iPS衍生的自然杀伤细胞中删除抑制基因可增强其抗肿瘤活性

2020/7/28 10:56:12 本站原创 佚名 【字体:

Deleting an inhibitory gene in iPS-derived natural killer cells to boost their anti-tumor activity

iPS衍生的自然杀伤细胞中删除抑制基因可增强其抗肿瘤活性

 

廖联明     编译

 

Using induced pluripotent stem cells (iPSCs) and deleting a key gene, researchers at University of California San Diego School of Medicine have created natural killer cells with measurably stronger activity against a form of leukemia, both in vivo and in vitro.

加利福尼亚大学圣地亚哥分校医学院的研究人员使用诱导性多能干细胞(iPSC)并删除一个关键基因,产生了一种在体内和体外都对白血病有显著活性的自然杀伤细胞。

 

The findings are published in the June 11, 2020 online issue of Cell Stem Cell.

这项研究结果发表在2020611日的《细胞-干细胞》电子版上。

 

Natural killer (NK) cells are lymphocytes in the same family as T and B cells, and are part of the innate immune system. They circulate throughout the body and are among the first to respond to the presence of foreign cells or invaders, most notably viruses and early signs of cancer.

自然杀伤(NK)细胞是与T细胞和B细胞属于同一家族的淋巴细胞,是先天性免疫系统的一部分。它们在体内循环,并且是最早对外来细胞或入侵者作出反应,尤其是病毒和癌症的早期征兆。

 

As such, they hold great promise as the basis for anticancer therapies, able to identify and target malignant cells.

因此,它们有很大潜力能够作为抗癌疗法的基础,能够识别和靶向肿瘤细胞。

 

In the new study, a research team at UC San Diego School of Medicine advanced their potential in two ways.

在这项新研究中,加州大学圣地亚哥分校医学院的一个研究小组在两个方面提升了NK的潜力。

 

First, they created NK cells from IPSCs, which are derived from skin or blood cells that have been reprogrammed back to an embryonic-like pluripotent state and then directed to become NK cells. This strategy produces a standardized cell population, rather than needing to isolate cells on a patient-specific basis

首先,他们从iPSCs中生产NK细胞,iPSCs来源于皮肤或血液细胞,这些皮肤或血液细胞被重新编程回到胚胎样的多能状态,然后定向分化为NK细胞。这种方法产生一个标准化的细胞群,而不需要在病人特定的组织上分离细胞

 

Second, the researchers deleted a gene called CISH in the stem cell-derived NK cells. The CISH gene regulates expression of a protein that suppresses cytokine signaling. Cytokines are mole     cules that signal other immune system cells, such as macrophages, lymphocytes and fibroblasts to sites of infection, inflammation and trauma.

其次,研究人员在干细胞衍生的NK细胞中删除了一个名为CISH的基因。CISH基因调节抑制细胞因子信号传导的蛋白质的表达。细胞因子是感染、炎症和创伤部位向其他免疫系统细胞,如巨噬细胞,淋巴细胞和成纤维细胞,传递信号的信号分子。

 

Deletion of CISH in NK cells removes an internal ‘checkpoint’ that is normally activated or expressed when NK cells are stimulated by cytokines, such as IL15. CISH-deleted iPSC-derived NK cells were able to effectively cure mice that harbor human leukemia cells, whereas mice treated with the unmodified NK cells died from the leukemia.

删除NK细胞中CISH相当于清除了内部“检查点”,当NK细胞受到细胞因子如IL15的刺激时,该“检查点”通常被激活或表达。iPSC衍生、CISH缺失的NK细胞能够有效地治疗携带有人类白血病细胞的小鼠,而未经修饰的NK细胞治疗的小鼠则死于白血病。

 

These studies demonstrate that the CISH deletion improves NK cell function in at least two different ways. First, it removes a brake on IL15 signaling, with improves NK cell activation and function, even at low IL15 concentrations. Second, it leads to metabolic reprogramming of the NK cells. They become more efficient at energy utilization, which improves their function in vivo.

这些研究表明,CISH缺失至少在两个不同的方面改善NK细胞的功能。首先,它消除了对IL15信号传导的抑制,改善了NK细胞的激活和功能,即使在低浓度IL15下也是如此。其次,它使NK细胞的代谢重新编程。它们在能量利用方面变得更加高效,从而改善了它们在体内的功能。

 

As iPSC-derived NK cells are now in clinical trials to treat both hematologic (blood) malignancies and solid tumors, they expect that CISH-deleted iPSC-NK cells can provide an even more effective treatment.

由于iPSC衍生的NK细胞目前正在治疗血液系统(血液)恶性肿瘤和实体瘤的临床试验中,他们希望CISH缺失的iPSC-NK细胞能够提供更有效的治疗方法。

 

Importantly, iPSCs provide a stable platform for gene modification and since NK cells can be used as allogeneic cells that do not need to be matched to individual patients, they can create a line of appropriately modified iPSC-derived NK cells suitable for treating hundreds or thousands of patients as a standardized, ‘off-the-shelf’ therapy.

重要的是,iPSC为基因修饰提供了一个稳定的平台,并且由于NK细胞可以作为异基因细胞使用,而不需要与单个患者匹配。因此他们可以创建一系列经过适当修饰的iPSC衍生的NK细胞,适合作为一种标准化的“现成的”治疗方法来治疗成百上千的患者。

 

原文出处: 

Huang Zhu et al, Metabolic Reprograming via Deletion of CISH in Human iPSC-Derived NK Cells Promotes In Vivo Persistence and Enhances Anti-tumor Activity, Cell Stem Cell (2020). DOI: 10.1016/j.stem.2020.05.008

 

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