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

Olli Dufva¹, Sara Gandolfi², Jani Huuhtanen³, Olga Dashevsky⁴, Hanna Duàn¹, Khalid Saeed⁵, Jay Klievink¹, Petra Nygren¹, Jonas Bouhlal¹, Jenni Lahtela⁶, Anna Näätänen⁶, Bishwa R Ghimire⁶, Tiina Hannunen⁶, Pekka Ellonen⁶, Hanna Lähteenmäki⁵, Pauliina Rumm⁵, Jason Theodoropoulos⁵, Essi Laajala¹, Jouni Härkönen⁷, Petri Pölönen⁸, Merja Heinäniemi⁷, Maija Hollmén⁹, Shizuka Yamano⁴, Ryosuke Shirasaki⁴, David A Barbie⁴, Jennifer A Roth¹⁰, Rizwan Romee¹¹, Michal Sheffer⁴, Harri Lähdesmäki¹², Dean A Lee¹³, Ricardo De Matos Simoes⁴, Matti Kankainen¹⁴, Constantine S Mitsiades¹⁵, Satu Mustjoki¹⁶

Affiliations

¹ Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center, 00290 Helsinki, Finland; Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, 00014 Helsinki, Finland; iCAN Digital Precision Cancer Medicine Flagship, 00290 Helsinki, Finland.
² Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center, 00290 Helsinki, Finland; Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, 00014 Helsinki, Finland; iCAN Digital Precision Cancer Medicine Flagship, 00290 Helsinki, Finland; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³ Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center, 00290 Helsinki, Finland; Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, 00014 Helsinki, Finland; iCAN Digital Precision Cancer Medicine Flagship, 00290 Helsinki, Finland; Department of Computer Science, Aalto University, 02150 Espoo, Finland.
⁴ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA; Ludwig Center, Harvard Medical School, Boston, MA 02215, USA.
⁵ Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center, 00290 Helsinki, Finland; Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, 00014 Helsinki, Finland.
⁶ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, 00014 Helsinki, Finland.
⁷ Faculty of Health Sciences, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland.
⁸ Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
⁹ Medicity Research Laboratory, University of Turku, 20014 Turku, Finland.
¹⁰ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA; Ludwig Center, Harvard Medical School, Boston, MA 02215, USA.
¹² Department of Computer Science, Aalto University, 02150 Espoo, Finland.
¹³ Hematology/Oncology/BMT, Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, Columbus, OH 43205, USA.
¹⁴ Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center, 00290 Helsinki, Finland; Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, 00014 Helsinki, Finland; iCAN Digital Precision Cancer Medicine Flagship, 00290 Helsinki, Finland; Laboratory of Genetics, HUS Diagnostic Center, Hospital District of Helsinki and Uusima (HUS), 00290 Helsinki, Finland.
¹⁵ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA; Ludwig Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address: constantine_mitsiades@dfci.harvard.edu.
¹⁶ Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center, 00290 Helsinki, Finland; Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, 00014 Helsinki, Finland; iCAN Digital Precision Cancer Medicine Flagship, 00290 Helsinki, Finland. Electronic address: satu.mustjoki@helsinki.fi.

PMID: 38091953
DOI: 10.1016/j.immuni.2023.11.008

Free article

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

Olli Dufva et al. Immunity. 2023.

Free article

. 2023 Dec 12;56(12):2816-2835.e13.

doi: 10.1016/j.immuni.2023.11.008.

Authors

Affiliations

¹ Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center, 00290 Helsinki, Finland; Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, 00014 Helsinki, Finland; iCAN Digital Precision Cancer Medicine Flagship, 00290 Helsinki, Finland.
² Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center, 00290 Helsinki, Finland; Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, 00014 Helsinki, Finland; iCAN Digital Precision Cancer Medicine Flagship, 00290 Helsinki, Finland; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³ Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center, 00290 Helsinki, Finland; Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, 00014 Helsinki, Finland; iCAN Digital Precision Cancer Medicine Flagship, 00290 Helsinki, Finland; Department of Computer Science, Aalto University, 02150 Espoo, Finland.
⁴ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA; Ludwig Center, Harvard Medical School, Boston, MA 02215, USA.
⁵ Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center, 00290 Helsinki, Finland; Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, 00014 Helsinki, Finland.
⁶ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, 00014 Helsinki, Finland.
⁷ Faculty of Health Sciences, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland.
⁸ Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
⁹ Medicity Research Laboratory, University of Turku, 20014 Turku, Finland.
¹⁰ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA; Ludwig Center, Harvard Medical School, Boston, MA 02215, USA.
¹² Department of Computer Science, Aalto University, 02150 Espoo, Finland.
¹³ Hematology/Oncology/BMT, Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, Columbus, OH 43205, USA.
¹⁴ Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center, 00290 Helsinki, Finland; Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, 00014 Helsinki, Finland; iCAN Digital Precision Cancer Medicine Flagship, 00290 Helsinki, Finland; Laboratory of Genetics, HUS Diagnostic Center, Hospital District of Helsinki and Uusima (HUS), 00290 Helsinki, Finland.
¹⁵ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA; Ludwig Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address: constantine_mitsiades@dfci.harvard.edu.
¹⁶ Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center, 00290 Helsinki, Finland; Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, 00014 Helsinki, Finland; iCAN Digital Precision Cancer Medicine Flagship, 00290 Helsinki, Finland. Electronic address: satu.mustjoki@helsinki.fi.

PMID: 38091953
DOI: 10.1016/j.immuni.2023.11.008

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

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Conflict of interest statement

Declaration of interests M.S. and C.S.M. are authors of a patent application related to antitumor activity of NK cells. C.S.M. is a member of the Scientific Advisory Board of Adicet Bio and also discloses consultant honoraria from Fate Therapeutics, Ionis Pharmaceuticals, FIMECS, Secura Bio, and Oncopeptides and research funding from Sanofi, Merck KGaA/EMD Serono, Arch Oncology, Karyopharm, Nurix, Eisai/H3 Biomedicine, Novartis, BMS, Abcuro, and Springworks. S.M. has received honoraria and research funding from Novartis, Pfizer, and Bristol-Myers Squibb and honoraria from Dren-Bio (not related to this study).

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials