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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE244180 | 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 [bulk ATAC-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 | GSE244183 | GEO

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

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PD1 completely suppresses the transcriptional response induced by the T cell receptor

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Mezigdomide is effective alone and in combination with Menin inhibition in Acute Myeloid Leukemia

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2024-02-15 | PXD041737 | Pride

Mezigdomide is effective alone and in combination with Menin inhibition in Acute Myeloid Leukemia

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Deletion of a state-specific PD-1 enhancer modulates exhausted T cell fate and function [RNA-Seq]

Project description:T cell exhaustion is a state of CD8+ T cell dysfunction elicited by chronic exposure to antigen and inflammation, arises in both cancer and chronic viral infection. The co-inhibitory receptor PD-1 plays a key role in mediating exhaustion, but complete ablation of PD-1 by gene knock-out leads to deeper functional deficits and poor T cell survival. We hypothesized that an intermediate level of PD-1 expression may confer an improved balance of exhausted CD8+ T cell functionality, so we deleted an exhaustion-associated enhancer of PD-1 which indeed resulted in a reduced expression level. We compared EnhDel, WT and PD-1 KO T cells using single-cell RNA-Seq and found that PD-1 KO but not EnhDel cells are strongly biased towards the terminally exhausted subset. EnhDel cells also uniquely enrich for effector-associated genes and gene signatures. However, all three genotypes (EnhDel, WT and PD-1 KO) exhibit a similar chromatin accessibility landscape by ATAC-Seq, controlling for exhausted subset. These data suggest that tuning of PD-1 expression may uniquely permit the maintenance of an “effector” transcriptional profile in exhausted CD8+ T cells.

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