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Updated: Oct 29, 2025
Measurement of Natural Killer Cell-Mediated Cytotoxicity and Migration in the Context of Hepatic Tumor Cells
Published on: February 22, 2020
Genome-scale screens identify factors regulating tumor cell responses to natural killer cells
Michal Sheffer1,2,3,4, Emily Lowry5, Nicky Beelen6,7
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Michal_Sheffer@dfci.havard.edu.
Abstract:
To systematically define molecular features in human tumor cells that determine their degree of sensitivity to human allogeneic natural killer (NK) cells, we quantified the NK cell responsiveness of hundreds of molecularly annotated 'DNA-barcoded' solid tumor cell lines in multiplexed format and applied genome-scale CRISPR-based gene-editing screens in several solid tumor cell lines, to functionally interrogate which genes in tumor cells regulate the response to NK cells. In these orthogonal studies, NK cell-sensitive tumor cells tend to exhibit 'mesenchymal-like' transcriptional programs; high transcriptional signature for chromatin remodeling complexes; high levels of B7-H6 (NCR3LG1); and low levels of HLA-E/antigen presentation genes. Importantly, transcriptional signatures of NK cell-sensitive tumor cells correlate with immune checkpoint inhibitor (ICI) resistance in clinical samples. This study provides a comprehensive map of mechanisms regulating tumor cell responses to NK cells, with implications for future biomarker-driven applications of NK cell immunotherapies.
Insights
Human tumor cells sensitive to natural killer (NK) cells show mesenchymal traits and specific gene expression. These features may predict resistance to immune checkpoint inhibitors, guiding NK cell therapy development.
Area of Science:
- Immunology
- Cancer Biology
- Genomics
Background:
- Natural killer (NK) cells are crucial for innate immunity and cancer surveillance.
- Understanding tumor cell factors influencing NK cell sensitivity is vital for immunotherapy development.
Purpose of the Study:
- To systematically identify molecular features of human tumor cells that dictate their sensitivity to allogeneic NK cells.
- To functionally interrogate genes regulating tumor cell response to NK cells using CRISPR screens.
Main Methods:
- Quantified NK cell responsiveness of hundreds of DNA-barcoded solid tumor cell lines.
- Performed genome-scale CRISPR-based gene-editing screens in solid tumor cell lines.
- Analyzed transcriptional programs, gene expression (B7-H6, HLA-E), and chromatin remodeling signatures.
Main Results:
- NK cell-sensitive tumor cells exhibit mesenchymal-like transcriptional programs.
- High expression of chromatin remodeling complexes and B7-H6 (NCR3LG1) correlates with sensitivity.
- Low expression of HLA-E and antigen presentation genes is associated with NK cell sensitivity.
- Transcriptional signatures of sensitive cells correlate with resistance to immune checkpoint inhibitors (ICIs) in clinical samples.
Conclusions:
- Identified key molecular determinants of tumor cell sensitivity to NK cells.
- Provides a comprehensive map of mechanisms regulating tumor cell-NK cell interactions.
- Findings have implications for developing biomarker-driven NK cell immunotherapies and predicting ICI resistance.
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