IL-4 drives exhaustion of CD8+ CART cells

Carli M. Stewart, Elizabeth L. Siegler, R. Leo Sakemura, Michelle J. Cox, Truc Huynh, Brooke Kimball, Long Mai, Ismail Can, Claudia Manriquez Roman, Kun Yun, Olivia Sirpilla, James H. Girsch, Ekene Ogbodo, Wazim Mohammed Ismail, Alexandre Gaspar-Maia, Justin Budka, Jenny Kim, Nathalie Scholler, Mike Mattie, Simone Filosto and Saad S. Kenderian ()
Additional contact information
Carli M. Stewart: Mayo Clinic
Elizabeth L. Siegler: Mayo Clinic
R. Leo Sakemura: Mayo Clinic
Michelle J. Cox: Mayo Clinic
Truc Huynh: Mayo Clinic
Brooke Kimball: Mayo Clinic
Long Mai: Mayo Clinic
Ismail Can: Mayo Clinic
Claudia Manriquez Roman: Mayo Clinic
Kun Yun: Mayo Clinic
Olivia Sirpilla: Mayo Clinic
James H. Girsch: Mayo Clinic
Ekene Ogbodo: Mayo Clinic
Wazim Mohammed Ismail: Mayo Clinic
Alexandre Gaspar-Maia: Mayo Clinic
Justin Budka: Gilead Sciences Inc.
Jenny Kim: Gilead Sciences Inc.
Nathalie Scholler: Gilead Sciences Inc.
Mike Mattie: Gilead Sciences Inc.
Simone Filosto: Gilead Sciences Inc.
Saad S. Kenderian: Mayo Clinic

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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 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.

Date: 2024
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DOI: 10.1038/s41467-024-51978-3

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