Single-cell functional genomics reveals determinants of sensitivity and resistance to natural killer cells in blood cancers

Olli Dufva; Sara Gandolfi; Jani Huuhtanen; Olga Dashevsky; Hanna Duàn; Khalid Saeed; Jay Klievink; Petra Nygren; Jonas Bouhlal; Jenni Lahtela; Anna Näätänen; Bishwa R. Ghimire; Tiina Hannunen; Pekka Ellonen; Hanna Lähteenmäki; Pauliina Rumm; Jason Theodoropoulos; Essi Laajala; Jouni Härkönen; Petri Pölönen; Merja Heinäniemi; Maija Hollmén; Shizuka Yamano; Ryosuke Shirasaki; David A. Barbie; Jennifer A. Roth; Rizwan Romee; Michal Sheffer; Harri Lähdesmäki; Dean A. Lee; Ricardo De Matos Simoes; Matti Kankainen; Constantine S. Mitsiades; Satu Mustjoki

doi:10.1016/j.immuni.2023.11.008

Single-cell functional genomics reveals determinants of sensitivity and resistance to natural killer cells in blood cancers

Olli Dufva, Sara Gandolfi, Jani Huuhtanen, Olga Dashevsky, Hanna Duàn, Khalid Saeed, Jay Klievink, Petra Nygren, Jonas Bouhlal, Jenni Lahtela, Anna Näätänen, Bishwa R. Ghimire, Tiina Hannunen, Pekka Ellonen, Hanna Lähteenmäki, Pauliina Rumm, Jason Theodoropoulos, Essi Laajala, Jouni Härkönen, Petri PölönenMerja Heinäniemi, Maija Hollmén, Shizuka Yamano, Ryosuke Shirasaki, David A. Barbie, Jennifer A. Roth, Rizwan Romee, Michal Sheffer, Harri Lähdesmäki, Dean A. Lee, Ricardo De Matos Simoes, Matti Kankainen, Constantine S. Mitsiades, Satu Mustjoki

Research output: Contribution to journal › Article › peer-review

25 Scopus citations

Abstract

Cancer cells can evade natural killer (NK) cell activity, thereby limiting anti-tumor immunity. To reveal genetic determinants of susceptibility to NK cell activity, we examined interacting NK cells and blood cancer cells using single-cell and genome-scale functional genomics screens. Interaction of NK and cancer cells induced distinct activation and type I interferon (IFN) states in both cell types depending on the cancer cell lineage and molecular phenotype, ranging from more sensitive myeloid to less sensitive B-lymphoid cancers. CRISPR screens in cancer cells uncovered genes regulating sensitivity and resistance to NK cell-mediated killing, including adhesion-related glycoproteins, protein fucosylation genes, and transcriptional regulators, in addition to confirming the importance of antigen presentation and death receptor signaling pathways. CRISPR screens with a single-cell transcriptomic readout provided insight into underlying mechanisms, including regulation of IFN-γ signaling in cancer cells and NK cell activation states. Our findings highlight the diversity of mechanisms influencing NK cell susceptibility across different cancers and provide a resource for NK cell-based therapies.

Original language	English
Pages (from-to)	2816-2835.e13
Journal	Immunity
Volume	56
Issue number	12
DOIs	https://doi.org/10.1016/j.immuni.2023.11.008
State	Published - 12 Dec 2023
Externally published	Yes

Keywords

cancer
CRISPR screening
CROP-seq
functional genomics
immunotherapy resistance
leukemia
lymphoma
myeloma
NK cell
single-cell RNA sequencing

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.immuni.2023.11.008

Cite this

Dufva, O., Gandolfi, S., Huuhtanen, J., Dashevsky, O., Duàn, H., Saeed, K., Klievink, J., Nygren, P., Bouhlal, J., Lahtela, J., Näätänen, A., Ghimire, B. R., Hannunen, T., Ellonen, P., Lähteenmäki, H., Rumm, P., Theodoropoulos, J., Laajala, E., Härkönen, J., ... Mustjoki, S. (2023). Single-cell functional genomics reveals determinants of sensitivity and resistance to natural killer cells in blood cancers. Immunity, 56(12), 2816-2835.e13. https://doi.org/10.1016/j.immuni.2023.11.008

