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UID:1037@biotech.technion.ac.il
DTSTART;TZID=Asia/Jerusalem:20210609T170000
DTEND;TZID=Asia/Jerusalem:20220202T164952
DTSTAMP:20220512T124718Z
URL:https://biotech.technion.ac.il/events/landscape-of-molecular-events-re
 gulating-tumor-cell-responses-to-natural-killer-cells-2/
SUMMARY:Landscape of molecular events regulating tumor cell responses to na
 tural killer cells
DESCRIPTION:Natural killer (NK) cells exhibit potent activity in pre-clinic
 al models of diverse hematologic malignancies and solid tumors and infusio
 n of high numbers of NK cells\, either autologous or allogeneic\, after th
 eir ex vivo expansion and activation\, has been feasible and safe in clini
 cal studies. To systematically define molecular features in human tumor ce
 lls which determine their degree of sensitivity to human allogeneic NK cel
 ls\, we quantified the NK cell responsiveness of hundreds of molecularly-a
 nnotated “DNA-barcoded” solid tumor cell lines in multiplexed format (
 PRISM\; Profiling Relative Inhibition Simultaneously in Mixtures approach)
 \, correlating cytotoxicity scores for each cell line with the CCLE transc
 riptional data (RNA-seq)\, to reveal genes that are associated with resist
 ance or sensitivity to NK cells. In addition\, we applied genome-scale CRI
 SPR-based gene editing screens in several solid tumor cell lines to interr
 ogate\, at a functional level\, which genes regulate tumor cell response t
 o NK cells. Based on these orthogonal studies\, NK sensitive tumor cells t
 end to exhibit high levels of the NK cell-activating ligand B7-H6 (NCR3LG1
 )\; low levels of the inhibitory ligand HLA-E\; microsatellite instability
  (MSI) status\; high transcriptional signature for chromatin remodeling co
 mplexes and low antigen presentation machinery genes. Treatment with an HD
 AC inhibitor reduced the sensitivity of SW620 colon cancer cells\, increas
 ed antigen presentation machinery\, including HLA-E\, and reduced B7-H6. I
 mportantly\, we observe that transcriptional signatures of NK cell-sensiti
 ve tumor cells correlate with immune checkpoint inhibitor resistance in cl
 inical samples. Strikingly\, comprehensive analysis of the CCLE transcript
 ional signatures revealed that cell lines with mesenchymal-like program te
 nd to be more sensitive to NK cells treatment\, compared with cell lines o
 f epithelial-like program. Indeed\, mesenchymal tumors tend to have lower 
 expression of antigen presentation machinery in both CCLE and TCGA\, sugge
 sting a link between these two machieneries. This study provides a compreh
 ensive map of mechanisms regulating tumor cell responses to NK cells\, wit
 h implications for future biomarker-driven applications of NK cell immunot
 herapies.
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