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Updated: Jun 5, 2026
Measurement of Natural Killer Cell-Mediated Cytotoxicity and Migration in the Context of Hepatic Tumor Cells
Published on: February 22, 2020
A human NK cell activation/inhibition threshold allows small changes in the target cell surface phenotype to
Tim D Holmes1, Yasser M El-Sherbiny, Adam Davison
1Leeds Institute of Molecular Medicine, University of Leeds, St. James's University Hospital, Leeds LS9 7TF, United Kingdom.
Abstract:
NK cell activation is negatively regulated by the expression of target cell MHC class I molecules. We show that this relationship is nonlinear due to an NK cell activation/inhibition threshold. Ewing's sarcoma family tumor cell monolayers, which were highly susceptible to NK cells in vitro, developed a highly resistant phenotype when cultured as three-dimensional multicellular tumor spheroid structures. This suggested that tumor architecture is likely to influence the susceptibility to NK cells in vivo. Resistance of the multicellular tumor spheroid was associated with the increased expression of MHC class I molecules and greatly reduced NK cell activation, implying that a threshold of NK cell activation/inhibition had been crossed. Reducing MHC class I expression on Ewing's sarcoma family tumor monolayers did not alter their susceptibility to NK cells, whereas increased expression of MHC class I rendered them resistant and allowed the threshold point to be identified. This threshold, as defined by MHC class I expression, was predictive of the number of NK-resistant target cells within a population. A threshold permits modest changes in the target cell surface phenotype to profoundly alter the susceptibility to NK cells. Whereas this allows for the efficient detection of target cells, it also provides a route for pathogens and tumors to evade NK cell attack.
Insights
Natural killer (NK) cell activation is regulated by a threshold of target cell MHC class I expression. Tumor architecture influences this threshold, impacting NK cell resistance and immune evasion.
Area of Science:
- Immunology
- Cancer Biology
- Cellular Biology
Background:
- Natural killer (NK) cell activation is typically inhibited by target cell MHC class I expression.
- The precise relationship between MHC class I expression and NK cell inhibition is not fully understood, particularly in complex 3D tumor structures.
Purpose of the Study:
- To investigate the role of a nonlinear activation/inhibition threshold in NK cell recognition.
- To determine how tumor architecture, specifically multicellular spheroid formation, affects NK cell susceptibility through MHC class I modulation.
Main Methods:
- Cultured Ewing's sarcoma family tumor cells as monolayers and 3D multicellular tumor spheroids.
- Assessed NK cell susceptibility and activation in relation to MHC class I expression levels.
- Manipulated MHC class I expression on tumor cells to identify the activation/inhibition threshold.
Main Results:
- Multicellular tumor spheroids exhibited increased resistance to NK cells compared to monolayers.
- This resistance correlated with elevated MHC class I expression, suggesting a crossed NK cell activation/inhibition threshold.
- A specific threshold of MHC class I expression was identified, predicting NK-resistant cell populations.
Conclusions:
- Tumor architecture significantly influences NK cell susceptibility by modulating MHC class I expression and crossing an activation/inhibition threshold.
- This threshold mechanism allows for profound changes in NK cell sensitivity and provides a strategy for tumor immune evasion.
- Understanding this threshold is crucial for developing targeted immunotherapies against tumors.
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