ST2/IL-33 axis blockade inhibits regulatory T cell cytotoxicity towards CD8 T cells in the leukemic niche
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 (T<sub>reg</sub> cells) and accelerate malignant progression in solid tumors, but their role in leukemia remains unclear. Here, we show that ST2<sup>+</sup> T<sub>reg</sub> cells are enriched in bone marrow (BM) of humans and mice with AML and promote CD8<sup>+</sup> T cells depletion and exhaustion. ST2 deficiency in T<sub>reg</sub> cells restores CD8<sup>+</sup> T cell function, decreasing AML growth via retention of ST2<sup>+</sup> T<sub>reg</sub> cells precursors in lymph nodes. AML-activated ST2<sup>+</sup> T<sub>reg</sub> cells lack T-bet, IFN-γ and Bcl-6, and kill intratumoral CD8<sup>+</sup> T cells by amplified granzyme B-mediated cytotoxicity compared to non-AML primed T<sub>reg</sub> cells. Engineered anti-ST2 antibodies induce ST2<sup>+</sup> T<sub>reg</sub> cells apoptosis to extend survival in AML models. Together, our findings suggest that ST2 is a potential checkpoint target for AML immunotherapy.
Authors
- Alan Long (ORCID: https://orcid.org/0000-0002-9600-326X)
- Anilkumar Gopalakrishnapillai (ORCID: https://orcid.org/0000-0002-0465-578X)
- Santhosh Kumar Pasupuleti (ORCID: https://orcid.org/0000-0001-5770-7187)
- Baskar Ramdas (ORCID: https://orcid.org/0009-0006-2206-5720)
- Abdulraouf Ramadan (ORCID: https://orcid.org/0000-0003-4128-0996)
- Nai‐Kong V. Cheung (ORCID: https://orcid.org/0000-0001-6323-5171)
- Reuben Kapur (ORCID: https://orcid.org/0000-0003-2225-1700)
- Stefano Berto (ORCID: https://orcid.org/0000-0001-9028-9458)
- Sophie Paczesny (ORCID: https://orcid.org/0000-0001-5571-2775)
- Hua Jiang (ORCID: https://orcid.org/0000-0002-7479-0039)
- Edward Simpson (ORCID: https://orcid.org/0000-0001-9015-9864)
- B. Jacob Kendrick (ORCID: https://orcid.org/0000-0001-9435-4720)
- Yunlong Liu (ORCID: https://orcid.org/0000-0002-2699-626X)
- Jinfeng Yang
- Ramesh Kumar (ORCID: https://orcid.org/0000-0002-7545-4619)
- Hongyu Gao (ORCID: https://orcid.org/0000-0002-7462-8883)
- Hong-Fen Guo
- Suganya Subramanian (ORCID: https://orcid.org/0009-0007-2822-9420)
- Jessica H. Hartman (ORCID: https://orcid.org/0000-0002-9134-7469)
- Denggang Fu (ORCID: https://orcid.org/0000-0003-0779-7975)
- Sonali P. Barwe (ORCID: https://orcid.org/0000-0003-4162-3004)
- Drew Moore (ORCID: https://orcid.org/0009-0005-0926-0874)
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- Medical University of South Carolina (US)
- Center for Cancer and Blood Disorders (US)
- Indiana University School of Medicine
- Indiana University – Purdue University Indianapolis (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-07-21
- DOI
- https://doi.org/10.1038/s41467-025-61647-8
- Citations
- 3
- Primary Topic
- IL-33, ST2, and ILC Pathways
- Type
- article
- Field-Weighted Citation Impact
- 2.39
Funders
- Fred Hutchinson Cancer Research Center
- Medical University of South Carolina
- University of South Carolina
- Hollings Cancer Center, Medical University of South Carolina
- Medical Research Council
- National Cancer Institute
- Moonshot Research and Development Program
- Cancer Moonshot