小柯机器人

英国威康桑格研究所Mathew J. Garnett研究团队发现碱基编辑筛选映射影响癌症干扰素-γ（IFN-γ）信号传导的突变。相关论文发表在2023年1月19日出版的《癌细胞》杂志上。

他们使用CRISPR-Cas9筛选和碱基编辑突变系统地研究了大肠癌症细胞中IFN-γ应答的遗传决定因素。用胞苷和腺嘌呤碱基编辑器对JAK1进行深度诱变，结合全途径筛选，揭示了功能丧失和功能获得突变，包括血液系统恶性肿瘤中的因果变异和免疫检查点阻断（ICB）难治患者中检测到的突变。他们在功能上验证了原发性肿瘤类器官中具有不确定意义的变体，其中JAK1中的工程错义突变增强或降低了对自体肿瘤反应性T细胞的敏感性。他们发现了300多个改变IFN-γ通路活性的预测错义突变，为解释基因变异功能提供了宝贵的资源。

研究人员表示，IFN-γ信号传导介导宿主对感染、炎症和抗肿瘤免疫的反应。干扰素-γ信号通路的突变导致癌症患者出现免疫紊乱、血液恶性肿瘤和对ICB的抵抗；然而，大多数临床观察到的变体的功能仍然未知。

附：英文原文

Title: Base editing screens map mutations affecting interferon-γ signaling in cancer

Author: Matthew A. Coelho, Sarah Cooper, Magdalena E. Strauss, Emre Karakoc, Shriram Bhosle, Emanuel Gonalves, Gabriele Picco, Thomas Burgold, Chiara M. Cattaneo, Vivien Veninga, Sarah Consonni, Cansu Diner, Sara F. Vieira, Freddy Gibson, Syd Barthorpe, Claire Hardy, Joel Rein, Mark Thomas, John Marioni, Emile E. Voest, Andrew Bassett, Mathew J. Garnett

Issue&Volume: 2023-01-19

Abstract: Interferon-γ (IFN-γ) signaling mediates host responses to infection, inflammation and anti-tumor immunity. Mutations in the IFN-γ signaling pathway cause immunological disorders, hematological malignancies, and resistance to immune checkpoint blockade (ICB) in cancer; however, the function of most clinically observed variants remains unknown. Here, we systematically investigate the genetic determinants of IFN-γ response in colorectal cancer cells using CRISPR-Cas9 screens and base editing mutagenesis. Deep mutagenesis of JAK1 with cytidine and adenine base editors, combined with pathway-wide screens, reveal loss-of-function and gain-of-function mutations, including causal variants in hematological malignancies and mutations detected in patients refractory to ICB. We functionally validate variants of uncertain significance in primary tumor organoids, where engineering missense mutations in JAK1 enhanced or reduced sensitivity to autologous tumor-reactive T cells. We identify more than 300 predicted missense mutations altering IFN-γ pathway activity, generating a valuable resource for interpreting gene variant function.

DOI: 10.1016/j.ccell.2022.12.009

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(22)00595-5

Cancer Cell：《癌细胞》，创刊于2002年。隶属于细胞出版社，最新IF：38.585
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