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
  • 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: [email protected].
  • 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: [email protected].
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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