免疫系をプログラミングし、がん細胞治療を強化する(Programming the Immune System to Supercharge Cancer Cell Therapies)

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2022-03-16 ニューヨーク大学

FDAが初めて承認した遺伝子治療薬は、がん患者から採取した免疫細胞を腫瘍細胞に作用するように操作した、生きた薬物です。しかし、多くの患者にとって、これらの先進的な治療法は長期的な寛解をもたらすものではありません。
ニューヨーク・ゲノム・センターとニューヨーク大学の科学者たちは、免疫細胞を強化し、より持続的に腫瘍細胞を駆逐する能力を高めることができる遺伝子を特定するための遺伝子スクリーニング・プラットフォームを開発しました。
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T細胞増殖の合成ドライバーを探索するゲノムスケールスクリーン A genome-scale screen for synthetic drivers of T cell proliferation

Mateusz Legut,Zoran Gajic,Maria Guarino,Zharko Daniloski,Jahan A. Rahman,Xinhe Xue,Congyi Lu,Lu Lu,Eleni P. Mimitou,Stephanie Hao,Teresa Davoli,Catherine Diefenbach,Peter Smibert & Neville E. Sanjana

Nature (2022)Cite this article 213 Altmetric Metricsdetails

Abstract

The engineering of autologous patient T cells for adoptive cell therapies has revolutionized the treatment of several types of cancer1. However, further improvements are needed to increase response and cure rates. CRISPR-based loss-of-function screens have been limited to negative regulators of T cell functions2,3,4 and raise safety concerns owing to the permanent modification of the genome. Here we identify positive regulators of T cell functions through overexpression of around 12,000 barcoded human open reading frames (ORFs). The top-ranked genes increased the proliferation and activation of primary human CD4+ and CD8+ T cells and their secretion of key cytokines such as interleukin-2 and interferon-γ. In addition, we developed the single-cell genomics method OverCITE-seq for high-throughput quantification of the transcriptome and surface antigens in ORF-engineered T cells. The top-ranked ORF—lymphotoxin-β receptor (LTBR)—is typically expressed in myeloid cells but absent in lymphocytes. When overexpressed in T cells, LTBR induced profound transcriptional and epigenomic remodelling, leading to increased T cell effector functions and resistance to exhaustion in chronic stimulation settings through constitutive activation of the canonical NF-κB pathway. LTBR and other highly ranked genes improved the antigen-specific responses of chimeric antigen receptor T cells and γδ T cells, highlighting their potential for future cancer-agnostic therapies5. Our results provide several strategies for improving next-generation T cell therapies by the induction of synthetic cell programmes.

細胞遺伝子工学
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