| Literature DB >> 34253920 |
Michal Sheffer1,2,3,4, Emily Lowry5, Nicky Beelen6,7, Minasri Borah5, Suha Naffar-Abu Amara8, Chris C Mader9, Jennifer A Roth9, Aviad Tsherniak9, Samuel S Freeman9, Olga Dashevsky5,10,9,11, Sara Gandolfi5,10,9,11, Samantha Bender9, Jordan G Bryan9, Cong Zhu9, Li Wang9, Ifrah Tariq9,12, Govinda M Kamath13, Ricardo De Matos Simoes5,10,9,11, Eugen Dhimolea5,10,9,11, Channing Yu5,10,9, Yiguo Hu5,14, Olli Dufva15,16,17, Marios Giannakis5,10,9, Vasilis Syrgkanis13, Ernest Fraenkel9,12, Todd Golub5,9, Rizwan Romee5,10, Satu Mustjoki15,16,17, Aedin C Culhane18,19, Lotte Wieten6,7, Constantine S Mitsiades20,21,22,23.
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.Entities:
Year: 2021 PMID： 34253920 DOI： 10.1038/s41588-021-00889-w
Source DB: PubMed Journal: Nat Genet ISSN： 1061-4036 Impact factor: 38.330