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研究揭示白血病肿瘤干细胞免疫逃逸机制
来源:小柯机器人 发布时间:2019/8/8 20:20:00

近日,德国科学家合作发现,NKG2D配体在白血病干细胞中缺失,并介导了肿瘤的免疫逃避。该研究于2019年8月8日发表于国际学术期刊《自然》上。

研究人员证明干性和免疫逃避在AML中密切相关。使用人类AML的异种移植瘤以及同基因白血病小鼠模型,研究人员发现,危险检测器NKG2Da的配体通常在大量AML细胞上表达但在LSC上不表达,这是一个通过细胞杀伤淋巴细胞(例如NK细胞)进行抗肿瘤免疫的关键介导者。具有LSC特性的AML细胞可以在CD34表达和不表达的AML病例中通过缺乏NKG2D配体(NKG2DL)的表达来分离。表达NKG2DL的AML细胞被NK细胞清除,而从相同个体分离的NKG2DL阴性白血病细胞可逃逸,从而不被NK细胞杀死。这些NKG2DL阴性AML细胞具有未成熟的形态,表现出分子和功能上的干性特征,并且可以在患者来源的异种移植模型中引起可再移植的白血病并在化疗中存活。在机制上,聚-ADP-核糖聚合酶1(PARP1)抑制NKG2DL的表达。PARP1的遗传或药物抑制增加LSC细胞膜上的NKG2DL,但不增加健康或白血病前体细胞。利用PARP1抑制剂治疗,然后移植多克隆NK细胞,可以在患者来源的异种移植模型中抑制白血病的发生。总之,这些发现将LSC概念与免疫逃逸联系起来,并为通过PARP1抑制(这使得白血病细胞在体内被NK细胞所控制)靶向治疗抗性LSC提供了强有力的理论基础。

据了解,急性髓性白血病(AML)患者在治疗后常常达到缓解,但随后死于由化疗耐药的白血病干细胞(LSC)引起的复发。LSC由其在免疫受损小鼠中引发白血病的能力而定义。然而,这排除了对它们作为抗肿瘤免疫的组分与淋巴细胞相互作用的分析,LSC必须逃脱才能引发癌症。

附:英文原文

Title: Absence of NKG2D ligands defines leukaemia stem cells and mediates their immune evasion

Author: Anna M. Paczulla, Kathrin Rothfelder, Simon Raffel, Martina Konantz, Julia Steinbacher, Hui Wang, Claudia Tandler, Marcelle Mbarga, Thorsten Schaefer, Mattia Falcone, Eva Nievergall, Daniela Drfel, Pauline Hanns, Jakob R. Passweg, Christoph Lutz, Juerg Schwaller, Robert Zeiser, Bruce R. Blazar, Michael A. Caligiuri, Stephan Dirnhofer, Pontus Lundberg, Lothar Kanz, Leticia Quintanilla-Martinez, Alexander Steinle, Andreas Trumpp, Helmut R. Salih, Claudia Lengerke

Issue&Volume:  Volume 572 Issue 7768

Abstract: Patients with acute myeloid leukaemia (AML) often achieve remission after therapy, but subsequently die of relapse that is driven by chemotherapy-resistant leukaemic stem cells (LSCs). LSCs are defined by their capacity to initiate leukaemia in immunocompromised mice. However, this precludes analyses of their interaction with lymphocytes as components of anti-tumour immunity, which LSCs must escape to induce cancer. Here we demonstrate that stemness and immune evasion are closely intertwined in AML. Using xenografts of human AML as well as syngeneic mouse models of leukaemia, we show that ligands of the danger detector NKG2Da critical mediator of anti-tumour immunity by cytotoxic lymphocytes, such as NK cells—are generally expressed on bulk AML cells but not on LSCs. AML cells with LSC properties can be isolated by their lack of expression of NKG2D ligands (NKG2DLs) in both CD34-expressing and non-CD34-expressing cases of AML. AML cells that express NKG2DLs are cleared by NK cells, whereas NKG2DL-negative leukaemic cells isolated from the same individual escape cell killing by NK cells. These NKG2DL-negative AML cells show an immature morphology, display molecular and functional stemness characteristics, and can initiate serially re-transplantable leukaemia and survive chemotherapy in patient-derived xenotransplant models. Mechanistically, poly-ADP-ribose polymerase 1 (PARP1) represses expression of NKG2DLs. Genetic or pharmacologic inhibition of PARP1 induces NKG2DLs on the LSC surface but not on healthy or pre-leukaemic cells. Treatment with PARP1 inhibitors, followed by transfer of polyclonal NK cells, suppresses leukaemogenesis in patient-derived xenotransplant models. In summary, our data link the LSC concept to immune escape and provide a strong rationale for targeting therapy-resistant LSCs by PARP1 inhibition, which renders them amenable to control by NK cells in vivo.

DOI: 10.1038/s41586-019-1410-1

Source: https://www.nature.com/articles/s41586-019-1410-1

期刊信息

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Volume 572 Issue 7768