دورية أكاديمية
أعرض في EDS

Multimodal pooled Perturb-CITE-seq screens in patient models define mechanisms of cancer immune evasion.

التفاصيل البيبلوغرافية
العنوان: Multimodal pooled Perturb-CITE-seq screens in patient models define mechanisms of cancer immune evasion.
المؤلفون: Frangieh CJ; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA, USA., Melms JC; Columbia Center for Translational Immunology, New York, NY, USA.; Department of Medicine, Division of Hematology and Oncology, Columbia University Medical Center, New York, NY, USA., Thakore PI; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Geiger-Schuller KR; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Genentech, South San Francisco, CA, USA., Ho P; Columbia Center for Translational Immunology, New York, NY, USA.; Department of Medicine, Division of Hematology and Oncology, Columbia University Medical Center, New York, NY, USA., Luoma AM; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA., Cleary B; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Jerby-Arnon L; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.; Chan Zuckerberg Biohub, San Francisco, CA, USA., Malu S; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Immunitas Therapeutics, Waltham, MA, USA., Cuoco MS; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Zhao M; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Ager CR; Columbia Center for Translational Immunology, New York, NY, USA., Rogava M; Columbia Center for Translational Immunology, New York, NY, USA.; Department of Medicine, Division of Hematology and Oncology, Columbia University Medical Center, New York, NY, USA., Hovey L; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Rotem A; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA, USA.; AstraZeneca, Waltham, MA, USA., Bernatchez C; Department of Melanoma Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA., Wucherpfennig KW; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA., Johnson BE; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA, USA., Rozenblatt-Rosen O; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Genentech, South San Francisco, CA, USA., Schadendorf D; Department of Dermatology, University Hospital Essen and German Cancer Consortium, Partner Site, Essen, Germany., Regev A; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. aregev@broadinstitute.org.; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. aregev@broadinstitute.org.; Howard Hughes Medical Institute, Chevy Chase, MD, USA. aregev@broadinstitute.org.; Genentech, South San Francisco, CA, USA. aregev@broadinstitute.org., Izar B; Columbia Center for Translational Immunology, New York, NY, USA. bi2175@cumc.columbia.edu.; Department of Medicine, Division of Hematology and Oncology, Columbia University Medical Center, New York, NY, USA. bi2175@cumc.columbia.edu.; Program for Mathematical Genomics, Columbia University, New York, NY, USA. bi2175@cumc.columbia.edu.
المصدر: Nature genetics [Nat Genet] 2021 Mar; Vol. 53 (3), pp. 332-341. Date of Electronic Publication: 2021 Mar 01.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Nature Pub. Co Country of Publication: United States NLM ID: 9216904 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1546-1718 (Electronic) Linking ISSN: 10614036 NLM ISO Abbreviation: Nat Genet Subsets: MEDLINE
أسماء مطبوعة: Original Publication: New York, NY : Nature Pub. Co., c1992-
مواضيع طبية MeSH: Tumor Escape*/genetics, CD58 Antigens/*immunology , Drug Resistance, Neoplasm/*immunology , Melanoma/*pathology , Single-Cell Analysis/*methods, CD58 Antigens/genetics ; CD58 Antigens/metabolism ; CRISPR-Cas Systems ; Coculture Techniques ; Computational Biology/methods ; Drug Resistance, Neoplasm/drug effects ; Drug Resistance, Neoplasm/genetics ; Epitopes/genetics ; Gene Knockout Techniques ; Humans ; Immune Checkpoint Inhibitors/pharmacology ; Interferon-gamma/immunology ; Interferon-gamma/metabolism ; Lymphocytes, Tumor-Infiltrating/pathology ; Melanoma/drug therapy ; Melanoma/immunology ; Sequence Analysis, RNA
مستخلص: Resistance to immune checkpoint inhibitors (ICIs) is a key challenge in cancer therapy. To elucidate underlying mechanisms, we developed Perturb-CITE-sequencing (Perturb-CITE-seq), enabling pooled clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 perturbations with single-cell transcriptome and protein readouts. In patient-derived melanoma cells and autologous tumor-infiltrating lymphocyte (TIL) co-cultures, we profiled transcriptomes and 20 proteins in ~218,000 cells under ~750 perturbations associated with cancer cell-intrinsic ICI resistance (ICR). We recover known mechanisms of resistance, including defects in the interferon-γ (IFN-γ)-JAK/STAT and antigen-presentation pathways in RNA, protein and perturbation space, and new ones, including loss/downregulation of CD58. Loss of CD58 conferred immune evasion in multiple co-culture models and was downregulated in tumors of melanoma patients with ICR. CD58 protein expression was not induced by IFN-γ signaling, and CD58 loss conferred immune evasion without compromising major histocompatibility complex (MHC) expression, suggesting that it acts orthogonally to known mechanisms of ICR. This work provides a framework for the deciphering of complex mechanisms by large-scale perturbation screens with multimodal, single-cell readouts, and discovers potentially clinically relevant mechanisms of immune evasion.
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معلومات مُعتمدة: U54 CA225088 United States CA NCI NIH HHS; R01 CA238039 United States CA NCI NIH HHS; T32 GM007367 United States GM NIGMS NIH HHS; K08 CA222663 United States CA NCI NIH HHS; F32 AI138458 United States AI NIAID NIH HHS; U19 AI133524 United States AI NIAID NIH HHS; P30 CA013696 United States CA NCI NIH HHS; United States HHMI Howard Hughes Medical Institute; P01 CA163222 United States CA NCI NIH HHS
المشرفين على المادة: 0 (CD58 Antigens)
0 (Epitopes)
0 (Immune Checkpoint Inhibitors)
82115-62-6 (Interferon-gamma)
تواريخ الأحداث: Date Created: 20210302 Date Completed: 20210408 Latest Revision: 20240403
رمز التحديث: 20240403
مُعرف محوري في PubMed: PMC8376399
DOI: 10.1038/s41588-021-00779-1
PMID: 33649592
قاعدة البيانات: MEDLINE
الوصف
تدمد:1546-1718
DOI:10.1038/s41588-021-00779-1