IKAROS levels are associated with antigen escape in CD19- and CD22-targeted therapies for B-cell malignancies
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. IKAROS<sup>low</sup> 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, IKAROS<sup>low</sup> 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.
Authors
- Jolanda Sarno (ORCID: https://orcid.org/0000-0003-3488-0248)
- Ash A. Alizadeh (ORCID: https://orcid.org/0000-0002-5153-5625)
- Kara L. Davis (ORCID: https://orcid.org/0000-0002-7182-2592)
- Milton Merchant
- Nirali N. Shah (ORCID: https://orcid.org/0000-0002-8474-9080)
- Robbie G. Majzner (ORCID: https://orcid.org/0000-0001-6969-8011)
- Bonnie Yates (ORCID: https://orcid.org/0009-0005-4288-3037)
- Astraea Jager
- Kaithlen Zen B Pacheco
- Sean C. Bendall (ORCID: https://orcid.org/0000-0003-1341-2453)
- Reema Baskar (ORCID: https://orcid.org/0000-0002-3872-0164)
- Allison Barz Leahy (ORCID: https://orcid.org/0000-0002-1368-4064)
- Charles Grenfell Mullighan (ORCID: https://orcid.org/0000-0002-1871-1850)
- Crystal L. Mackall (ORCID: https://orcid.org/0000-0001-6323-4304)
- Warren D. Reynolds (ORCID: https://orcid.org/0000-0002-1755-2835)
- Bita Sahaf (ORCID: https://orcid.org/0000-0002-4157-3863)
- Elena Sotillo (ORCID: https://orcid.org/0000-0002-3993-1932)
- Brian J. Sworder (ORCID: https://orcid.org/0000-0002-5902-5507)
- Maria Caterina Rotiroti (ORCID: https://orcid.org/0000-0002-3214-1540)
- Pablo Domizi (ORCID: https://orcid.org/0000-0003-2903-0337)
- Sean A. Yamada‐Hunter (ORCID: https://orcid.org/0000-0002-4372-6587)
- David M. Barrett (ORCID: https://orcid.org/0000-0001-8132-6819)
- Stephan A. Grupp (ORCID: https://orcid.org/0000-0001-8030-7595)
- Regina M. Myers (ORCID: https://orcid.org/0000-0002-2542-2061)
- Hao‐Wei Wang (ORCID: https://orcid.org/0000-0002-5408-9253)
- Yuxuan Liu (ORCID: https://orcid.org/0000-0003-4426-9290)
Institutions
- National Institutes of Health (US)
- St. Jude Children's Research Hospital (US)
- Children's Hospital of Philadelphia (US)
- California Institute for Regenerative Medicine (US)
- Institute for Stem Cell Biology and Regenerative Medicine (IN)
- Dana-Farber Cancer Institute (US)
- Stanford Medicine (US)
- National Cancer Institute (US)
- Kite (United States) (US)
- Center for Cancer Research (US)
- University of Milano-Bicocca (IT)
- University of Pennsylvania (US)
- Stanford University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-23
- DOI
- https://doi.org/10.1038/s41467-025-58868-2
- Citations
- 9
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 9.41
Funders
- V Foundation for Cancer Research
- National Cancer Institute