2. Academic Validation
  3. Remodeling of the immune microenvironment is linked to adverse outcome in pediatric T cell acute lymphoblastic leukemia

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

  • Nat Commun. 2025 Nov 21;16(1):10263. doi: 10.1038/s41467-025-65134-y.
Caroline R M Wiggers 1 2,  Eugene Y Cho 1,  Merve Ozdemir 1,  Gbolahan Bamgbose 3,  Justin Hegel 1,  Julia Frede 2 4,  Frederike Warlitz 1,  Tayla B Heavican-Foral 1 2,  Ioana Pop 3,  Rawan Shraim 5,  Petri Pölönen 6,  Victoria Koch 1,  Thai Hoa Tran 7,  Charles G Mullighan 6,  David T Teachey 5,  Jacob R Bledsoe 8,  Yana Pikman 1 2 9,  Marian H Harris 8,  Andrew E Place 1 2 9,  Lewis B Silverman 10,  Jens G Lohr 11 12 13 14,  Birgit Knoechel 15 16 17 18 19
Affiliations

Affiliations

  • 1 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 2 Harvard Medical School, Boston, MA, USA.
  • 3 Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
  • 4 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 5 Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
  • 6 Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 7 Division of Pediatric Hematology-Oncology, Charles-Bruneau Cancer Center, Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC, Canada.
  • 8 Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • 9 Department of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
  • 10 Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Columbia University Irving Medical Center, New York, NY, USA.
  • 11 Harvard Medical School, Boston, MA, USA. jens.lohr@hci.utah.edu.
  • 12 Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. jens.lohr@hci.utah.edu.
  • 13 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. jens.lohr@hci.utah.edu.
  • 14 Broad Institute of MIT and Harvard, Cambridge, MA, USA. jens.lohr@hci.utah.edu.
  • 15 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. birgit.knoechel@hci.utah.edu.
  • 16 Harvard Medical School, Boston, MA, USA. birgit.knoechel@hci.utah.edu.
  • 17 Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. birgit.knoechel@hci.utah.edu.
  • 18 Department of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. birgit.knoechel@hci.utah.edu.
  • 19 Broad Institute of MIT and Harvard, Cambridge, MA, USA. birgit.knoechel@hci.utah.edu.
PMID: 41271691 DOI: 10.1038/s41467-025-65134-y
Abstract

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.

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