RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题:Trying to Kill a Killer; Impressive Killing of Patient Derived Glioblastoma Cultures Using NK-92 Natural Killer Cells Reveals Both Sensitive and Highly Resistant Glioblastoma Cells.
Trying to Kill a Killer; Impressive Killing of Patient Derived Glioblastoma Cultures Using NK-92 Natural Killer Cells Reveals Both Sensitive and Highly Resistant Glioblastoma Cells.
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本工作的总体目标是评估NK 细胞杀伤患者来源的胶质母细胞瘤细胞培养物的能力。在此,我们报告了在5:1和1:1的ET(效应细胞:靶细胞)比率下观察到的NK-92介导的对多种患者来源胶质母细胞瘤培养物的显著杀伤水平。这使得能够在更广泛的胶质母细胞瘤培养物范围内直接比较胶质母细胞瘤细胞损失的程度。
重要的是,即使在5:1的高ET比率下,始终存在一些亚群胶质母细胞瘤细胞被证明极难杀伤,它们能够逃避NK-92细胞。本研究的价值在于应用了ECIS(电细胞-基底阻抗传感)生物传感器技术实时监测胶质母细胞瘤细胞,从而能够对NK-92细胞进行时间维度评估。ECIS在揭示以下现象方面发挥了强大作用:在较高ET比率下,胶质母细胞瘤细胞对NK-92细胞高度敏感,且观察到的胶质母细胞瘤细胞死亡得到了高内涵成像数据的支持。
此外,长期ECIS实验揭示,存活的胶质母细胞瘤细胞随后能够生长并重新播种培养物,这在加入NK-92细胞后300-500小时变得明显。这一现象在多个胶质母细胞瘤细胞系中均被观察到。
此外,我们的成像提供了证据表明,一些NK-92细胞似乎在早期就受到损害,这与胶质母细胞瘤肿瘤细胞强大的逃避机制相一致。本研究强烈突出了NK-92细胞杀伤胶质母细胞瘤肿瘤细胞的潜力,并为识别存活胶质母细胞瘤细胞所利用的机制提供了基础,我们现在需要靶向这些机制以实现对耐药胶质母细胞瘤细胞的最大限度的细胞溶解。正是高度耐药的胶质母细胞瘤克隆的存活导致了肿瘤复发。
The overall goal of this work was to assess the ability of Natural Killer cells to kill cultures of patient-derived glioblastoma cells.
Herein we report impressive levels of NK-92 mediated killing of various patient-derived glioblastoma cultures observed at ET (effector: target) ratios of 5:1 and 1:1. This enabled direct comparison of the degree of glioblastoma cell loss across a broader range of glioblastoma cultures.
Importantly, even at high ET ratios of 5:1, there are always subpopulations of glioblastoma cells that prove very challenging to kill that evade the NK-92 cells. Of value in this study has been the application of ECIS (Electric Cell-Substrate Impedance Sensing) biosensor technology to monitor the glioblastoma cells in real-time, enabling temporal assessment of the NK-92 cells.
ECIS has been powerful in revealing that at higher ET ratios, the glioblastoma cells are acutely sensitive to the NK-92 cells, and the observed glioblastoma cell death is supported by the high-content imaging data.
Moreover, long-term ECIS experiments reveal that the surviving glioblastoma cells were then able to grow and reseed the culture, which was evident 300-500 h after the addition of the NK-92 cells. This was observed for multiple glioblastoma lines.
In addition, our imaging provides evidence that some NK-92 cells appear to be compromised early, which would be consistent with potent evasive mechanisms by the glioblastoma tumour cells.
This research strongly highlights the potential for NK-92 cells to kill glioblastoma tumour cells and provides a basis to identify the mechanism utilised by the surviving glioblastoma cells that we now need to target to achieve maximal cytolysis of the resistant glioblastoma cells. It is survival of the highly resistant glioblastoma clones that results in tumour relapse.
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