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

doi:10.1038/s41467-025-61647-8

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

Nemours Children's Health Research

Medical University of South Carolina
Indiana University Bloomington
Memorial Sloan-Kettering Cancer Center

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

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 (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.

Original language	English
Article number	6580
Pages (from-to)	6580
Journal	Nature Communications
Volume	16
Issue number	1
DOIs	https://doi.org/10.1038/s41467-025-61647-8
State	Published - 21 Jul 2025

Keywords

Animals
Apoptosis
CD8-Positive T-Lymphocytes/immunology
Cytotoxicity, Immunologic
Female
Granzymes/metabolism
Humans
Interleukin-1 Receptor-Like 1 Protein/metabolism
Interleukin-33/metabolism
Leukemia, Myeloid, Acute/immunology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
T-Lymphocytes, Regulatory/immunology

Access to Document

10.1038/s41467-025-61647-8

Cite this

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., ... Paczesny, S. (2025). ST2/IL-33 axis blockade inhibits regulatory T cell cytotoxicity towards CD8 T cells in the leukemic niche. Nature Communications, 16(1), 6580. Article 6580. https://doi.org/10.1038/s41467-025-61647-8

@article{4f839163d0e74caa8c692d624e6c3e0d,

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.",

keywords = "Animals, Apoptosis, CD8-Positive T-Lymphocytes/immunology, Cytotoxicity, Immunologic, Female, Granzymes/metabolism, Humans, Interleukin-1 Receptor-Like 1 Protein/metabolism, Interleukin-33/metabolism, Leukemia, Myeloid, Acute/immunology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, T-Lymphocytes, Regulatory/immunology",

author = "Hua Jiang and Denggang Fu and Pasupuleti, \{Santhosh Kumar\} and Baskar Ramdas and Alan Long and Ramadan, \{Abdulraouf M.\} and Jinfeng Yang and Ramesh Kumar and Hartman, \{Jessica H.\} and Kendrick, \{B. Jacob\} and Ed Simpson and Hongyu Gao and Yunlong Liu and Drew Moore and Suganya Subramanian and Stefano Berto and Anilkumar Gopalakrishnapillai and Barwe, \{Sonali P.\} and Hongfen Guo and Cheung, \{Nai Kong V.\} and Reuben Kapur and Sophie Paczesny",

note = "{\textcopyright} 2025. The Author(s).",

year = "2025",

month = jul,

day = "21",

doi = "10.1038/s41467-025-61647-8",

language = "English",

volume = "16",

pages = "6580",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Jiang, H, Fu, D, Pasupuleti, SK, Ramdas, B, Long, A, Ramadan, AM, Yang, J, Kumar, R, Hartman, JH, Kendrick, BJ, Simpson, E, Gao, H, Liu, Y, Moore, D, Subramanian, S, Berto, S, Gopalakrishnapillai, A , Barwe, SP, Guo, H, Cheung, NKV, Kapur, R & Paczesny, S 2025, 'ST2/IL-33 axis blockade inhibits regulatory T cell cytotoxicity towards CD8 T cells in the leukemic niche', Nature Communications, vol. 16, no. 1, 6580, pp. 6580. https://doi.org/10.1038/s41467-025-61647-8

TY - JOUR

T1 - ST2/IL-33 axis blockade inhibits regulatory T cell cytotoxicity towards CD8 T cells in the leukemic niche

AU - Jiang, Hua

AU - Fu, Denggang

AU - Pasupuleti, Santhosh Kumar

AU - Ramdas, Baskar

AU - Long, Alan

AU - Ramadan, Abdulraouf M.

AU - Yang, Jinfeng

AU - Kumar, Ramesh

AU - Hartman, Jessica H.

AU - Kendrick, B. Jacob

AU - Simpson, Ed

AU - Gao, Hongyu

AU - Liu, Yunlong

AU - Moore, Drew

AU - Subramanian, Suganya

AU - Berto, Stefano

AU - Gopalakrishnapillai, Anilkumar

AU - Barwe, Sonali P.

AU - Guo, Hongfen

AU - Cheung, Nai Kong V.

AU - Kapur, Reuben

AU - Paczesny, Sophie

PY - 2025/7/21

Y1 - 2025/7/21

N2 - 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.

AB - 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.

KW - Animals

KW - Apoptosis

KW - CD8-Positive T-Lymphocytes/immunology

KW - Cytotoxicity, Immunologic

KW - Female

KW - Granzymes/metabolism

KW - Humans

KW - Interleukin-1 Receptor-Like 1 Protein/metabolism

KW - Interleukin-33/metabolism

KW - Leukemia, Myeloid, Acute/immunology

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - T-Lymphocytes, Regulatory/immunology

UR - https://www.scopus.com/pages/publications/105011209853

U2 - 10.1038/s41467-025-61647-8

DO - 10.1038/s41467-025-61647-8

M3 - Article

C2 - 40691440

AN - SCOPUS:105011209853

SN - 2041-1723

VL - 16

SP - 6580

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 6580

ER -

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

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this