Remodeling of the immune microenvironment is linked to adverse outcome in pediatric T cell acute lymphoblastic leukemia

作者：Caroline R.M. Wiggers, Eugene Y. Cho, Merve Özdemir, Gbolahan Bamgbose, Justin Hegel, Julia Frede, Frederike Warlitz, Tayla B. Heavican‐Foral, Ioana Pop, Rawan Shraim, Petri Pölönen, Victoria B. Koch, Thai Hoa Tran, Charles Grenfell Mullighan, David T. Teachey, Jacob R. Bledsoe, Yana Pikman, Marian H. Harris, Andrew E. Place, Lewis B. Silverman, Jens G. Lohr, Birgit Knoechel · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-65134-y · 被引用次数：4 · 研究领域：Acute Lymphoblastic Leukemia research、Acute Myeloid Leukemia Research、Lymphoma Diagnosis and Treatment

Changes in the immune microenvironment are frequent in cancers occurring in adult patients, yet our understanding of the pediatric cancer immune microenvironment and its clinical relevance is limited. We investigate the immune microenvironment in pediatric T cell acute lymphoblastic leukemia (T-ALL), using single-cell CITE-seq and immune repertoire analyses. We identify a T-ALL subgroup characterized by a remodeled immune microenvironment, which is associated with adverse clinical outcome in minimal residual disease low patients. This adverse immune landscape is dominated by the presence of a population of non-malignant CD4-CD8-TCRαβ T cells that interact with CXCL16 expressing non-classical monocytes. Leukemia cell intrinsic transcriptional rewiring in these patients is associated with activation of Rap1 signaling. Inhibiting Rap1 signaling results in increased sensitivity to the BCL2/BCL-XL inhibitor navitoclax. Our study provides insights into the immune microenvironment of pediatric hematologic malignancies, forming the basis for identifying potential (immuno) therapeutic targets and risk stratification for treatment. Understanding of the immune microenvironment in pediatric acute T cell lymphoblastic leukemia is limited. By analyzing single-cell transcriptome, surface protein expression and immune repertoire data, the authors here identify non-malignant CD4-CD8- TCRαβ T cells that are present in a subset of patients with Rap1 signaling in leukemia cells and are associate...