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 Yu; Yiguo Hu; Olli Dufva; Marios Giannakis; Vasilis Syrgkanis; Ernest Fraenkel; Todd Golub; Rizwan Romee; Satu Mustjoki; Aedin C. Culhane; Lotte Wieten; Constantine S. Mitsiades

doi:10.1038/s41588-021-00889-w

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 journal › Article › peer-review

37 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 language	English (US)
Pages (from-to)	1196-1206
Number of pages	11
Journal	Nature Genetics
Volume	53
Issue number	8
DOIs	https://doi.org/10.1038/s41588-021-00889-w
State	Published - Aug 2021
Externally published	Yes

ASJC Scopus subject areas

Genetics

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Sheffer, M., Lowry, E., Beelen, N., Borah, M., Amara, S. N. A., Mader, C. C., Roth, J. A., Tsherniak, A., Freeman, S. S., Dashevsky, O., Gandolfi, S., Bender, S., Bryan, J. G., Zhu, C., Wang, L., Tariq, I., Kamath, G. M., Simoes, R. D. M., Dhimolea, E., ... Mitsiades, C. S. (2021). Genome-scale screens identify factors regulating tumor cell responses to natural killer cells. Nature Genetics, 53(8), 1196-1206. https://doi.org/10.1038/s41588-021-00889-w

Sheffer, M, Lowry, E, Beelen, N, Borah, M, Amara, SNA, 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 2021, 'Genome-scale screens identify factors regulating tumor cell responses to natural killer cells', Nature Genetics, vol. 53, no. 8, pp. 1196-1206. https://doi.org/10.1038/s41588-021-00889-w

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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 = "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",

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AU - Sheffer, Michal

AU - Lowry, Emily

AU - Beelen, Nicky

AU - Borah, Minasri

AU - Amara, Suha Naffar Abu

AU - Mader, Chris C.

AU - Roth, Jennifer A.

AU - Tsherniak, Aviad

AU - Freeman, Samuel S.

AU - Dashevsky, Olga

AU - Gandolfi, Sara

AU - Bender, Samantha

AU - Bryan, Jordan G.

AU - Zhu, Cong

AU - Wang, Li

AU - Tariq, Ifrah

AU - Kamath, Govinda M.

AU - Simoes, Ricardo De Matos

AU - Dhimolea, Eugen

AU - Yu, Channing

AU - Hu, Yiguo

AU - Dufva, Olli

AU - Giannakis, Marios

AU - Syrgkanis, Vasilis

AU - Fraenkel, Ernest

AU - Golub, Todd

AU - Romee, Rizwan

AU - Mustjoki, Satu

AU - Culhane, Aedin C.

AU - Wieten, Lotte

AU - Mitsiades, Constantine S.

PY - 2021/8

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N2 - 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.

AB - 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.

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

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