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

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

Journal

Immunity
ISSN: 1097-4180
Titre abrégé: Immunity
Pays: United States
ID NLM: 9432918

Informations de publication

Date de publication:
12 Dec 2023
Historique:
received: 31 10 2022
revised: 19 06 2023
accepted: 13 11 2023
medline: 14 12 2023
pubmed: 14 12 2023
entrez: 13 12 2023
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.immuni.2023.11.008 PMID: 38091953
pubmed: 38091953
pii: S1074-7613(23)00490-9
doi: 10.1016/j.immuni.2023.11.008
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

2816-2835.e13

Informations de copyright

Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

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).

Auteurs

Olli Dufva (O)

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.

Sara Gandolfi (S)

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.

Jani Huuhtanen (J)

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.

Olga Dashevsky (O)

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.

Hanna Duàn (H)

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.

Khalid Saeed (K)

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.

Jay Klievink (J)

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.

Petra Nygren (P)

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.

Jonas Bouhlal (J)

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.

Jenni Lahtela (J)

Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, 00014 Helsinki, Finland.

Anna Näätänen (A)

Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, 00014 Helsinki, Finland.

Bishwa R Ghimire (BR)

Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, 00014 Helsinki, Finland.

Tiina Hannunen (T)

Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, 00014 Helsinki, Finland.

Pekka Ellonen (P)

Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, 00014 Helsinki, Finland.

Hanna Lähteenmäki (H)

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.

Pauliina Rumm (P)

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.

Jason Theodoropoulos (J)

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.

Essi Laajala (E)

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.

Jouni Härkönen (J)

Faculty of Health Sciences, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland.

Petri Pölönen (P)

Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

Merja Heinäniemi (M)

Faculty of Health Sciences, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland.

Maija Hollmén (M)

Medicity Research Laboratory, University of Turku, 20014 Turku, Finland.

Shizuka Yamano (S)

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.

Ryosuke Shirasaki (R)

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.

David A Barbie (DA)

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.

Jennifer A Roth (JA)

Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Rizwan Romee (R)

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.

Michal Sheffer (M)

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.

Harri Lähdesmäki (H)

Department of Computer Science, Aalto University, 02150 Espoo, Finland.

Dean A Lee (DA)

Hematology/Oncology/BMT, Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, Columbus, OH 43205, USA.

Ricardo De Matos Simoes (R)

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.

Matti Kankainen (M)

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.

Constantine S Mitsiades (CS)

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.

Satu Mustjoki (S)

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.

Classifications MeSH