小柯机器人

美国加州大学旧金山分校Alexander Marson等研究人员合作发现，CRISPR筛选解码触发γδ T细胞检测的癌细胞通路。该项研究成果于2023年8月30日在线发表在《自然》杂志上。

研究人员表示，γδ T细胞是一种强大的抗癌效应因子，具有广泛靶向肿瘤的潜力，不受患者特异性新抗原或人类白细胞抗原背景的影响。γδ T细胞能感知转化细胞中普遍存在的保守细胞应激信号，但其靶向应激靶细胞背后的机制仍鲜为人知。Vγ9Vδ2 T细胞，即人类γδ T细胞中最丰富的亚群，可识别含有butyrophilin 2A1（BTN2A1）和BTN3A1的蛋白复合物，butyrophilin 2A1是一种广泛表达的细胞表面蛋白，可被肿瘤细胞产生的大量磷酸抗原激活。

研究人员结合对靶癌细胞的全基因组CRISPR筛选来确定了调控γδ T细胞杀伤和BTN3A细胞表面表达的途径。筛选结果表明，BTN3A在细胞表面的丰度以及通过转录、翻译后修饰和膜转运触发γδ T细胞的多层调控是以前从未认识到的。此外，研究人员还发现各种基因扰乱和抑制剂破坏了癌细胞的代谢途径，尤其是ATP生成过程，从而改变了BTN3A的水平。在代谢危机期间，BTN3A和BTN2A1的这种诱导作用依赖于AMP激活蛋白激酶（AMPK）。

最后，在细胞系模型和患者衍生的肿瘤器官组织中，小分子激活AMPK可导致BTN2A1-BTN3A复合物的表达增加，并增加Vγ9Vδ2 T细胞受体介导的杀伤力。这种依赖于AMPK的代谢应激诱导配体上调的机制加深了人们对γδ T细胞应激监测的理解，并提出了增强γδ T细胞抗癌活性的新途径。

附：英文原文

Title: CRISPR screens decode cancer cell pathways that trigger γδ T cell detection

Author: Mamedov, Murad R., Vedova, Shane, Freimer, Jacob W., Sahu, Avinash Das, Ramesh, Amrita, Arce, Maya M., Meringa, Angelo D., Ota, Mineto, Chen, Peixin Amy, Hanspers, Kristina, Nguyen, Vinh Q., Takeshima, Kirsten A., Rios, Anne C., Pritchard, Jonathan K., Kuball, Jrgen, Sebestyen, Zsolt, Adams, Erin J., Marson, Alexander

Issue&Volume: 2023-08-30

Abstract: γδ T cells are potent anticancer effectors with the potential to target tumours broadly, independent of patient-specific neoantigens or human leukocyte antigen background1,2,3,4,5. γδ Tcells can sense conserved cell stress signals prevalent in transformed cells2,3, although the mechanisms behind the targeting of stressed target cells remain poorly characterized. Vγ9Vδ2 Tcells—the most abundant subset of human γδ Tcells4—recognize a protein complex containing butyrophilin 2A1 (BTN2A1) and BTN3A1 (refs. 6,7,8), a widely expressed cell surface protein that is activated by phosphoantigens abundantly produced by tumour cells. Here we combined genome-wide CRISPR screens in target cancer cells to identify pathways that regulate γδ Tcell killing and BTN3A cell surface expression. The screens showed previously unappreciated multilayered regulation of BTN3A abundance on the cell surface and triggering of γδ Tcells through transcription, post-translational modifications and membrane trafficking. In addition, diverse genetic perturbations and inhibitors disrupting metabolic pathways in the cancer cells, particularly ATP-producing processes, were found to alter BTN3A levels. This induction of both BTN3A and BTN2A1 during metabolic crises is dependent on AMP-activated protein kinase (AMPK). Finally, small-molecule activation of AMPK in a cell line model and in patient-derived tumour organoids led to increased expression of the BTN2A1–BTN3A complex and increased Vγ9Vδ2 Tcell receptor-mediated killing. This AMPK-dependent mechanism of metabolic stress-induced ligand upregulation deepens our understanding of γδ Tcell stress surveillance and suggests new avenues available to enhance γδ Tcell anticancer activity.

DOI: 10.1038/s41586-023-06482-x

Source: https://www.nature.com/articles/s41586-023-06482-x

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