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研究实现T细胞增殖合成驱动因素的基因组规模筛选
2022-03-20 16:29
来源：小柯机器人

近日，美国纽约大学Neville E. Sanjana、Mateusz Legut等研究人员合作实现T细胞增殖合成驱动因素的基因组规模筛选。相关论文于2022年3月16日在线发表在《自然》杂志上。

研究人员通过过表达大约12,000个编码的人类开放阅读框架（ORF）来确定了T细胞功能的正向调节因子。排名靠前的基因增加了原代人类CD4+和CD8+ T细胞的增殖和激活，以及它们分泌的关键细胞因子，如白细胞介素-2和干扰素-γ。此外，研究人员开发了单细胞基因组学方法OverCITE-seq，对ORF工程化T细胞的转录组和表面抗原进行高通量量化。排名第一的ORF-淋巴毒素-β受体（LTBR）-通常在骨髓细胞中表达，但在淋巴细胞中不存在。
 
当在T细胞中过量表达时，LTBR诱导了深刻的转录和表观基因组重塑，导致T细胞效应功能的增加，并通过经典NF-κB途径的组成性激活，在慢性刺激环境中抵抗衰竭。LTBR和其他高等级的基因改善了嵌合抗原受体T细胞和γδT细胞的抗原特异性反应，突出了它们在未来癌症诊断疗法中的潜力。这些结果为通过诱导合成细胞方案改善下一代T细胞疗法提供了几种策略。
 
据了解，自体患者T细胞用于采用细胞疗法的工程已经彻底改变了几种类型癌症的治疗方法。然而，还需要进一步改进以提高反应和治愈率。基于CRISPR的功能缺失筛查仅限于T细胞功能的负面调节因子，并且由于基因组的永久性修改而引起安全问题。
 
附：英文原文
 
Title: A genome-scale screen for synthetic drivers of T cell proliferation

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

Issue&Volume: 2022-03-16

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.

DOI: 10.1038/s41586-022-04494-7

Source: https://www.nature.com/articles/s41586-022-04494-7

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html


本期文章：《自然》：Online/在线发表

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