IKAROS levels are associated with antigen escape in CD19- and CD22-targeted therapies for B-cell malignancies
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.
Article Details
Authors (26)
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
Department of Pediatric Oncology, Dana-Farber Cancer Institute Division of Hematology and Oncology, Boston Children’s Hospital, Harvard Medical School
Crystal L. Mackall
Stephan A. Grupp
David M. Barrett
Elena Sotillo
Kara L. Davis