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

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

  • Immunity. 2023 Dec 12;56(12):2816-2835.e13. doi: 10.1016/j.immuni.2023.11.008.
Olli Dufva 1,  Sara Gandolfi 2,  Jani Huuhtanen 3,  Olga Dashevsky 4,  Hanna Duàn 1,  Khalid Saeed 5,  Jay Klievink 1,  Petra Nygren 1,  Jonas Bouhlal 1,  Jenni Lahtela 6,  Anna Näätänen 6,  Bishwa R Ghimire 6,  Tiina Hannunen 6,  Pekka Ellonen 6,  Hanna Lähteenmäki 5,  Pauliina Rumm 5,  Jason Theodoropoulos 5,  Essi Laajala 1,  Jouni Härkönen 7,  Petri Pölönen 8,  Merja Heinäniemi 7,  Maija Hollmén 9,  Shizuka Yamano 4,  Ryosuke Shirasaki 4,  David A Barbie 4,  Jennifer A Roth 10,  Rizwan Romee 11,  Michal Sheffer 4,  Harri Lähdesmäki 12,  Dean A Lee 13,  Ricardo De Matos Simoes 4,  Matti Kankainen 14,  Constantine S Mitsiades 15,  Satu Mustjoki 16
Affiliations

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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