Regulatory T cells promote the stemness of leukemia stem cells through IL10 cytokine-related signaling pathway
Regulatory T cells promote the stemness of leukemia stem cells through IL10 cytokine-related signaling pathway
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DOI：
10.1038/s41375-021-01375-2
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发表时间：
2021-08-11
期刊：
影响因子：
11.4
通讯作者：
Wang, Jianxiang
中科院分区：
文献类型：
--
作者：
Xu, Yingxi;Mou, Junli;Wang, Jianxiang
调节性T细胞（Treg）可以维持干细胞的特性并抑制正常造血干/祖细胞的分化。最近的研究表明，Tregs作为急性髓系白血病（AML）微环境的重要组成部分，可以帮助AML细胞逃避免疫监视。然而，它们直接调节 AML 细胞干性的功能仍然难以捉摸。在这项研究中，Tregs 促进的 AML 细胞干性增加在体外和体内得到了验证。对Tregs释放的细胞因子进行了探索，发现高表达的抗炎细胞因子IL10可以通过激活PI3K/AKT信号通路促进AML细胞的干性。此外，破坏AML/ETO c-kit(mut) (A/Ec)白血病小鼠的IL10/IL10R/PI3K/AKT信号可以延长小鼠的存活时间并降低A/Ec白血病细胞的干性。最后在患者样本中证实，Tregs与白血病干细胞（LSC）的比例呈正相关，并且在CD34（+）原代AML细胞中，Tregs浸润高的患者中PI3K/AKT的激活更强。 rhIL10 处理后，原代 AML 细胞表现出 PI3K/AKT 信号传导增强。因此，阻断Tregs与AML细胞之间的相互作用可能是靶向LSCs治疗AML的新方法。
Regulatory T cells (Tregs) could maintain the characteristics of stem cells and inhibit the differentiation of normal hematopoietic stem/progenitor cells. Recent studies have shown that Tregs, as an important component of acute myeloid leukemia (AML) microenvironments, can help AML cells to evade immune surveillance. However, their function in directly regulating the stemness of AML cells remains elusive. In this study, the increased stemness of AML cells promoted by Tregs was verified in vitro and in vivo. The cytokines released by Tregs were explored, the highly expressed anti-inflammatory cytokine IL10 was found, which could promote the stemness of AML cells through the activation of PI3K/AKT signal pathway. Moreover, disrupting the IL10/IL10R/PI3K/AKT signal in AML/ETO c-kit(mut) (A/Ec) leukemia mice could prolong the mice survival and reduce the stemness of A/Ec leukemia cells. Finally, it was confirmed in patient samples that the proportion of Tregs to leukemia stem cells (LSCs) was positively correlated, and in CD34(+) primary AML cells, the activation of PI3K/AKT was stronger in patients with high Tregs' infiltration. After rhIL10 treatment, primary AML cells showed increased activation of PI3K/AKT signaling. Therefore, blocking the interaction between Tregs and AML cells may be a new approach to target LSCs in AML treatment.