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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Oct 01, 2019 |
| Title |
CAR T cells Overexpressing cJun Are Exhaustion-Resistant and Mediate Enhanced Antitumor Activity |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
CAR T cells mediate antitumor effects in a small subset of cancer patients, but dysfunction due to T cell exhaustion is an important barrier to progress. To investigate the biology of exhaustion in human T cells expressing CAR receptors, we used a model system employing a tonically signaling CAR, which induces hallmarks of exhaustion described in other settings. Exhaustion was associated with a profound defect in IL-2 production alongside increased chromatin accessibility of AP-1 transcription factor motifs, and overexpression of numerous bZIP and IRF transcription factors that have been implicated in inhibitory activity. Here we demonstrate that engineering CAR T cells to overexpress c-Jun, a canonical AP-1 factor, enhanced expansion potential, increased functional capacity, diminished terminal differentiation and improved antitumor potency in numerous in vivo tumor models. We conclude that a functional deficiency in c-Jun mediates dysfunction in exhausted human T cells and that engineering CAR T cells to overexpress c-Jun renders them exhaustion-resistant, thereby addressing a major barrier to progress for this emerging class of therapeutics.
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| Overall design |
ChIP-seq or input controls from CAR-T cells overexpressing either JUN-HA or HA tag alone from two distinct viral transductions.
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| Contributor(s) |
Nagaraja S, Monje M |
| Citation(s) |
31802004 |
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| Submission date |
Sep 04, 2019 |
| Last update date |
Jan 02, 2020 |
| Contact name |
Michelle Monje |
| E-mail(s) |
mmonje@stanford.edu
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| Organization name |
Stanford University
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| Street address |
265 Campus Drive, SIM1 G3035
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| City |
Stanford |
| State/province |
CA |
| ZIP/Postal code |
94305 |
| Country |
USA |
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| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
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| Samples (11)
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| GSM4059672 |
HA only, replicate 1 [ha-1-inp-CGATGT_S1] |
| GSM4059673 |
HA only, replicate 1 [ha-1-irf4-TTAGGC_S2] |
| GSM4059674 |
HA only, replicate 1 [ha-1-jun-TGACCA_S3] |
| GSM4059675 |
HA only, replicate 2 [ha-2-inp-ACTTGA_S7] |
| GSM4059676 |
HA only, replicate 2 [ha-2-irf4-GATCAG_S8] |
| GSM4059677 |
JUN-HA, replicate 1 [jun-1-inp-ACAGTG_S4] |
| GSM4059678 |
JUN-HA, replicate 1 [jun-1-irf4-GCCAAT_S5] |
| GSM4059679 |
JUN-HA, replicate 1 [jun-1-jun-CAGATC_S6] |
| GSM4059680 |
JUN-HA, replicate 2 [jun-2-inp-TAGCTT_S9] |
| GSM4059681 |
JUN-HA, replicate 2 [jun-2-irf4-GGCTAC_S10] |
| GSM4059682 |
JUN-HA, replicate 2 [jun-2-jun-CTTGTA_S11] |
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| Relations |
| BioProject |
PRJNA563871 |
| SRA |
SRP220313 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE136853_RAW.tar |
5.5 Gb |
(http)(custom) |
TAR (of BW, NARROWPEAK) |
| GSE136853_readme.txt |
1.2 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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