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Abstract：
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a tumour entity with unmet medical need. To assess the therapeutic potential of oncolytic virotherapy (OVT) against PDAC, different oncolytic viruses (OVs) are currently investigated in clinical trials. However, systematic comparisons of these different OVs in terms of efficacy against PDAC and biomarkers predicting therapeutic response are lacking.
METHODS: We screened fourteen patient-derived PDAC cultures which reflect the intra- and intertumoural heterogeneity of PDAC for their sensitivity to five clinically relevant OVs, namely serotype 5 adenovirus Ad5-hTERT, herpes virus T-VEC, measles vaccine strain MV-NIS, reovirus jin-3, and protoparvovirus H-1PV. Live cell analysis, quantification of viral genome/gene expression, cell viability as well as cytotoxicity assays and titration of viral progeny were conducted. Transcriptome profiling was employed to identify potential predictive biomarkers for response to OV treatment.
RESULTS: Patient-derived PDAC cultures showed individual response patterns to OV treatment. Twelve of fourteen cultures were responsive to at least one OV, with no single OV proving superior or inferior across all cultures. Known host factors for distinct viruses were retrieved as potential biomarkers. Compared to the classical molecular subtype, the quasi-mesenchymal or basal-like subtype of PDAC was found to be more sensitive to H-1PV, jin-3, and T-VEC. Generally, expression of viral entry receptors did not correlate with sensitivity to OV treatment, with one exception: Expression of Galectin-1 (LGALS1), a factor involved in H-1PV entry, positively correlated with H-1PV induced cell killing. Rather, cellular pathways controlling immunological, metabolic and proliferative signaling appeared to determine outcome. For instance, high baseline expression of interferon-stimulated genes (ISGs) correlated with relative resistance to oncolytic measles virus, whereas low cyclic GMP-AMP synthase (cGAS) expression was associated with exceptional response. Combination treatment of MV-NIS with a cGAS inhibitor improved tumour cell killing in several PDAC cultures and cells overexpressing cGAS were found to be less sensitive to MV oncolysis.
CONCLUSIONS: Considering the heterogeneity of PDAC and the complexity of biological therapies such as OVs, no single biomarker can explain the spectrum of response patterns. For selection of a particular OV, PDAC molecular subtype, ISG expression as well as activation of distinct signaling and metabolic pathways should be considered. Combination therapies can overcome resistance in specific constellations. Overall, oncolytic virotherapy is a viable treatment option for PDAC, which warrants further development. This study highlights the need for personalised treatment in OVT. By providing all primary data, this study provides a rich source and guidance for ongoing developments.
BACKGROUND: German National Science Foundation (Deutsche Forschungsgemeinschaft, DFG), German Cancer Aid (Deutsche Krebshilfe), German National Academic Scholarship Foundation (Studienstiftung des deutschen Volkes), Survival with Pancreatic Cancer Foundation.
METHODS: We screened fourteen patient-derived PDAC cultures which reflect the intra- and intertumoural heterogeneity of PDAC for their sensitivity to five clinically relevant OVs, namely serotype 5 adenovirus Ad5-hTERT, herpes virus T-VEC, measles vaccine strain MV-NIS, reovirus jin-3, and protoparvovirus H-1PV. Live cell analysis, quantification of viral genome/gene expression, cell viability as well as cytotoxicity assays and titration of viral progeny were conducted. Transcriptome profiling was employed to identify potential predictive biomarkers for response to OV treatment.
RESULTS: Patient-derived PDAC cultures showed individual response patterns to OV treatment. Twelve of fourteen cultures were responsive to at least one OV, with no single OV proving superior or inferior across all cultures. Known host factors for distinct viruses were retrieved as potential biomarkers. Compared to the classical molecular subtype, the quasi-mesenchymal or basal-like subtype of PDAC was found to be more sensitive to H-1PV, jin-3, and T-VEC. Generally, expression of viral entry receptors did not correlate with sensitivity to OV treatment, with one exception: Expression of Galectin-1 (LGALS1), a factor involved in H-1PV entry, positively correlated with H-1PV induced cell killing. Rather, cellular pathways controlling immunological, metabolic and proliferative signaling appeared to determine outcome. For instance, high baseline expression of interferon-stimulated genes (ISGs) correlated with relative resistance to oncolytic measles virus, whereas low cyclic GMP-AMP synthase (cGAS) expression was associated with exceptional response. Combination treatment of MV-NIS with a cGAS inhibitor improved tumour cell killing in several PDAC cultures and cells overexpressing cGAS were found to be less sensitive to MV oncolysis.
