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_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.