@article{bc54fdad253947e7a41054268541f519,

title = "Single-cell functional genomics reveals determinants of sensitivity and resistance to natural killer cells in blood cancers",

abstract = "Cancer cells can evade natural killer (NK) cell activity, thereby limiting anti-tumor immunity. To reveal genetic determinants of susceptibility to NK cell activity, we examined interacting NK cells and blood cancer cells using single-cell and genome-scale functional genomics screens. Interaction of NK and cancer cells induced distinct activation and type I interferon (IFN) states in both cell types depending on the cancer cell lineage and molecular phenotype, ranging from more sensitive myeloid to less sensitive B-lymphoid cancers. CRISPR screens in cancer cells uncovered genes regulating sensitivity and resistance to NK cell-mediated killing, including adhesion-related glycoproteins, protein fucosylation genes, and transcriptional regulators, in addition to confirming the importance of antigen presentation and death receptor signaling pathways. CRISPR screens with a single-cell transcriptomic readout provided insight into underlying mechanisms, including regulation of IFN-γ signaling in cancer cells and NK cell activation states. Our findings highlight the diversity of mechanisms influencing NK cell susceptibility across different cancers and provide a resource for NK cell-based therapies.",

keywords = "cancer, CRISPR screening, CROP-seq, functional genomics, immunotherapy resistance, leukemia, lymphoma, myeloma, NK cell, single-cell RNA sequencing",

author = "Olli Dufva and Sara Gandolfi and Jani Huuhtanen and Olga Dashevsky and Hanna Du{\`a}n and Khalid Saeed and Jay Klievink and Petra Nygren and Jonas Bouhlal and Jenni Lahtela and Anna N{\"a}{\"a}t{\"a}nen and Ghimire, {Bishwa R.} and Tiina Hannunen and Pekka Ellonen and Hanna L{\"a}hteenm{\"a}ki and Pauliina Rumm and Jason Theodoropoulos and Essi Laajala and Jouni H{\"a}rk{\"o}nen and Petri P{\"o}l{\"o}nen and Merja Hein{\"a}niemi and Maija Hollm{\'e}n and Shizuka Yamano and Ryosuke Shirasaki and Barbie, {David A.} and Roth, {Jennifer A.} and Rizwan Romee and Michal Sheffer and Harri L{\"a}hdesm{\"a}ki and Lee, {Dean A.} and {De Matos Simoes}, Ricardo and Matti Kankainen and Mitsiades, {Constantine S.} and Satu Mustjoki",

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = dec,

day = "12",

doi = "10.1016/j.immuni.2023.11.008",

language = "英語",

volume = "56",

pages = "2816--2835.e13",

journal = "Immunity",

issn = "1074-7613",

publisher = "Cell Press",

number = "12",

}

Dufva, O, Gandolfi, S, Huuhtanen, J, Dashevsky, O, Duàn, H, Saeed, K, Klievink, J, Nygren, P, Bouhlal, J, Lahtela, J, Näätänen, A, Ghimire, BR, Hannunen, T, Ellonen, P, Lähteenmäki, H, Rumm, P, Theodoropoulos, J, Laajala, E, Härkönen, J, Pölönen, P, Heinäniemi, M, Hollmén, M, Yamano, S, Shirasaki, R, Barbie, DA, Roth, JA, Romee, R, Sheffer, M, Lähdesmäki, H, Lee, DA, De Matos Simoes, R, Kankainen, M, Mitsiades, CS & Mustjoki, S 2023, 'Single-cell functional genomics reveals determinants of sensitivity and resistance to natural killer cells in blood cancers', Immunity, vol. 56, no. 12, pp. 2816-2835.e13. https://doi.org/10.1016/j.immuni.2023.11.008

TY - JOUR

T1 - Single-cell functional genomics reveals determinants of sensitivity and resistance to natural killer cells in blood cancers

AU - Dufva, Olli

AU - Gandolfi, Sara

AU - Huuhtanen, Jani

AU - Dashevsky, Olga

AU - Duàn, Hanna

AU - Saeed, Khalid

AU - Klievink, Jay

AU - Nygren, Petra

AU - Bouhlal, Jonas

AU - Lahtela, Jenni

AU - Näätänen, Anna

AU - Ghimire, Bishwa R.

