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Series GSE160139 Query DataSets for GSE160139
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
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.
 
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.
 
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
Submission date Oct 26, 2020
Last update date Mar 07, 2022
Contact name Gregory Donahue
Organization name The University of Pennsylvania
Department Cell & Developmental Biology
Lab Zaret Lab
Street address 3400 Civic Center Blvd, Bldg 421
City Philadelphia
State/province PA
ZIP/Postal code 19104
Country USA
 
Platforms (1)
GPL18573 Illumina NextSeq 500 (Homo sapiens)
Samples (8)
GSM4861210 R2 Control Day 0 CAR+ T1 [ATAC-seq]
GSM4861211 R2 Continuous CAR+ T1 [ATAC-seq]
GSM4861212 R3 Control Day 0 CAR+ T1 [ATAC-seq]
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
Relations
BioProject PRJNA672075
SRA SRP288617

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

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 SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file
Processed data are available on Series record

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