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

Producción científica › revisión exhaustiva

10 Citas (Scopus)

Resumen

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.

Idioma original	English
Número de artículo	6580
Páginas (desde-hasta)	6580
Publicación	Nature Communications
Volumen	16
N.º	1
DOI	https://doi.org/10.1038/s41467-025-61647-8
Estado	Published - 21 jul 2025

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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. Artículo 6580. https://doi.org/10.1038/s41467-025-61647-8

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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.",

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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",

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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, n.º 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

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