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Genome-scale screens identify factors regulating tumor cell responses to natural killer cells.

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机构: [1]Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA [2]Department of Medicine, Harvard Medical School, Boston, MA, USA [3]Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA [4]Ludwig Center, Harvard Medical School, Boston,MA, USA [5]Department of Transplantation Immunology, Maastricht University Medical Center+, Maastricht, the Netherlands [6]School for Oncology andDevelopmental Biology, Maastricht University Medical Center+ GROW, Maastricht, the Netherlands [7]Department of Cell Biology, Harvard Medical School,Boston, MA, USA [8]Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA [9]Microsoft Research, Cambridge,MA, USA [10]Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland [11]Translational ImmunologyResearch Program and Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland [12]iCAN Digital Precision Cancer MedicineFlagship, Helsinki, Finland [13]Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA [14]Department of Biostatistics, Harvard TH ChanSchool of Public Health, Boston, MA, USA [15]Present address: Sichuan University, Chengdu, China
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To systematically define molecular features in human tumor cells that determine their degree of sensitivity to human allogeneic natural killer (NK) cells, we quantified the NK cell responsiveness of hundreds of molecularly annotated 'DNA-barcoded' solid tumor cell lines in multiplexed format and applied genome-scale CRISPR-based gene-editing screens in several solid tumor cell lines, to functionally interrogate which genes in tumor cells regulate the response to NK cells. In these orthogonal studies, NK cell-sensitive tumor cells tend to exhibit 'mesenchymal-like' transcriptional programs; high transcriptional signature for chromatin remodeling complexes; high levels of B7-H6 (NCR3LG1); and low levels of HLA-E/antigen presentation genes. Importantly, transcriptional signatures of NK cell-sensitive tumor cells correlate with immune checkpoint inhibitor (ICI) resistance in clinical samples. This study provides a comprehensive map of mechanisms regulating tumor cell responses to NK cells, with implications for future biomarker-driven applications of NK cell immunotherapies.© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

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出版当年[2021]版:
大类 | 1 区 生物学
小类 | 1 区 遗传学
最新[2023]版:
大类 | 1 区 生物学
小类 | 1 区 遗传学
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第一作者机构: [1]Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA [2]Department of Medicine, Harvard Medical School, Boston, MA, USA [3]Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA [4]Ludwig Center, Harvard Medical School, Boston,MA, USA
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通讯机构: [1]Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA [2]Department of Medicine, Harvard Medical School, Boston, MA, USA [3]Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA [4]Ludwig Center, Harvard Medical School, Boston,MA, USA
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