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多模式单细胞筛选揭示抑制性免疫检查点的分子调控
2021-03-04 14:25

美国纽约大学Rahul Satija小组利用多模式单细胞筛选揭示抑制性免疫检查点的分子调控。这一研究成果于2021年3月1日在线发表在国际学术期刊《自然—遗传学》上。

研究人员应用了扩展的CRISPR兼容(EC)CITE-seq技术,该方法将汇集的CRISPR筛选与单细胞mRNA和表面蛋白测量相结合,进而探索调节PD-L1表达的分子网络。研究人员还开发了一种计算框架mixscape,它可以通过识别和消除混淆的变异源来显着提高单细胞扰动屏幕中的信噪比。通过这些工具,研究人员可以鉴定和验证PD-L1的调控因子,并利用该多模式数据来识别调控的转录和转录后调控模式。

具体而言,研究人员发现干扰素(IFN)-γ刺激后,Kelch样蛋白KEAP1和转录激活因子NRF2介导PD-L1的上调。这些结果确定了一种调节免疫检查点的新机制,并提出了一种强大的分析框架来用于分析多模式单细胞扰动筛选。 

据了解,人类癌症中经常观察到抑制性免疫检查点分子的表达,例如PD-L1,可导致T细胞介导的免疫反应受到抑制。

附:英文原文

Title: Characterizing the molecular regulation of inhibitory immune checkpoints with multimodal single-cell screens

Author: Efthymia Papalexi, Eleni P. Mimitou, Andrew W. Butler, Samantha Foster, Bernadette Bracken, William M. Mauck, Hans-Hermann Wessels, Yuhan Hao, Bertrand Z. Yeung, Peter Smibert, Rahul Satija

Issue&Volume: 2021-03-01

Abstract: The expression of inhibitory immune checkpoint molecules, such as programmed death-ligand (PD-L)1, is frequently observed in human cancers and can lead to the suppression of T cell–mediated immune responses. Here, we apply expanded CRISPR-compatible (EC)CITE-seq, a technology that combines pooled CRISPR screens with single-cell mRNA and surface protein measurements, to explore the molecular networks that regulate PD-L1 expression. We also develop a computational framework, mixscape, that substantially improves the signal-to-noise ratio in single-cell perturbation screens by identifying and removing confounding sources of variation. Applying these tools, we identify and validate regulators of PD-L1 and leverage our multimodal data to identify both transcriptional and post-transcriptional modes of regulation. Specifically, we discover that the Kelch-like protein KEAP1 and the transcriptional activator NRF2 mediate the upregulation of PD-L1 after interferon (IFN)-γ stimulation. Our results identify a new mechanism for the regulation of immune checkpoints and present a powerful analytical framework for the analysis of multimodal single-cell perturbation screens.

DOI: 10.1038/s41588-021-00778-2

Source: https://www.nature.com/articles/s41588-021-00778-2

Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:41.307
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex


本期文章:《自然—遗传学》:Online/在线发表

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