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
- Sophie Paczesny
2025-07-21
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 reg cells) and accelerate malignant progression in solid tumors, but their role in leukemia remains unclear. Here, we show that ST2 + T reg cells are enriched in bone marrow (BM) of humans and mice with AML and promote CD8 + T cells depletion and exhaustion. ST2 deficiency in T reg cells restores CD8 + T cell function, decreasing AML growth via retention of ST2 + T reg cells precursors in lymph nodes. AML-activated ST2 + T reg 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 T reg cells. Engineered anti-ST2 antibodies induce ST2 + T reg cells apoptosis to extend survival in AML models. Together, our findings suggest that ST2 is a potential checkpoint target for AML immunotherapy.