Here, we show that the tetra-transmembrane protein CMTM4 is a subunit of the IL-17 receptor (IL-17R). CMTM4 constitutively associated with IL-17R subunit C (IL-17RC) to mediate its stability, posttranslational modification, and plasma membrane localization. Both mouse and human cell lines deficient in CMTM4 were largely unresponsive to IL-17A, due to their inability to assemble the IL-17 receptor signaling complex. Accordingly, CMTM4-deficient mice were largely resistant to experimental psoriasis. Collectively, our data identified CMTM4 as an essential component of the IL-17 receptor and a potential therapeutic target for treating IL-17-mediated autoimmune diseases.

2022-12-02 | PXD036366 | Pride

Multiomics analysis of immune-related adverse events in melanoma patients treated with immune checkpoint inhibitors

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

Role of PIP5K1a in human Th17 gene expression

Project description:This data was performed as part of Revu et al, "Human IL-17A protein expression is controlled through a PIP5K1a-dependent ARS2 checkpoint". IL-17 secreted by TH17 cells is beneficial for microbial control, but causes inflammation and pathological tissue remodeling in autoimmunity. Hence TH17 differentiation and IL-17 production must be tightly regulated, but to date this has been defined only in terms of transcriptional control. Phosphatidyinositols are second messengers activated during T cell activation that transduce signals from the TCR and costimulatory receptors at the cell membrane. Here we show phosphatidylinositol(4,5)bisphosphate (PIP2) was unexpectedly enriched in the nucleus of human TH17 cells, dependent on the kinase PIP5K1, and that blockade of PIP5K1 impaired IL-17A production. In contrast, nuclear PIP2 enrichment was not observed in Th1 or Th2 cells and these subsets did not require PIP5K1 for cytokine production. In multiple sclerosis patient T cells, IL-17 production elicited by myelin basic protein could be inhibited by PIP5K1 blockade. Surprisingly, PIP5K1 blockade did not alter IL17A mRNA levels or stability in TH17 cells. Instead, analysis of PIP5K1-interacting proteins revealed that PIP5K1 targets ARS2, a nuclear cap binding complex scaffold protein, to facilitate ARS2 binding to IL17A mRNA and subsequent IL-17 protein expression, uncovering a new mechanism for regulating IL-17A protein production and suggesting a novel mechanism of translation control of cytokines.

2023-05-15 | GSE232436 | GEO

T cell characteristics associated with toxicity to immune checkpoint blockade in patients with melanoma [BCR and TCR scRNA-Seq]

Project description:Severe immune-related adverse events (irAEs) occur in up to 60% of melanoma patients treated with immune checkpoint inhibitors (ICIs). However, it remains unknown whether a common baseline immunological state precedes irAE development. Leveraging CyTOF, single-cell RNA sequencing, bulk RNA sequencing, and T cell receptor sequencing to analyze pretreatment blood from metastatic melanoma patients treated with ICIs, we investigated cellular factors associated with severe irAE development regardless of organ system involvement. Our results demonstrate circulating T cell characteristics associated with ICI-induced toxicity, with implications for improved diagnostics and clinical management.

2022-01-13 | GSE189126 | GEO

T cell characteristics associated with toxicity to immune checkpoint blockade in patients with melanoma [scRNA-Seq]

2022-01-13 | GSE189125 | GEO