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IL-4 drives exhaustion of CD8+ CART cells

Author

Listed:
  • Carli M. Stewart

    (Mayo Clinic
    Mayo Clinic
    Mayo Clinic)

  • Elizabeth L. Siegler

    (Mayo Clinic
    Mayo Clinic)

  • R. Leo Sakemura

    (Mayo Clinic
    Mayo Clinic)

  • Michelle J. Cox

    (Mayo Clinic)

  • Truc Huynh

    (Mayo Clinic
    Mayo Clinic)

  • Brooke Kimball

    (Mayo Clinic
    Mayo Clinic)

  • Long Mai

    (Mayo Clinic
    Mayo Clinic)

  • Ismail Can

    (Mayo Clinic
    Mayo Clinic)

  • Claudia Manriquez Roman

    (Mayo Clinic)

  • Kun Yun

    (Mayo Clinic
    Mayo Clinic
    Mayo Clinic)

  • Olivia Sirpilla

    (Mayo Clinic
    Mayo Clinic
    Mayo Clinic)

  • James H. Girsch

    (Mayo Clinic
    Mayo Clinic
    Mayo Clinic)

  • Ekene Ogbodo

    (Mayo Clinic
    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
    Mayo Clinic
    Mayo Clinic)

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.

Suggested Citation

  • 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. Girsc, 2024. "IL-4 drives exhaustion of CD8+ CART cells," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51978-3
    DOI: 10.1038/s41467-024-51978-3
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