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ST2/IL-33 axis blockade inhibits regulatory T cell cytotoxicity towards CD8 T cells in the leukemic niche

Author

Listed:
  • Hua Jiang

    (Medical University of South Carolina
    Indiana University School of Medicine)

  • Denggang Fu

    (Medical University of South Carolina
    Indiana University School of Medicine)

  • Santhosh Kumar Pasupuleti

    (Indiana University School of Medicine)

  • Baskar Ramdas

    (Indiana University School of Medicine)

  • Alan Long

    (Memorial Sloan Kettering Cancer Center)

  • Abdulraouf M. Ramadan

    (Indiana University School of Medicine)

  • Jinfeng Yang

    (Indiana University School of Medicine)

  • Ramesh Kumar

    (Indiana University School of Medicine)

  • Jessica H. Hartman

    (Medical University of South Carolina)

  • B. Jacob Kendrick

    (Medical University of South Carolina)

  • Ed Simpson

    (Indiana University School of Medicine)

  • Hongyu Gao

    (Indiana University School of Medicine)

  • Yunlong Liu

    (Indiana University School of Medicine)

  • Drew Moore

    (Medical University of South Carolina)

  • Suganya Subramanian

    (Medical University of South Carolina)

  • Stefano Berto

    (Medical University of South Carolina)

  • Anilkumar Gopalakrishnapillai

    (Lisa Dean Moseley Foundation Institute of Cancer and Blood Disorders)

  • Sonali P. Barwe

    (Lisa Dean Moseley Foundation Institute of Cancer and Blood Disorders)

  • Hongfen Guo

    (Memorial Sloan Kettering Cancer Center)

  • Nai-Kong V. Cheung

    (Memorial Sloan Kettering Cancer Center)

  • Reuben Kapur

    (Indiana University School of Medicine)

  • Sophie Paczesny

    (Medical University of South Carolina
    Indiana University School of Medicine)

Abstract

Acute myeloid leukemia (AML) patients present with CD8 exhaustion signatures, and pharmacologic inhibition of checkpoints can have therapeutic benefit. The alarmin IL-33 and its receptor STimulation-2 (ST2) promote activation of tissue-regulatory T cells (Treg cells) and accelerate malignant progression in solid tumors, but their role in leukemia remains unclear. Here, we show that ST2+ Treg cells are enriched in bone marrow (BM) of humans and mice with AML and promote CD8+ T cells depletion and exhaustion. ST2 deficiency in Treg cells restores CD8+ T cell function, decreasing AML growth via retention of ST2+ Treg cells precursors in lymph nodes. AML-activated ST2+ Treg cells lack T-bet, IFN-γ and Bcl-6, and kill intratumoral CD8+ T cells by amplified granzyme B-mediated cytotoxicity compared to non-AML primed Treg cells. Engineered anti-ST2 antibodies induce ST2+ Treg cells apoptosis to extend survival in AML models. Together, our findings suggest that ST2 is a potential checkpoint target for AML immunotherapy.

Suggested Citation

  • Hua Jiang & Denggang Fu & Santhosh Kumar Pasupuleti & Baskar Ramdas & Alan Long & Abdulraouf M. Ramadan & Jinfeng Yang & Ramesh Kumar & Jessica H. Hartman & B. Jacob Kendrick & Ed Simpson & Hongyu Gao, 2025. "ST2/IL-33 axis blockade inhibits regulatory T cell cytotoxicity towards CD8 T cells in the leukemic niche," Nature Communications, Nature, vol. 16(1), pages 1-26, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61647-8
    DOI: 10.1038/s41467-025-61647-8
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