EZH2促进NK/ILC1细胞转化在急性髓系白血病免疫逃逸中作用及机制研究

Immune escape is considered as a fundamental reason for AML refractoriness and relapse, in which the decreased proportion of natural killer cells and their functional defects play a key role. The most recent study reported that abnormal NK/ILC1 transformation served as a novel mechanism for tumor immune escape. We newly found that NK cells decreased while ILC1 cells increased in both AML patients and mouse models. Co-culture with AML blasts promoted NK cells from healthy donors to transform into ILC1 cells. However the specific mechanisms underlying NK/ILC1 transformation in AML remain to be elucidated. We further revealed that EZH2 was upregulated in NK cells from AML patients. Applying small molecular inhibitor of EZH2 in the co-culture system partially blocked NK/ILC1 transformation. Therefore we proposed that upregulation of EZH2 might participate in AML immune escape by facilitating NK/ILC1 transformation. In the following study, we intend to investigate the influences that NK/ILC1 transformation exert on AML immune escape and clarify the underlying molecular mechanisms by which EZH2 mediates this transformation process. By using conditional knockout mice, we will discuss whether targeting EZH2 specifically in NK cells could reverse NK/ILC1 transformation and thus assist AML therapy in vivo.

免疫逃逸是急性髓系白血病（AML）难治、复发的重要原因，AML患者NK细胞比例降低、功能缺陷在其中起到关键作用。最新研究表明，NK/ILC1细胞异常转化是肿瘤免疫逃逸的新机制。我们发现AML患者和AML模型鼠中NK细胞比例降低，ILC1比例升高；将正常受试者NK细胞与AML细胞共培养可促进其表型向ILC1转化，然而具体机制尚不明确。进一步研究发现AML患者NK细胞中EZH2表达较对照上调，而EZH2抑制剂可阻断共培养体系中NK细胞向ILC1转化。因此我们推测EZH2可通过促进NK/ILC1转化参与AML免疫逃逸。本项目拟在前期工作基础上，研究NK/ILC1细胞异常转化对AML免疫逃逸的影响，阐明EZH2促进NK/ILC1转化的分子机制，利用条件敲除鼠模型在体内探讨靶向EZH2逆转NK/ILC1转化辅助治疗AML的可行性。预期目标的实现将揭示AML免疫逃逸新机制，对AML治疗具有重要意义。

免疫逃逸是急性髓系白血病（AML）难治、复发的重要原因，AML患者NK细胞比例降低、功能缺陷在其中起到关键作用，本项目以研究AML中NK细胞功能失调的机制为主要目标。我们发现AML患者和AML模型鼠中NK细胞比例降低，ILC1比例升高；将AML原始细胞与NK细胞共培养可促进其表型向ILC1转化，进一步研究发现AML患者NK细胞中EZH2的表达较对照上调，而EZH2抑制剂可阻断共培养体系中NK细胞向ILC1转化。我们还发现乏氧环境能够诱导AML细胞CD155表达上调，进而通过CD155/Tigit通路负性调控NK细胞的功能，影响其抗白血病效应。本研究还发现PARP1抑制剂能够通过抑制NK/ILC1转化，部分恢复AML模型鼠NK细胞的杀伤功能。我们还做了2例AML患者来源NK细胞的单细胞RNA测序，进行聚类分析，寻找差异基因。本研究通过体内、体外实验探讨靶向EZH2及CD155/Tigit恢复NK细胞功能，抑制AML细胞免疫逃逸的可能性，对AML的免疫治疗、新药筛选等具有重要意义。