AI Article Synopsis
- The study aimed to identify molecular features in human tumor cells that affect their sensitivity to natural killer (NK) cells by analyzing various solid tumor cell lines with a focus on genetic factors.
- High NK cell responsiveness was associated with tumor cells exhibiting 'mesenchymal-like' traits, significant expression of chromatin remodeling complexes, increased levels of B7-H6, and decreased expression of HLA-E and antigen presentation genes.
- The findings suggest that the characteristics of NK cell-sensitive tumors also correlate with resistance to immune checkpoint inhibitors, indicating potential for developing biomarkers to enhance NK cell immunotherapy strategies.
Article 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.
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| http://dx.doi.org/10.1038/s41588-021-00889-w | DOI Listing |
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