Mach Nicolas, Gao Jian, Schaffarczyk Lukas, Janz Sebastian, Ehrke-Schulz Eric, Dittmar Thomas, Ehrhardt Anja, Zhang Wenli
Virology and Microbiology, Center for Biomedical Education and Research (ZBAF), Department of Human Medicine, Faculty of Health, Witten/Herdecke University, 58453 Witten, Germany.
Chair for Immunology & Experimental Oncology, Center for Biomedical Education and Research (ZBAF), Department of Human Medicine, Faculty of Health, Witten/Herdecke University, 58453 Witten, Germany.
Cancers (Basel). 2020 May 29;12(6):1403. doi: 10.3390/cancers12061403.
Oncolytic adenoviruses (Ads) are promising tools for cancer therapeutics. However, most Ad-based therapies utilize Ad type 5 (Ad5), which displays unsatisfying efficiency in clinical trials, partly due to the low expression levels of its primary coxsackievirus and adenovirus receptor (CAR) on tumor cells. Since the efficacy of virotherapy strongly relies on efficient transduction of targeted tumor cells, initial screening of a broad range of viral agents to identify the most effective vehicles is essential. Using a novel Ad library consisting of numerous human Ads representing known Ad species, we evaluated the transduction efficiencies in four breast cancer (BC) cell lines. For each cell line over 20 Ad types were screened in a high-throughput manner based on reporter assays. Ad types featuring high transduction efficiencies were further investigated with respect to the percentage of transgene-positive cells and efficiencies of cellular entry in individual cell lines. Additionally, oncolytic assay was performed to test tumor cell lysis efficacy of selected Ad types. We found that all analyzed BC cell lines show low expression levels of CAR, while alternative receptors such as CD46, DSG-2, and integrins were also detected. We identified Ad3, Ad35, Ad37, and Ad52 as potential candidates for BC virotherapy.
溶瘤腺病毒是癌症治疗的有前景的工具。然而，大多数基于腺病毒的疗法使用5型腺病毒（Ad5），其在临床试验中显示出不尽人意的效率，部分原因是其主要的柯萨奇病毒和腺病毒受体（CAR）在肿瘤细胞上的表达水平较低。由于病毒疗法的疗效强烈依赖于靶向肿瘤细胞的有效转导，因此初步筛选广泛的病毒载体以鉴定最有效的载体至关重要。我们使用了一个由众多代表已知腺病毒种类的人类腺病毒组成的新型腺病毒文库，评估了其在四种乳腺癌（BC）细胞系中的转导效率。对于每种细胞系，基于报告基因测定以高通量方式筛选了超过20种腺病毒类型。对具有高转导效率的腺病毒类型，进一步研究了转基因阳性细胞的百分比和在各个细胞系中的细胞进入效率。此外，进行了溶瘤试验以测试所选腺病毒类型的肿瘤细胞裂解功效。我们发现，所有分析的乳腺癌细胞系中CAR的表达水平都很低，同时还检测到了替代受体，如CD46、桥粒芯糖蛋白-2和整合素。我们确定Ad3、Ad35、Ad37和Ad52作为乳腺癌病毒疗法的潜在候选者。
