Genome-scale screens identify factors regulating tumor cell responses to natural killer cells

Michal Sheffer, Emily Lowry, Nicky Beelen, Minasri Borah, Suha Naffar Abu Amara, Chris C. Mader, Jennifer A. Roth, Aviad Tsherniak, Samuel S. Freeman, Olga Dashevsky, Sara Gandolfi, Samantha Bender, Jordan G. Bryan, Cong Zhu, Li Wang, Ifrah Tariq, Govinda M. Kamath, Ricardo De Matos Simoes, Eugen Dhimolea, Channing YuYiguo Hu, Olli Dufva, Marios Giannakis, Vasilis Syrgkanis, Ernest Fraenkel, Todd Golub, Rizwan Romee, Satu Mustjoki, Aedin C. Culhane, Lotte Wieten, Constantine S. Mitsiades

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1196-1206
Number of pages11
JournalNature Genetics
Volume53
Issue number8
DOIs
StatePublished - Aug 2021
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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