Single-cell functional genomics reveals determinants of sensitivity and resistance to natural killer cells in blood cancers.
Immunity
; 56(12): 2816-2835.e13, 2023 Dec 12.
Article
em En
| MEDLINE
| ID: mdl-38091953
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.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias Hematológicas
/
Neoplasias
Limite:
Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article