利用全基因组 CRISPR 筛选技术鉴定参与溶瘤病毒疗法的限制性分子。

IF 29.5 1区 医学 Q1 HEMATOLOGY
Yiye Zhong, Huangying Le, Xue Zhang, Yao Dai, Fang Guo, Xiaojuan Ran, Guohong Hu, Qi Xie, Dawei Wang, Yujia Cai
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引用次数: 0

摘要

肿瘤溶解病毒(OV)为治疗实体瘤提供了一种新方法;然而,由于各种限制因素,其疗效往往不尽如人意。为了应对这一挑战,我们设计了一种含有神经元特异性微RNA-124和粒细胞-巨噬细胞集落刺激因子(GM-CSF)靶点的OV,大大提高了其对神经元的安全性,同时将其复制能力降至最低。此外,我们还通过全基因组 CRISPR 筛选确定了 PARP1 作为 HSV-1 复制限制因子。在胶质母细胞瘤(GBM)和三阴性乳腺癌(TNBC)模型中,我们发现 OV 和 PARP 抑制剂(PARPi)的联合治疗效果优于单药治疗。此外,单细胞RNA测序(scRNA-seq)显示,这种联合疗法使TNBC对免疫检查点阻断增敏,而免疫检查点抑制剂(ICI)的加入进一步提高了肿瘤小鼠的存活率。PARPi和ICI的组合协同增强了OV建立持久的肿瘤特异性免疫反应的能力。我们的研究有效克服了OV疗法的固有局限性,为TNBC、GBM和其他恶性肿瘤的临床治疗提供了有价值的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Identification of restrictive molecules involved in oncolytic virotherapy using genome-wide CRISPR screening.

Oncolytic viruses (OVs) offer a novel approach to treat solid tumors; however, their efficacy is frequently suboptimal due to various limiting factors. To address this challenge, we engineered an OV containing targets for neuron-specific microRNA-124 and Granulocyte-macrophage colony-stimulating factor (GM-CSF), significantly enhancing its neuronal safety while minimally compromising its replication capacity. Moreover, we identified PARP1 as an HSV-1 replication restriction factor using genome-wide CRISPR screening. In models of glioblastoma (GBM) and triple-negative breast cancer (TNBC), we showed that the combination of OV and a PARP inhibitor (PARPi) exhibited superior efficacy compared to either monotherapy. Additionally, single-cell RNA sequencing (scRNA-seq) revealed that this combination therapy sensitized TNBC to immune checkpoint blockade, and the incorporation of an immune checkpoint inhibitor (ICI) further increased the survival rate of tumor-bearing mice. The combination of PARPi and ICI synergistically enhanced the ability of OV to establish durable tumor-specific immune responses. Our study effectively overcomes the inherent limitations of OV therapy, providing valuable insights for the clinical treatment of TNBC, GBM, and other malignancies.

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来源期刊
CiteScore
48.10
自引率
2.10%
发文量
169
审稿时长
6-12 weeks
期刊介绍: The Journal of Hematology & Oncology, an open-access journal, publishes high-quality research covering all aspects of hematology and oncology, including reviews and research highlights on "hot topics" by leading experts. Given the close relationship and rapid evolution of hematology and oncology, the journal aims to meet the demand for a dedicated platform for publishing discoveries from both fields. It serves as an international platform for sharing laboratory and clinical findings among laboratory scientists, physician scientists, hematologists, and oncologists in an open-access format. With a rapid turnaround time from submission to publication, the journal facilitates real-time sharing of knowledge and new successes.
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