IL-4 drives exhaustion of CD8⁺ CART cells.

ABSTRACT: 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 I

SUBMITTER: Stewart CM 

PROVIDER: S-EPMC11393358 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature