Artikel ; Online: A versatile CRISPR-Cas13d platform for multiplexed transcriptomic regulation and metabolic engineering in primary human T cells.
2024 Band 187, Heft 5, Seite(n) 1278–1295.e20
Abstract: CRISPR technologies have begun to revolutionize T cell therapies; however, conventional CRISPR-Cas9 genome-editing tools are limited in their safety, efficacy, and scope. To address these challenges, we developed multiplexed effector guide arrays (MEGA), ...
Abstract | CRISPR technologies have begun to revolutionize T cell therapies; however, conventional CRISPR-Cas9 genome-editing tools are limited in their safety, efficacy, and scope. To address these challenges, we developed multiplexed effector guide arrays (MEGA), a platform for programmable and scalable regulation of the T cell transcriptome using the RNA-guided, RNA-targeting activity of CRISPR-Cas13d. MEGA enables quantitative, reversible, and massively multiplexed gene knockdown in primary human T cells without targeting or cutting genomic DNA. Applying MEGA to a model of CAR T cell exhaustion, we robustly suppressed inhibitory receptor upregulation and uncovered paired regulators of T cell function through combinatorial CRISPR screening. We additionally implemented druggable regulation of MEGA to control CAR activation in a receptor-independent manner. Lastly, MEGA enabled multiplexed disruption of immunoregulatory metabolic pathways to enhance CAR T cell fitness and anti-tumor activity in vitro and in vivo. MEGA offers a versatile synthetic toolkit for applications in cancer immunotherapy and beyond. |
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Mesh-Begriff(e) | Humans ; Gene Expression Profiling ; Metabolic Engineering/methods ; RNA ; T-Lymphocytes ; Transcriptome |
Chemische Substanzen | RNA (63231-63-0) |
Sprache | Englisch |
Erscheinungsdatum | 2024-02-21 |
Erscheinungsland | United States |
Dokumenttyp | Journal Article |
ZDB-ID | 187009-9 |
ISSN | 1097-4172 ; 0092-8674 |
ISSN (online) | 1097-4172 |
ISSN | 0092-8674 |
DOI | 10.1016/j.cell.2024.01.035 |
Datenquelle | MEDical Literature Analysis and Retrieval System OnLINE |
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