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ST2/IL-33轴阻断抑制白血病龛中调节性T细胞对CD8 T细胞的细胞毒性。

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

作者信息

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

机构信息

Department of Microbiology and Immunology and Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA.

Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.

出版信息

Nat Commun. 2025 Jul 21;16(1):6580. doi: 10.1038/s41467-025-61647-8.

DOI:10.1038/s41467-025-61647-8
PMID:40691440
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12279971/
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 cells) and accelerate malignant progression in solid tumors, but their role in leukemia remains unclear. Here, we show that ST2 T 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 cells restores CD8 T cell function, decreasing AML growth via retention of ST2 T cells precursors in lymph nodes. AML-activated ST2 T 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 cells. Engineered anti-ST2 antibodies induce ST2 T cells apoptosis to extend survival in AML models. Together, our findings suggest that ST2 is a potential checkpoint target for AML immunotherapy.

摘要

急性髓系白血病（AML）患者存在CD8耗竭特征，而检查点的药物抑制可能具有治疗益处。警报素白细胞介素-33（IL-33）及其受体刺激因子2（ST2）可促进组织调节性T细胞（T细胞）的活化，并加速实体瘤的恶性进展，但其在白血病中的作用仍不清楚。在此，我们表明ST2+ T细胞在患有AML的人类和小鼠的骨髓（BM）中富集，并促进CD8+ T细胞的耗竭和功能耗竭。T细胞中ST2的缺失可恢复CD8+ T细胞功能，通过将ST2+ T细胞前体保留在淋巴结中来减少AML的生长。与非AML启动的T细胞相比，AML激活的ST2+ T细胞缺乏T-bet、干扰素-γ（IFN-γ）和Bcl-6，并通过增强颗粒酶B介导的细胞毒性杀死肿瘤内的CD8+ T细胞。工程化抗ST2抗体可诱导ST2+ T细胞凋亡，从而延长AML模型中的生存期。总之，我们的研究结果表明ST2是AML免疫治疗的一个潜在检查点靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ef0/12279971/2cb43d158ee7/41467_2025_61647_Fig10_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ef0/12279971/c8ab5460e80b/41467_2025_61647_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ef0/12279971/09b5ab629885/41467_2025_61647_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ef0/12279971/065e405b70c4/41467_2025_61647_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ef0/12279971/f360f7413930/41467_2025_61647_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ef0/12279971/d567b6b1a0d1/41467_2025_61647_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ef0/12279971/ab81ccdeb35f/41467_2025_61647_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ef0/12279971/c06aa8fc7d6c/41467_2025_61647_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ef0/12279971/563ffc0bcca3/41467_2025_61647_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ef0/12279971/53ce42663ec7/41467_2025_61647_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ef0/12279971/2cb43d158ee7/41467_2025_61647_Fig10_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ef0/12279971/c8ab5460e80b/41467_2025_61647_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ef0/12279971/09b5ab629885/41467_2025_61647_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ef0/12279971/065e405b70c4/41467_2025_61647_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ef0/12279971/f360f7413930/41467_2025_61647_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ef0/12279971/d567b6b1a0d1/41467_2025_61647_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ef0/12279971/ab81ccdeb35f/41467_2025_61647_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ef0/12279971/c06aa8fc7d6c/41467_2025_61647_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ef0/12279971/563ffc0bcca3/41467_2025_61647_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ef0/12279971/53ce42663ec7/41467_2025_61647_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ef0/12279971/2cb43d158ee7/41467_2025_61647_Fig10_HTML.jpg

相似文献

[1]
ST2/IL-33 axis blockade inhibits regulatory T cell cytotoxicity towards CD8 T cells in the leukemic niche.

Nat Commun. 2025-7-21

[2]
Dual targeting of tumoral cells and immune microenvironment by blocking the IL-33/IL1RL1 pathway.

Nat Commun. 2025-7-14

[3]
Lymph node macrophages drive immune tolerance and resistance to cancer therapy by induction of the immune-regulatory cytokine IL-33.

Cancer Cell. 2025-5-12

[4]
The IL-33/ST2 axis and tissue Treg maintain epithelial homeostasis and restrain cancer development in the skin.

Cell Rep. 2025-6-24

[5]
IL-33 Has a Protective Effect Against Perinatal Listeriosis by Regulating Mitophagy of CD8 T Lymphocytes.

J Interferon Cytokine Res. 2025-8

[6]
The IL-33-ST2 axis plays a vital role in endometriosis via promoting epithelial-mesenchymal transition by phosphorylating β-catenin.

Cell Commun Signal. 2024-6-10

[7]
Spatial and functional targeting of intratumoral Tregs reverses CD8+ T cell exhaustion and promotes cancer immunotherapy.

J Clin Invest. 2024-5-23

[8]
IL-33 regulates abnormally increased expression of ST2 in bone marrow follicular helper T cell in SLE with hematological abnormalities.

Clin Immunol. 2025-10

[9]
Temporal optimization of CD25-biased IL-2 agonists and immune checkpoint blockade leads to synergistic anticancer activity despite robust regulatory T cell expansion.

J Immunother Cancer. 2025-8-11

[10]
Treatment-induced arteriolar revascularization and miR-126 enhancement in bone marrow niche protect leukemic stem cells in AML.

J Hematol Oncol. 2021-8-9

本文引用的文献

[1]
A type 1 immunity-restricted promoter of the IL-33 receptor gene directs antiviral T-cell responses.

Nat Immunol. 2024-2

[2]
IL-33-ST2 signaling promotes stemness in subtypes of myeloid leukemia cells through the Wnt and Notch pathways.

Sci Signal. 2023-8-29

[3]
An IL1RL1 genetic variant lowers soluble ST2 levels and the risk effects of APOE-ε4 in female patients with Alzheimer's disease.

Nat Aging. 2022-7

[4]
Loss of Dnmt3a impairs hematopoietic homeostasis and myeloid cell skewing via the PI3Kinase pathway.

JCI Insight. 2023-5-8

[5]
BATF epigenetically and transcriptionally controls the activation program of regulatory T cells in human tumors.

Sci Immunol. 2022-10-14

[6]
Integrated stem cell signature and cytomolecular risk determination in pediatric acute myeloid leukemia.

Nat Commun. 2022-9-19

[7]
Immune dysfunction signatures predict outcomes and define checkpoint blockade-unresponsive microenvironments in acute myeloid leukemia.

J Clin Invest. 2022-11-1

[8]
Combined heterozygosity of FLT3 ITD, TET2, and DNMT3A results in aggressive leukemia.

JCI Insight. 2022-9-8

[9]
The complex role of tumor-infiltrating macrophages.

Nat Immunol. 2022-8

[10]
Doublet identification in single-cell sequencing data using .

F1000Res. 2021

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