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GEO help: Mouse over screen elements for information. |
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Status |
Public on Dec 06, 2021 |
Title |
Induction of T cell dysfunction and NK-like T cell differentiation in vitro and in patients after CAR T cell treatment [ATAC-seq] |
Organism |
Homo sapiens |
Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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Summary |
Chimeric antigen receptor (CAR) T cell therapy has achieved remarkable success in hematological malignancies but remains largely ineffective in solid tumors. A major factor leading to the reduced efficacy of CAR T cell therapy is T cell dysfunction, and the mechanisms mediating this dysfunction are under investigation. Here we establish a robust in vitro model to study mesothelin-redirected CAR T cell dysfunction in pancreatic cancer. Continuous antigen exposure results in hallmark features of exhaustion including reduced proliferation capacity and cytotoxicity, and severe defects in cytokine production. Here we identified a transcriptional signature at both population and single-cell levels in CAR T cells after chronic antigen exposure. In addition, TCR lineage tracing revealed a CD8+ T-to-NK-like T cell plasticity that results in reduced antigen- dependent tumor cell killing. The transcription factors SOX4 and ID3 are specifically expressed in the dysfunctional CAR NK-like T cells and are predicted to be master regulators of the dysfunction gene expression signature and of the post-thymic acquisition of an NK-like T cell fate. Finally, we identified the emergence of CAR NK-like T cells in a subset of patients after infusion of CAR T cells. The findings gleaned from this study reveal new approaches to improve the efficacy of CAR T cell therapy in solid tumors by preventing or revitalizing CAR T cell dysfunction and shed light on the plasticity of human CAR T cells.
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Overall design |
Examines chromatin openness by paired-end ATAC-seq in CD8+ T cells across four biological replicates, with one variable: antigen exposure (values: control or continuous). Some samples are re-sequenced and were pooled to add coverage; see Data Processing section for details. Replicates are R2, R3, R4, and R5. Each has a single control day 0 and a continuous day 28 sample.
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Contributor(s) |
Kuramitsu S, Good CR, Samareh P, Donahue G, Ishiyama K, Ma Y, Wellhausen N, Tian L, Agarwal S, Guedan S, Aznar MA, Alexander KA, Zhang Z, Singh N, Richardson MW, Watanabe K, Tanyi JL, O'Hara MH, Ruella M, Lacey SF, Moon EK, Schuster SJ, Albelda SM, Lanier LL, Young RM, Berger SL, June CH |
Citation(s) |
34861191 |
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Submission date |
Oct 26, 2020 |
Last update date |
Mar 07, 2022 |
Contact name |
Gregory Donahue |
Organization name |
The University of Pennsylvania
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Department |
Cell & Developmental Biology
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Lab |
Zaret Lab
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Street address |
3400 Civic Center Blvd, Bldg 421
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City |
Philadelphia |
State/province |
PA |
ZIP/Postal code |
19104 |
Country |
USA |
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Platforms (1) |
GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
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Samples (8)
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This SubSeries is part of SuperSeries: |
GSE160174 |
Induction of T cell dysfunction and NK-like T cell differentiation in vitro and in patients after CAR T cell treatment |
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Relations |
BioProject |
PRJNA672075 |
SRA |
SRP288617 |
Supplementary file |
Size |
Download |
File type/resource |
GSE160139_Continuous.Common.NoBL.bed.gz |
50.6 Kb |
(ftp)(http) |
BED |
GSE160139_Control.Common.NoBL.bed.gz |
81.8 Kb |
(ftp)(http) |
BED |
GSE160139_RAW.tar |
1.0 Gb |
(http)(custom) |
TAR (of BW) |
SRA Run Selector |
Raw data are available in SRA |
Processed data provided as supplementary file |
Processed data are available on Series record |
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