@article{27fe29d0883b4abd91f6739dce812116,
title = "Genome-scale screens identify factors regulating tumor cell responses to natural killer cells",
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 {\textquoteleft}DNA-barcoded{\textquoteright} 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 {\textquoteleft}mesenchymal-like{\textquoteright} 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.",
author = "Michal Sheffer and Emily Lowry and Nicky Beelen and Minasri Borah and Amara, {Suha Naffar Abu} and Mader, {Chris C.} and Roth, {Jennifer A.} and Aviad Tsherniak and Freeman, {Samuel S.} and Olga Dashevsky and Sara Gandolfi and Samantha Bender and Bryan, {Jordan G.} and Cong Zhu and Li Wang and Ifrah Tariq and Kamath, {Govinda M.} and Simoes, {Ricardo De Matos} and Eugen Dhimolea and Channing Yu and Yiguo Hu and Olli Dufva and Marios Giannakis and Vasilis Syrgkanis and Ernest Fraenkel and Todd Golub and Rizwan Romee and Satu Mustjoki and Culhane, {Aedin C.} and Lotte Wieten and Mitsiades, {Constantine S.}",
note = "Funding Information: C.C.M., J.A.R., C.Y., T.G., L. Wieten, M.S. and C.S.M. are authors of a patent application related to antitumor activity of NK cells. C.S.M. also discloses consultant/honoraria from Fate Therapeutics, Ionis Pharmaceuticals and FIMECS; employment of a relative with Takeda; and research funding from Janssen/Johnson & Johnson, TEVA, EMD Serono, Abbvie, Arch Oncology, Karyopharm, Sanofi, Nurix and H3 Biomedicine. M.G. receives research funding from Bristol-Myers Squibb and Merck. A.T. is a consultant for Tango Therapeutics. S.M. has received honoraria and research funding from Novartis, Pfizer and Bristol-Myers Squibb (not related to this study). The remaining authors declare no competing interests. Funding Information: This work was supported by the Stand Up To Cancer (SU2C) Convergence 2.0 Grant (M.S., A.C.C., C.S.M.), a collaboration by SU2C and the Society for Immunotherapy of Cancer; the SU2C Phillip A. Sharp Award for Innovation in Collaboration (grant number: SU2C-AACR-PS-22) (M.S., C.S.M.); the Claudia Adams Barr Program in Innovative Basic Cancer Research at Dana–Farber Cancer Institute (M.S., E.D., C.S.M., E.L.); the Human Frontier Science Program (HFSP) Fellowship (LT000834/2014-L, M.S.); the Leukemia and Lymphoma Society (LLS) Scholar Award (C.S.M.); and the Ludwig Center at Harvard (C.S.M.). The collaborating laboratories have also been partially supported by grants NIH R01 CA050947 (C.S.M.), CA196664 (C.S.M.) and U01 CA225730 (C.S.M.); de Gunzburg Myeloma Research Fund (C.S.M.); International Myeloma Society (C.S.M.), the Shawna Ashlee Corman Investigatorship in Multiple Myeloma Research (C.S.M.); Cobb Family Myeloma Research Fund (C.S.M.); the Department of Defense grants W81XWH-15-1-0012 (C.S.M.) and W81XWH-15-1-0013 (A.C.); the Finnish Cancer Organizations, Sigrid Juselius Foundation, Academy of Finland (S.M.); the Health Foundation Limburg, Nijbakker-Morra Stichting (N.B.); and the Dutch Cancer Association (KWF Kanker Bestrijding, UM2012-5375) (L. Wieten). We thank M. Sade-Feldman for technical advice and discussion, A. Rotem for the gift of Malme-3M cell line and Y. Maruvka for assistance with MSI profiling. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2021",
month = aug,
doi = "10.1038/s41588-021-00889-w",
language = "English (US)",
volume = "53",
pages = "1196--1206",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "8",
}