Scholarlink

<p>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<sub>reg</sub> cells) and accelerate malignant progression in solid tumors, but their role in leukemia remains unclear. Here, we show that ST2<sup>+</sup> T<sub>reg</sub> cells are enriched in bone marrow (BM) of humans and mice with AML and promote CD8<sup>+</sup> T cells depletion and exhaustion. ST2 deficiency in T<sub>reg</sub> cells restores CD8<sup>+</sup> T cell function, decreasing AML growth via retention of ST2<sup>+</sup> T<sub>reg</sub> cells precursors in lymph nodes. AML-activated ST2<sup>+</sup> T<sub>reg</sub> cells lack T-bet, IFN-γ and Bcl-6, and kill intratumoral CD8<sup>+</sup> T cells by amplified granzyme B-mediated cytotoxicity compared to non-AML primed T<sub>reg</sub> cells. Engineered anti-ST2 antibodies induce ST2<sup>+</sup> T<sub>reg</sub> cells apoptosis to extend survival in AML models. Together, our findings suggest that ST2 is a potential checkpoint target for AML immunotherapy.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年7月21日

查看全文
  • 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

摘要

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.