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

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. Sworder, Bita Sahaf, Sean C. Bendall, Charles G. Mullighan, Ash A. Alizadeh, Allison B. Leahy, Regina M. Myers, Bonnie Yates, Hao-Wei Wang, Nirali N. Shah, Robbie G. Majzner, Crystal L. Mackall, Stephan A. Grupp, David M. Barrett, Elena Sotillo and Kara L. Davis ()
Additional contact information
Pablo Domizi: Stanford University
Jolanda Sarno: Stanford University
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
Allison B. Leahy: Children’s Hospital of Philadelphia
Regina M. Myers: Children’s Hospital of Philadelphia
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
David M. Barrett: Kite Pharma
Elena Sotillo: Stanford University School of Medicine
Kara L. Davis: Stanford University

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58868-2

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