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.

in Cells by Jane Yu, Hyeon Joo Kim, Jordyn Reinecke, James Hucklesby, Tennille Read, Akshata Anchan, Catherine E Angel, Euan Scott Graham

TLDR

  • The study demonstrates the ability of NK-92 cells to kill patient-derived glioblastoma cells, with a potential for future targeting of highly resistant glioblastoma clones.
  • Key findings include impressive levels of killing at ET ratios of 5:1 and 1:1, and the ability of surviving glioblastoma cells to reseed the culture.

Abstract

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.

Overview

  • The study aimed to assess the ability of Natural Killer cells (NK-92) to kill patient-derived glioblastoma cells.
  • The study used ECIS biosensor technology to monitor the glioblastoma cells in real-time, enabling temporal assessment of the NK-92 cells.
  • The primary objective was to identify the mechanism utilized by the surviving glioblastoma cells that need to be targeted to achieve maximal cytolysis.

Comparative Analysis & Findings

  • NK-92 cells showed impressive levels of killing against various patient-derived glioblastoma cultures at ET ratios of 5:1 and 1:1.
  • Long-term ECIS experiments revealed that the surviving glioblastoma cells were able to grow and reseed the culture, evident 300-500 h after the addition of the NK-92 cells.
  • The study found that at higher ET ratios, the glioblastoma cells were acutely sensitive to the NK-92 cells, and the observed glioblastoma cell death was supported by high-content imaging data.

Implications and Future Directions

  • This research highlights the potential for NK-92 cells to kill glioblastoma tumour cells and provides a basis for identifying the mechanism used by surviving glioblastoma cells.
  • Future studies should focus on targeting the highly resistant glioblastoma clones to achieve maximal cytolysis.
  • The identification of potent evasive mechanisms by the glioblastoma tumour cells could lead to the development of novel therapeutic strategies to enhance the effectiveness of NK-92 cells.
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