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

IKAROS levels are associated with antigen escape in CD19- and CD22-targeted therapies for B-cell malignancies. Nature communications Domizi, P., Sarno, J., Jager, A., Merchant, M., Pacheco, K. Z., Yamada-Hunter, S. A., Rotiroti, M. C., Liu, Y., Baskar, R., Reynolds, W. D., Sworder, B. J., Sahaf, B., Bendall, S. C., Mullighan, C. G., Alizadeh, A. A., Leahy, A. B., Myers, R. M., Yates, B., Wang, H. W., Shah, N. N., Majzner, R. G., Mackall, C. L., Grupp, S. A., Barrett, D. M., Sotillo, E., Davis, K. L. 2025; 16 (1): 3800

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.

View details for DOI 10.1038/s41467-025-58868-2

View details for PubMedID 40268897

View details for PubMedCentralID PMC12019336