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

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, Yunlong Liu, Drew Moore, Suganya Subramanian, Stefano Berto, Anilkumar Gopalakrishnapillai, Sonali P. Barwe, Hongfen Guo, Nai-Kong V. Cheung, Reuben Kapur and Sophie Paczesny ()
Additional contact information
Hua Jiang: Medical University of South Carolina
Denggang Fu: Medical University of South Carolina
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

Nature Communications, 2025, vol. 16, issue 1, 1-26

Abstract: 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.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-61647-8 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61647-8

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-61647-8

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().