| Autor: |
Stewart, Carli M., Siegler, Elizabeth L., Sakemura, R. Leo, Cox, Michelle J., Huynh, Truc, Kimball, Brooke, Mai, Long, Can, Ismail, Manriquez Roman, Claudia, Yun, Kun, Sirpilla, Olivia, Girsch, James H., Ogbodo, Ekene, Mohammed Ismail, Wazim, Gaspar-Maia, Alexandre, Budka, Justin, Kim, Jenny, Scholler, Nathalie, Mattie, Mike, Filosto, Simone |
| Předmět: |
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| Zdroj: |
Nature Communications; 9/12/2024, Vol. 15 Issue 1, p1-17, 17p |
| Abstrakt: |
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. The application and therapeutic success of CAR-T cell approaches are limited by the development of T cell exhaustion. Here, Stewart et al discover a role for IL-4 in driving CD8+ CAR-T cell exhaustion and demonstrate the improvement of CAR-T cell effectivity with interruption of IL-4 signalling. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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