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Degradation of Ikaros prevents epigenetic progression of T cell exhaustion in novel antigen-specific assay

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE244184 | GEO | 2024/09/02

REPOSITORIES: GEO

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Degradation of Ikaros prevents epigenetic progression of T cell exhaustion in novel antigen-specific assay [scRNA-seq]

Project description:Epigenetic regulation drives the differentiation of T cells into phenotypically stable subsets including a dysfunctional state termed exhaustion, the presence of these epigenetically distinct T cells in tumors make them non-responsive to checkpoint blockade. Cancer immunotherapies restoring T cell function have transformed cancer treatment by preventing immune evasion of tumor cells allowed by T cell exhaustion. However, some patients develop resistance to immunotherapy or do not respond. Recent literature has demonstrated that epigenetic regulation governs the transition from effector to exhausted T cells. Here, we describe a novel antigen-specific assay for T-cell exhaustion that produces T cells biologically and epigenetically similar to their in vivo exhausted counterpart. We perform a CRISPR KO screen for epigenetic regulators of the human genome and validate Ikaros as a driver of T-cell exhaustion. We determined that the Ikaros degrader iberdomide prevents exhaustion by blocking chromatin remodeling at T cell effector enhancers by preserving activity of key transcription factors AP-1, NF-κB and NFAT using transcription factor footprinting analysis. Thus, our study uncovers a role for Ikaros, degraded by the drug iberdomide, as a driver of T-cell exhaustion.

2024-09-02 | GSE244180 | GEO

Degradation of Ikaros prevents epigenetic progression of T cell exhaustion in novel antigen-specific assay [scATAC-seq]

2024-09-02 | GSE244162 | GEO

Degradation of Ikaros prevents epigenetic progression of T cell exhaustion in novel antigen-specific assay [bulk ATAC-seq]

2024-09-02 | GSE244183 | GEO

Degradation of IKZF1 prevents epigenetic progression of T cell exhaustion in an antigen-specific assay.

Project description:In cancer, chronic antigen stimulation drives effector T cells to exhaustion, limiting the efficacy of T cell therapies. Recent studies have demonstrated that epigenetic rewiring governs the transition of T cells from effector to exhausted states and makes a subset of exhausted T cells non-responsive to PD1 checkpoint blockade. Here, we describe an antigen-specific assay for T cell exhaustion that generates T cells phenotypically and transcriptionally similar to those found in human tumors. We perform a screen of human epigenetic regulators, identifying IKZF1 as a driver of T cell exhaustion. We determine that the IKZF1 degrader iberdomide prevents exhaustion by blocking chromatin remodeling at T cell effector enhancers and preserving the binding of AP-1, NF-κB, and NFAT. Thus, our study uncovers a role for IKZF1 as a driver of T cell exhaustion through epigenetic modulation, providing a rationale for the use of iberdomide in solid tumors to prevent T cell exhaustion.

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Degradation of Ikaros prevents epigenetic progression of T cell exhaustion in novel antigen-specific assay

Project description:Degradation of Ikaros prevents epigenetic progression of T cell exhaustion in novel antigen-specific assay

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Degradation of Ikaros prevents epigenetic progression of T cell exhaustion in novel antigen-specific assay [scATAC-seq]

Project description:Degradation of Ikaros prevents epigenetic progression of T cell exhaustion in novel antigen-specific assay [scATAC-seq]

| PRJNA1021606 | ENA

Degradation of Ikaros prevents epigenetic progression of T cell exhaustion in novel antigen-specific assay [scRNA-seq]

Project description:Degradation of Ikaros prevents epigenetic progression of T cell exhaustion in novel antigen-specific assay [scRNA-seq]

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Degradation of Ikaros prevents epigenetic progression of T cell exhaustion in novel antigen-specific assay [bulk ATAC-seq]

Project description:Degradation of Ikaros prevents epigenetic progression of T cell exhaustion in novel antigen-specific assay [bulk ATAC-seq]

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Targeting USP8 inhibits Cancer Progression and Prevents EV-TβRII-Induced Exhaustion of CD8+ T cells

Project description:TGF-β signalling is a key player in tumor progression, immune evasion, and poor response to cancer immunotherapies. Here, we identified USP8 as a metastasis enhancer and a highly active deubiquitinase in aggressive breast tumors. USP8 acts as a cancer stemness-promoting factor that also mediates the activation of the TGF-β/SMAD signalling pathway. USP8 directly deubiquitinates and stabilises TβRII, increasing its expression in the plasma membrane and in tumor-derived extracellular vesicles (TEVs). Frequent gain of USP8 function was observed in patients resistant to neoadjuvant chemotherapies. USP8 promotes TGF-β/SMAD-induced epithelial to mesenchymal transition (EMT), invasion, and metastasis in tumor cells, and meanwhile, USP8 enables the TβRII+ circulating extracellular vesicles (crEVs) induce T-cell-exhaustion and chemoimmunotherapy resistance. Pharmacological inhibition of USP8 antagonises TGF-β/SMAD signalling and effectively reduces TβRII stability and the number of TβRII+ crEVs, thereby preventing CD8+ T cell exhaustion and reactivating anti-tumor immunity. Our findings not only identified a novel mechanism whereby USP8 regulates the cancer microenvironment, but also demonstrated the therapeutic advantages of engineering USP8 inhibitors to simultaneously suppress metastasis and improve the efficacy of cancer immunotherapy.

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Itaconate promotes hepatocellular carcinoma progression by epigenetic induction of CD8<sup>+</sup> T-cell exhaustion.

Project description:Itaconate is a well-known immunomodulatory metabolite; however, its role in hepatocellular carcinoma (HCC) remains unclear. Here, we find that macrophage-derived itaconate promotes HCC by epigenetic induction of Eomesodermin (EOMES)-mediated CD8+ T-cell exhaustion. Our results show that the knockout of immune-responsive gene 1 (IRG1), responsible for itaconate production, suppresses HCC progression. Irg1 knockout leads to a decreased proportion of PD-1+ and TIM-3+ CD8+ T cells. Deletion or adoptive transfer of CD8+ T cells shows that IRG1-promoted tumorigenesis depends on CD8+ T-cell exhaustion. Mechanistically, itaconate upregulates PD-1 and TIM-3 expression levels by promoting succinate-dependent H3K4me3 of the Eomes promoter. Finally, ibuprofen is found to inhibit HCC progression by targeting IRG1/itaconate-dependent tumor immunoevasion, and high IRG1 expression in macrophages predicts poor prognosis in HCC patients. Taken together, our results uncover an epigenetic link between itaconate and HCC and suggest that targeting IRG1 or itaconate might be a promising strategy for HCC treatment.

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