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

   

Authors:	Jiang, H.; Fu, D.; Pasupuleti, S. K.; Ramdas, B.; Long, A.; Ramadan, A. M.; Yang, J.; Kumar, R.; Hartman, J. H.; Kendrick, B. J.; Simpson, E.; Gao, H.; Liu, Y.; Moore, D.; Subramanian, S.; Berto, S.; Gopalakrishnapillai, A.; Barwe, S. P.; Guo, H.; Cheung, N. K. V.; Kapur, R.; Paczesny, S.
Article Title:	ST2/IL-33 axis blockade inhibits regulatory T cell cytotoxicity towards CD8 T cells in the leukemic niche
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. © The Author(s) 2025.
Keywords:	immunohistochemistry; survival; adult; cancer survival; controlled study; human tissue; cancer growth; nonhuman; flow cytometry; ki 67 antigen; transcription factor foxp3; cd8+ t lymphocyte; mouse; animal tissue; interleukin 2; cancer immunotherapy; apoptosis; transcription factor gata 3; bone marrow; spleen; transforming growth factor beta; interleukin 10; animal experiment; animal model; cytotoxicity; granzyme b; regulatory t lymphocyte; whole body radiation; gamma interferon; cd4+ t lymphocyte; bone; cytokine production; protein bcl 6; transcription factor t bet; monocyte; cytotoxic t lymphocyte antigen 4; macrophage; stem cell niche; immunocompetent cell; granulocyte; peripheral blood mononuclear cell; lysosome associated membrane protein 1; growth rate; memory t lymphocyte; dna methyltransferase 3a; inhibition; cd135 antigen; lymphocyte activation gene 3 protein; acute myeloid leukemia; interleukin 3; interleukin 1 receptor; interleukin 33; cell component; human; article; rna sequencing; t cell exhaustion; hepatitis a virus cellular receptor 2; alarmin; single cell rna seq; interleukin 1 receptor like 1 protein
Journal Title:	Nature Communications
Volume:	16
ISSN:	2041-1723
Publisher:	Nature Publishing Group
Date Published:	2025-07-12
Start Page:	6580
Language:	English
DOI:	10.1038/s41467-025-61647-8
PROVIDER:	scopus
PMCID:	PMC12279971
PUBMED:	40691440
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-105011209853&doi=10.1038%2fs41467-025-61647-8&partnerID=40&md5=93c0e3363889550d1cfc1feb8c1a9db9
Notes:	Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/227334