Single-cell functional genomics reveals determinants of sensitivity and resistance to natural killer cells in blood cancers
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A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä
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Date
2023-12-12
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Language
en
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2816-2835
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IMMUNITY, Volume 56, issue 12
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.Description
Funding Information: We thank Prof. Yenan Bryceson and Drs. Mikko Keränen, Oscar Brück, Mikko Myllymäki, Sofie Lundgren, Leo Meriranta, and Francesca De Lorenzo for insightful comments. We acknowledge the Biomedicum Sequencing Laboratory and Virus Core supported by the Biocentrum Helsinki; the Helsinki Institute of Life Science (HiLIFE), the Biomedicum Helsinki Flow Cytometry Core Unit , and the FIMM Single-Cell Analytics and Sequencing units supported by HiLIFE and Biocenter Finland; the Finnish Red Cross Blood Service biobank; and the Team 11 of the Centre de Recherche en Cancérologie et Immunologie Intégrée de Nantes-Angers (CRCI 2 NA) led by Dr. Catherine Pellat-Deceunynck for their support and services. The study was supported by grants from the Cancer Foundation Finland , Academy of Finland , Jane and Aatos Erkko Foundation , Sigrid Juselius Foundation , Gyllenberg Foundation , State funding for the University-level Health Research in Finland , and HiLIFE fellow funds (to S.M.), Stand Up To Cancer ( SU2C ) Convergence 2.0 Grant (S.G., M.S., and C.S.M.), SU2C Phillip A. Sharp Award for Innovation in Collaboration (M.S. and C.S.M.), Leukemia and Lymphoma Society (LLS) Scholar Award (C.S.M.), de Gunzburg Myeloma Research Fund (O. Dashevsky and C.S.M.), International Myeloma Society (IMS) (C.S.M.), Shawna Ashlee Corman Investigatorship in Multiple Myeloma Research (C.S.M.), Cobb Family Myeloma Research Fund (S.G. and C.S.M.), and Ludwig Center at Harvard (C.S.M.). The collaborating laboratories have also been partially supported by grants from the NIH ( R01 CA276156 to C.S.M. and S.M., R01 CA196664 to C.S.M., and U01 CA225730 to C.S.M.), the Lauri Strauss Leukemia Foundation (to O. Dashevsky and R.S.), and LLS Translational Research Program (C.S.M. and S.M.). O. Dufva was supported by grants from the Biomedicum Helsinki Foundation , Finnish Medical Society , Cancer Foundation Finland , K. Albin Johansson Foundation , Emil Aaltonen Foundation , Ida Montin Foundation , Paulo Foundation , Finnish Blood Disease Research Foundation , and Finnish Hematology Association . S.G. was supported by the ASCO Conquer Cancer Young Investigator Award , the IMS-Paula and Rodger Riney Foundation Career Development Award , and the Associazione Italiana per la Ricerca sul Cancro (AIRC, Italian Association for Cancer Research). Publisher Copyright: © 2023 The Author(s)
Keywords
cancer, CRISPR screening, CROP-seq, functional genomics, immunotherapy resistance, leukemia, lymphoma, myeloma, NK cell, single-cell RNA sequencing
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Citation
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, Pölönen, P, Heinäniemi, M, Hollmén, M, Yamano, S, Shirasaki, R, Barbie, D A, Roth, J A, Romee, R, Sheffer, M, Lähdesmäki, H, Lee, D A, De Matos Simoes, R, Kankainen, M, Mitsiades, C S & 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, e13, pp. 2816-2835 . https://doi.org/10.1016/j.immuni.2023.11.008