AU - Hannunen, Tiina

AU - Ellonen, Pekka

AU - Lähteenmäki, Hanna

AU - Rumm, Pauliina

AU - Theodoropoulos, Jason

AU - Laajala, Essi

AU - Härkönen, Jouni

AU - Pölönen, Petri

AU - Heinäniemi, Merja

AU - Hollmén, Maija

AU - Yamano, Shizuka

AU - Shirasaki, Ryosuke

AU - Barbie, David A.

AU - Roth, Jennifer A.

AU - Romee, Rizwan

AU - Sheffer, Michal

AU - Lähdesmäki, Harri

AU - Lee, Dean A.

AU - De Matos Simoes, Ricardo

AU - Kankainen, Matti

AU - Mitsiades, Constantine S.

AU - Mustjoki, Satu

PY - 2023/12/12

Y1 - 2023/12/12

N2 - Cancer cells can evade natural killer (NK) cell activity, thereby limiting anti-tumor immunity. To reveal genetic determinants of susceptibility to NK cell activity, we examined interacting NK cells and blood cancer cells using single-cell and genome-scale functional genomics screens. Interaction of NK and cancer cells induced distinct activation and type I interferon (IFN) states in both cell types depending on the cancer cell lineage and molecular phenotype, ranging from more sensitive myeloid to less sensitive B-lymphoid cancers. CRISPR screens in cancer cells uncovered genes regulating sensitivity and resistance to NK cell-mediated killing, including adhesion-related glycoproteins, protein fucosylation genes, and transcriptional regulators, in addition to confirming the importance of antigen presentation and death receptor signaling pathways. CRISPR screens with a single-cell transcriptomic readout provided insight into underlying mechanisms, including regulation of IFN-γ signaling in cancer cells and NK cell activation states. Our findings highlight the diversity of mechanisms influencing NK cell susceptibility across different cancers and provide a resource for NK cell-based therapies.

AB - Cancer cells can evade natural killer (NK) cell activity, thereby limiting anti-tumor immunity. To reveal genetic determinants of susceptibility to NK cell activity, we examined interacting NK cells and blood cancer cells using single-cell and genome-scale functional genomics screens. Interaction of NK and cancer cells induced distinct activation and type I interferon (IFN) states in both cell types depending on the cancer cell lineage and molecular phenotype, ranging from more sensitive myeloid to less sensitive B-lymphoid cancers. CRISPR screens in cancer cells uncovered genes regulating sensitivity and resistance to NK cell-mediated killing, including adhesion-related glycoproteins, protein fucosylation genes, and transcriptional regulators, in addition to confirming the importance of antigen presentation and death receptor signaling pathways. CRISPR screens with a single-cell transcriptomic readout provided insight into underlying mechanisms, including regulation of IFN-γ signaling in cancer cells and NK cell activation states. Our findings highlight the diversity of mechanisms influencing NK cell susceptibility across different cancers and provide a resource for NK cell-based therapies.

KW - cancer

KW - CRISPR screening

KW - CROP-seq

KW - functional genomics

KW - immunotherapy resistance

KW - leukemia

KW - lymphoma

KW - myeloma

KW - NK cell

KW - single-cell RNA sequencing

UR - http://www.scopus.com/inward/record.url?scp=85179470331&partnerID=8YFLogxK

U2 - 10.1016/j.immuni.2023.11.008

DO - 10.1016/j.immuni.2023.11.008

M3 - 記事

C2 - 38091953

AN - SCOPUS:85179470331

SN - 1074-7613

VL - 56

SP - 2816-2835.e13

JO - Immunity

JF - Immunity

IS - 12

ER -

Single-cell functional genomics reveals determinants of sensitivity and resistance to natural killer cells in blood cancers

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this