scRNA-seq reveals an immune microenvironment and JUN-mediated NK cell exhaustion in relapsed T-ALL

T-cell acute lymphoblastic leukemia (T-ALL) is a heterogeneous disease characterized with high relapse rate. By single-cell transcriptome analysis, we characterized the bone marrow immune microenvironment in T-ALL patients, identifying 13 major cell clusters. These patients exhibited abnormally expanded HSCs and GMPs, immunosuppressive traits in CD4+T, CD8+T, and NK cells. Subdividing CD4+T cells revealed two subsets transitioning between Th1/Th2, ANXA1-GATA3-CD4+T and ANXA1+GATA3+CD4+T. Additionally, NK cells demonstrated exhaustion in the tumor microenvironment of relapse T-ALL patients, with JUN identified as a critical factor. Additionally, JUN was also highly expressed in T-ALL and was crucial for maintaining its proliferation. The JUN inhibitor exhibited successful lethality toward leukemia cells and ameliorate NK cell exhaustion in relapse T-ALL cell line, as well as in CDX, PDX, and NOTCH1 mutant mouse models. In summary, our findings enhance the understanding of T-ALL relapsed mechanisms and support the development of innovative immunotherapies for T-ALL relapsed patients.