Association of (tumor-) stem cell characteristics with failure of NKG2D-mediated immunosurveillance

（肿瘤）干细胞特征与 NKG2D 介导的免疫监视失败的关联

• 批准号: 242417332
• 负责人: Professor Dr. Helmut Rainer Salih
• 金额: --
• 依托单位: Klinische Kooperationseinheit Translationale Immunologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/242417332?language=en
• 关键词: Association; tumor; stem; cell; characteristics

Available data suggest that only a subset of tumor cells, the so-called tumor stem cells (TSC), are responsible for initiation, maintenance and also relapse after conventional therapy of cancer. However, the development and course of malignant diseases also largely depends on the ability of the transformed cells to evade tumor immunesurveillance, for which NK cells as cytotoxic lymphocytes of innate immunity play an important role. NKG2D is an activating NK receptor, the discovery of which has led to the renaissance of the immune surveillance hypothesis, because its ligands (NKG2DL) are induced upon malignant transformation and potently stimulate anti-tumor immunity. Tumor cells employ various strategies to evade NKG2D-mediated immunesurveillance, which, among others, comprise shedding of NKG2DL from the cell surface to reduce the amount of stimulatory signals for NK cells. Other mechanisms involve direct modulation of NKG2DL-expression, for example via epigenetic regulation. Only little is currently known about the interactions between TSC and the immune system and on whether TSC, as compared to non-TSC, possess special properties to evade immunesurveillance. Our preliminary analyses with leukemia cells of patients with Acute Myeloid Leukemia (AML) reveals that AML-TSC (characterized by expression of CD34, their in vitro clonogenic ability and their in vivo leukaemia-initiating properties upon xenotransplantation in NSG mice) display substantially reduced NKG2DL expression as compared to Non-TSC, which also results in functionally impaired NK cell reactivity specifically against the TSC fraction. Moreover, lack of NKG2DL-expression is able to identify a subpopulation of AML cells displaying enhanced clonogenic capacity independently of CD34 expression, suggesting that lacking NKG2DL expression may be used as a novel marker for the identification of TSC in AML. Based on these data, in the proposed project we aim to comprehensively characterize NKG2DL expression in AML-TSC versus Non-TSC and the consequences for NK-mediated AML immunesurveillance. Moreover, we plan to elucidate the molecular mechanisms responsible for the differential NKG2DL levels in AML-TSC versus Non-TSC as well as the possibilities to therapeutically induce NKG2DL expression in AML-TSC to reinforce anti-tumor immunity. Finally the prevalence of NKG2DL expression on AML-TSC will be correlated with the clinical course of the disease in patients. Taken together, the proposed project serves to further elucidate properties of AML-TSC, especially with regard to their ability to evade tumor immunesurveillance and thereby also holds promise to identify novel immune-sculpting characteristics associated with stemness properties of malignant cells in general.

现有的数据表明，只有一个肿瘤细胞的子集，所谓的肿瘤干细胞（TSC），是负责启动，维持和癌症的常规治疗后复发。然而，恶性疾病的发展和进程在很大程度上也取决于转化细胞逃避肿瘤免疫监视的能力，其中NK细胞作为天然免疫的细胞毒性淋巴细胞起着重要作用。NKG 2D是一种活化NK受体，其发现导致免疫监视假说的复兴，因为其配体（NKG 2DL）在恶性转化时被诱导并有效刺激抗肿瘤免疫。肿瘤细胞采用各种策略来逃避NKG 2D介导的免疫监视，其中包括从细胞表面脱落NKG 2DL以减少NK细胞的刺激信号的量。其他机制涉及直接调节NKG 2DL表达，例如通过表观遗传调控。目前对TSC和免疫系统之间的相互作用以及TSC与非TSC相比是否具有逃避免疫监视的特殊性质知之甚少。我们对急性髓性白血病（AML）患者的白血病细胞的初步分析显示，与非TSC相比，AML-TSC（其特征在于表达CD 34，其体外克隆形成能力及其在NSG小鼠中异种移植后的体内白血病引发特性）显示出显著降低的NKG 2DL表达，这也导致NK细胞特异性针对TSC组分的功能受损。此外，NKG 2DL表达的缺乏能够鉴定AML细胞亚群，其显示出独立于CD 34表达的增强的克隆形成能力，这表明NKG 2DL表达的缺乏可用作鉴定AML中TSC的新标志物。基于这些数据，在拟议的项目中，我们的目标是全面表征AML-TSC与非TSC中的NKG 2DL表达以及NK介导的AML免疫监测的后果。此外，我们计划阐明AML-TSC与非TSC中NKG 2DL水平差异的分子机制，以及治疗性诱导AML-TSC中NKG 2DL表达以增强抗肿瘤免疫力的可能性。最后，AML-TSC上NKG 2DL表达的流行率将与患者的疾病临床病程相关。综上所述，所提出的项目有助于进一步阐明AML-TSC的特性，特别是关于它们逃避肿瘤免疫监测的能力，从而也有望确定与一般恶性细胞的干细胞特性相关的新的免疫雕刻特征。