IL-4 drives exhaustion of CD8+ CART cells
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<sup>+</sup> CART cells develop signs of exhaustion independently of the presence of CD4<sup>+</sup> 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.
Authors
- Michelle J. Cox (ORCID: https://orcid.org/0000-0002-2984-0834)
- Elizabeth L. Siegler (ORCID: https://orcid.org/0000-0002-8336-4373)
- İsmail Can (ORCID: https://orcid.org/0000-0003-0569-5326)
- Carli M. Stewart (ORCID: https://orcid.org/0000-0002-2288-2230)
- Nathalie Scholler (ORCID: https://orcid.org/0000-0003-3743-7102)
- Wazim Mohammed Ismail (ORCID: https://orcid.org/0000-0002-1782-7296)
- Mike Mattie (ORCID: https://orcid.org/0000-0003-0868-3865)
- Justin A. Budka (ORCID: https://orcid.org/0000-0003-0908-1508)
- Olivia Sirpilla (ORCID: https://orcid.org/0000-0002-0634-407X)
- Ekene J. Ogbodo (ORCID: https://orcid.org/0009-0009-3552-0384)
- Simone Filosto
- Saad S. Kenderian (ORCID: https://orcid.org/0000-0003-2767-3830)
- Alexandre Gaspar‐Maia (ORCID: https://orcid.org/0000-0001-8528-5575)
- Truc Huynh (ORCID: https://orcid.org/0009-0003-7521-4185)
- Jenny Kim (ORCID: https://orcid.org/0009-0008-6816-1499)
- James H. Girsch (ORCID: https://orcid.org/0000-0003-4592-4015)
- Brooke Kimball (ORCID: https://orcid.org/0009-0009-3308-2704)
- Claudia Manriquez Roman (ORCID: https://orcid.org/0000-0003-0082-9735)
- Reona Sakemura (ORCID: https://orcid.org/0000-0002-0293-5577)
- Kun Yun
- Long Mai
Institutions
- Mayo Clinic (US)
- Mayo Clinic in Arizona (US)
- Gilead Sciences (United States) (US)
- Mayo Clinic in Florida (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-12
- DOI
- https://doi.org/10.1038/s41467-024-51978-3
- Citations
- 29
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 8.19
Funders
- U.S. Department of Defense
- Gilead Sciences
- National Institutes of Health
- Center for Individualized Medicine, Mayo Clinic