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IKAROS levels are associated with antigen escape in CD19- and CD22-targeted therapies for B-cell malignancies

Author

Listed:
  • Pablo Domizi

    (Stanford University)

  • Jolanda Sarno

    (Stanford University
    Fondazione IRCCS San Gerardo dei Tintori
    University of Milano-Bicocca)

  • Astraea Jager

    (Stanford University)

  • Milton Merchant

    (Stanford University)

  • Kaithlen Zen B. Pacheco

    (Stanford University School of Medicine)

  • Sean A. Yamada-Hunter

    (Stanford University School of Medicine)

  • Maria Caterina Rotiroti

    (Dana-Farber Cancer Institute)

  • Yuxuan Liu

    (Stanford University)

  • Reema Baskar

    (Stanford University)

  • Warren D. Reynolds

    (Stanford University School of Medicine)

  • Brian J. Sworder

    (Stanford University School of Medicine)

  • Bita Sahaf

    (Stanford University School of Medicine)

  • Sean C. Bendall

    (Stanford University)

  • Charles G. Mullighan

    (St. Jude Children’s Research Hospital)

  • Ash A. Alizadeh

    (Stanford University School of Medicine
    Stanford University
    Stanford University)

  • Allison B. Leahy

    (Children’s Hospital of Philadelphia
    University of Pennsylvania)

  • Regina M. Myers

    (Children’s Hospital of Philadelphia
    University of Pennsylvania)

  • Bonnie Yates

    (National Institutes of Health)

  • Hao-Wei Wang

    (National Institutes of Health)

  • Nirali N. Shah

    (National Institutes of Health)

  • Robbie G. Majzner

    (Dana-Farber Cancer Institute)

  • Crystal L. Mackall

    (Stanford University School of Medicine)

  • Stephan A. Grupp

    (Children’s Hospital of Philadelphia
    University of Pennsylvania)

  • David M. Barrett

    (Kite Pharma)

  • Elena Sotillo

    (Stanford University School of Medicine)

  • Kara L. Davis

    (Stanford University
    Stanford University School of Medicine)

Abstract

Antigen escape relapse is a major challenge in targeted immunotherapies, including CD19- and CD22-directed chimeric antigen receptor (CAR) T-cell for B-cell acute lymphoblastic leukemia (B-ALL). To identify tumor-intrinsic factors driving antigen loss, we perform single-cell analyses on 61 B-ALL patient samples treated with CAR T cells. Here we show that low levels of IKAROS in pro-B-like B-ALL cells before CAR T treatment correlate with antigen escape. IKAROSlow B-ALL cells undergo epigenetic and transcriptional changes that diminish B-cell identity, making them resemble progenitor cells. This shift leads to reduced CD19 and CD22 surface expression. We demonstrate that CD19 and CD22 expression is IKAROS dose-dependent and reversible. Furthermore, IKAROSlow cells exhibit higher resistance to CD19- and CD22-targeted therapies. These findings establish a role for IKAROS as a regulator of antigens targeted by widely used immunotherapies and in the risk of antigen escape relapse, identifying it as a potential prognostic target.

Suggested Citation

  • Pablo Domizi & Jolanda Sarno & Astraea Jager & Milton Merchant & Kaithlen Zen B. Pacheco & Sean A. Yamada-Hunter & Maria Caterina Rotiroti & Yuxuan Liu & Reema Baskar & Warren D. Reynolds & Brian J. S, 2025. "IKAROS levels are associated with antigen escape in CD19- and CD22-targeted therapies for B-cell malignancies," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58868-2
    DOI: 10.1038/s41467-025-58868-2
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    References listed on IDEAS

    as
    1. Sean A. Yamada-Hunter & Johanna Theruvath & Brianna J. McIntosh & Katherine A. Freitas & Frank Lin & Molly T. Radosevich & Amaury Leruste & Shaurya Dhingra & Naiara Martinez-Velez & Peng Xu & Jing Hua, 2024. "Engineered CD47 protects T cells for enhanced antitumour immunity," Nature, Nature, vol. 630(8016), pages 457-465, June.
    2. Anna C. Belkina & Christopher O. Ciccolella & Rina Anno & Richard Halpert & Josef Spidlen & Jennifer E. Snyder-Cappione, 2019. "Automated optimized parameters for T-distributed stochastic neighbor embedding improve visualization and analysis of large datasets," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    3. Elad Jacoby & Sang M. Nguyen & Thomas J. Fountaine & Kathryn Welp & Berkley Gryder & Haiying Qin & Yinmeng Yang & Christopher D. Chien & Alix E. Seif & Haiyan Lei & Young K. Song & Javed Khan & Daniel, 2016. "CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity," Nature Communications, Nature, vol. 7(1), pages 1-10, November.
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