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ATAC Sequencing of Baseline and Chronically Stimulated CART19-28z Cells in the Manuscript IL-4 Drives Exhaustion of CD8+ CART Cells

GSE273297 Homo sapiens Genome binding/occupancy profiling by high throughput sequencing 6 samples Submitted 2024/08/01 Platform GPL20301
Summary
Durable response to chimeric antigen receptor T (CART) cell therapy remains limited in part due to CART cell exhaustion. Here, we investigate the regulation of CART cell exhaustion with three independent approaches including: a genome-wide CRISPR knockout screen using an in vitro model for exhaustion, RNA and ATAC sequencing on baseline and exhausted CART cells, and RNA and ATAC sequencing on pre-infusion CART cell products from responders and non-responders in the ZUMA-1 clinical trial. Each of these approaches identify interleukin (IL)-4 as a regulator of CART cell dysfunction. Further, IL-4-treated CD8+ CART cells develop signs of exhaustion independently of the presence of CD4+ CART cells. Conversely, IL-4 pathway editing or the combination of CART cells with an IL-4 monoclonal antibody improves antitumor efficacy and reduces signs of CART cell exhaustion in mantle cell lymphoma xenograft mouse models. Therefore, we identify both a role for IL-4 in inducing CART exhaustion and translatable approaches to improve CART cell therapy.
Published in
IL-4 drives exhaustion of CD8(+) CART cells
Stewart CM, Siegler EL, Sakemura RL et al. · Nature communications 2024 · PMID 39266501 · doi:10.1038/s41467-024-51978-3
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Also filed as BioProject PRJNA1141383 and SRA study SRP522772. Searching any of these in the dataset finder brings you back here.

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