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| Status |
Public on Sep 02, 2024 |
| Title |
Degradation of Ikaros prevents epigenetic progression of T cell exhaustion in novel antigen-specific assay [bulk ATAC-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
SHARE-seq to profile chromatin accessibility and gene expression in T cells from four healthy human donors. Donor PBMCs were expanded for antigen-specific T cells using viral peptide cocktail over the course of 7 or 14 days. Iberdomide or DMSO was used to treat cells from day 7 -14.
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| Contributor(s) |
Tay T, Bommakanti G |
| Citation missing |
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| Submission date |
Sep 27, 2023 |
| Last update date |
Sep 02, 2024 |
| Contact name |
Tristan Tay |
| E-mail(s) |
taytristan@gmail.com, ttay@g.harvard.edu
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| Organization name |
Harvard University
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| Department |
Stem Cell & Regenerative Biology
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| Lab |
Buenrostro
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| Street address |
7 Divinity Avenue
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| City |
Cambridge |
| State/province |
MA |
| ZIP/Postal code |
02138 |
| Country |
USA |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (11)
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| This SubSeries is part of SuperSeries: |
| GSE244184 |
Degradation of Ikaros prevents epigenetic progression of T cell exhaustion in novel antigen-specific assay |
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| Relations |
| BioProject |
PRJNA1021618 |
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