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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Sheffer, M; Lowry, E; Beelen, N; Borah, M; Amara, SN-A; Mader, CC; Roth, JA; Tsherniak, A; Freeman, SS; Dashevsky, O; Gandolfi, S; Bender, S; Bryan, JG; Zhu, C; Wang, L; Tariq, I; Kamath, GM; Simoes, RDM; Dhimolea, E; Yu, C; Hu, Y; Dufva, O; Giannakis, M; Syrgkanis, V; Fraenkel, E; Golub, T; Romee, R; Mustjoki, S; Culhane, AC; Wieten, L; Mitsiades, CS

Published Date

  • August 2021

Published In

Volume / Issue

  • 53 / 8

Start / End Page

  • 1196 - 1206

PubMed ID

  • 34253920

Electronic International Standard Serial Number (EISSN)

  • 1546-1718

International Standard Serial Number (ISSN)

  • 1061-4036

Digital Object Identifier (DOI)

  • 10.1038/s41588-021-00889-w

Language

  • eng