Remodeling of the immune microenvironment is linked to adverse outcome in pediatric T cell acute lymphoblastic leukemia
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<sup>-</sup>CD8<sup>-</sup>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.
Authors
- Victoria Koch
- Thai Hoa Tran
- Birgit Knoechel (ORCID: https://orcid.org/0000-0002-8040-0535)
- Gbolahan Bamgbose (ORCID: https://orcid.org/0009-0000-5406-1894)
- David T. Teachey (ORCID: https://orcid.org/0000-0001-7373-8987)
- Petri Pölönen (ORCID: https://orcid.org/0000-0001-6128-9985)
- Andrew E. Place (ORCID: https://orcid.org/0000-0002-9604-4213)
- Merve Özdemir (ORCID: https://orcid.org/0009-0009-6825-6305)
- Rawan Shraim (ORCID: https://orcid.org/0009-0005-5350-3386)
- Marian H. Harris (ORCID: https://orcid.org/0000-0002-9956-664X)
- Charles Grenfell Mullighan (ORCID: https://orcid.org/0000-0002-1871-1850)
- Lewis B. Silverman (ORCID: https://orcid.org/0009-0007-7275-7650)
- Jens G. Lohr (ORCID: https://orcid.org/0000-0003-3486-2445)
- Tayla B. Heavican‐Foral (ORCID: https://orcid.org/0000-0002-8384-6217)
- Julia Frede (ORCID: https://orcid.org/0000-0002-4380-9673)
- Yana Pikman (ORCID: https://orcid.org/0000-0002-5336-0216)
- Jacob R. Bledsoe (ORCID: https://orcid.org/0000-0002-2387-5462)
- Eugene Y. Cho (ORCID: https://orcid.org/0000-0003-1250-2932)
- Justin Hegel (ORCID: https://orcid.org/0009-0004-7091-8578)
- Caroline R.M. Wiggers (ORCID: https://orcid.org/0000-0001-6633-1468)
- I. Pop
- Frederike Warlitz
Institutions
- Broad Institute (US)
- Boston Children's Hospital (US)
- St. Jude Children's Research Hospital (US)
- Children's Hospital of Philadelphia (US)
- Harvard University (US)
- University of Utah (US)
- Columbia University Irving Medical Center (US)
- Huntsman Cancer Institute (US)
- Centre Hospitalier Universitaire Sainte-Justine (CA)
- Dana-Farber Cancer Institute (US)
- University of Pennsylvania (US)
- Philadelphia University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-21
- DOI
- https://doi.org/10.1038/s41467-025-65134-y
- Primary Topic
- Acute Lymphoblastic Leukemia research
- Type
- article
- Field-Weighted Citation Impact
- 0.00