Characterizing the molecular regulation of inhibitory immune checkpoints with multimodal single-cell screens.
Characterizing the molecular regulation of inhibitory immune checkpoints with multimodal single-cell screens.
复制标题
用多模式单细胞筛选表征抑制性免疫检查点的分子调节。
DOI：
10.1038/s41588-021-00778-2
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发表时间：
2021-03
期刊：
影响因子：
30.8
通讯作者：
Satija R
中科院分区：
文献类型：
--
作者：
Papalexi E;Mimitou EP;Butler AW;Foster S;Bracken B;Mauck WM 3rd;Wessels HH;Hao Y;Yeung BZ;Smibert P;Satija R
抑制性免疫检查点分子（如PD-L1）的表达经常在人类癌症中观察到，并可导致T细胞介导的免疫应答受到抑制。在这里，我们应用ECCITE-seq，一种将合并的CRISPR筛选与单细胞mRNA和表面蛋白测量相结合的技术，来探索调节PD-L1表达的分子网络。我们还开发了一个计算框架，mixscape，通过识别和去除混杂的变化源，大大提高了单细胞扰动屏幕的信噪比。应用这些工具，我们识别和验证PD-L1的调控因子，并利用我们的多模式数据来识别转录和转录后调控模式。具体来说，我们发现kelch样蛋白KEAP 1和转录激活因子NRF 2介导IFNγ刺激后PD-L1上调水平。我们的研究结果确定了一种新的免疫检查点的调节机制，并提出了一个强大的分析框架，用于分析多模态单细胞扰动屏幕。
The expression of inhibitory immune checkpoint molecules such as PD-L1 is frequently observed in human cancers and can lead to the suppression of T cell-mediated immune responses. Here, we apply ECCITE-seq, a technology which 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 multi-modal 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 levels of PD-L1 upregulation after IFNγ stimulation. Our results identify a novel mechanism for the regulation of immune checkpoints and present a powerful analytical framework for the analysis of multi-modal single-cell perturbation screens.
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