生物
免疫系统
抑制性突触后电位
计算生物学
细胞生物学
细胞
遗传学
神经科学
作者
Efthymia Papalexi,Eleni P. Mimitou,Andrew Butler,Samantha D. Foster,Bernadette Bracken,William M. Mauck,Hans-Hermann Wessels,Yuhan Hao,Bertrand Z. Yeung,Peter Smibert,Rahul Satija
出处
期刊:Nature Genetics
[Springer Nature]
日期:2021-03-01
卷期号:53 (3): 322-331
被引量:70
标识
DOI:10.1038/s41588-021-00778-2
摘要
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.
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