CONCLUSIONS: Considering the heterogeneity of PDAC and the complexity of biological therapies such as OVs, no single biomarker can explain the spectrum of response patterns. For selection of a particular OV, PDAC molecular subtype, ISG expression as well as activation of distinct signaling and metabolic pathways should be considered. Combination therapies can overcome resistance in specific constellations. Overall, oncolytic virotherapy is a viable treatment option for PDAC, which warrants further development. This study highlights the need for personalised treatment in OVT. By providing all primary data, this study provides a rich source and guidance for ongoing developments.
BACKGROUND: German National Science Foundation (Deutsche Forschungsgemeinschaft, DFG), German Cancer Aid (Deutsche Krebshilfe), German National Academic Scholarship Foundation (Studienstiftung des deutschen Volkes), Survival with Pancreatic Cancer Foundation.
摘要：
背景：胰腺导管腺癌（PDAC）是一种未满足医疗需求的肿瘤实体。为了评估溶瘤病毒疗法（OVT）对PDAC的治疗潜力，目前在临床试验中研究了不同的溶瘤病毒（OVs）。然而,这些不同OVs在抗PDAC疗效和预测治疗反应的生物标志物方面缺乏系统比较.
方法：我们筛选了14种患者来源的PDAC培养物，这些培养物反映了PDAC对5种临床相关OVs的敏感性，即血清型5腺病毒Ad5-hTERT，疱疹病毒T-VEC,麻疹疫苗株MV-NIS，呼肠孤病毒jin-3和原病毒H-1PV。活细胞分析,病毒基因组/基因表达的定量，进行细胞活力以及细胞毒性测定和病毒后代的滴定。转录组分析用于鉴定对OV治疗的反应的潜在预测性生物标志物。
结果：患者来源的PDAC培养物显示出对OV治疗的个体反应模式。十四个培养物中有十二个对至少一个OV有反应，在所有文化中，没有单一的OV被证明是优越还是低劣。检索不同病毒的已知宿主因子作为潜在生物标志物。与经典分子亚型相比，发现PDAC的准间充质或基底样亚型对H-1PV更敏感，jin-3和T-VEC。一般来说,病毒进入受体的表达与OV治疗的敏感性无关，有一个例外：半乳糖凝集素-1（LGALS1）的表达，参与H-1PV进入的一个因素，与H-1PV诱导的细胞杀伤呈正相关。相反，细胞途径控制免疫学，代谢和增殖信号似乎决定了结局.例如,干扰素刺激基因（ISGs）的高基线表达与溶瘤麻疹病毒的相对抗性相关，而低环状GMP-AMP合酶（cGAS）表达与异常反应相关。MV-NIS与cGAS抑制剂的组合治疗可改善几种PDAC培养物中的肿瘤细胞杀伤，并且发现过表达cGAS的细胞对MV溶瘤的敏感性较低。
结论：考虑到PDAC的异质性和OVs等生物疗法的复杂性，没有单一的生物标志物可以解释反应模式的频谱.为了选择特定的OV，PDAC分子亚型,应考虑ISG表达以及不同信号传导和代谢途径的激活。组合疗法可以克服特定星座中的抗性。总的来说,溶瘤病毒疗法是PDAC的可行治疗选择，这需要进一步发展。这项研究强调了OVT个性化治疗的必要性。通过提供所有主要数据，这项研究为正在进行的发展提供了丰富的资源和指导。
背景：德国国家科学基金会（DeutscheForschungsgemeinschaft，DFG），德国癌症援助组织（DeutscheKrebshilfe），德国国家学术奖学金基金会（StudienstiftungdesdeutschenVolkes），胰腺癌基金会的生存。
方法：我们筛选了14种患者来源的PDAC培养物，这些培养物反映了PDAC对5种临床相关OVs的敏感性，即血清型5腺病毒Ad5-hTERT，疱疹病毒T-VEC,麻疹疫苗株MV-NIS，呼肠孤病毒jin-3和原病毒H-1PV。活细胞分析,病毒基因组/基因表达的定量，进行细胞活力以及细胞毒性测定和病毒后代的滴定。转录组分析用于鉴定对OV治疗的反应的潜在预测性生物标志物。
结果：患者来源的PDAC培养物显示出对OV治疗的个体反应模式。十四个培养物中有十二个对至少一个OV有反应，在所有文化中，没有单一的OV被证明是优越还是低劣。检索不同病毒的已知宿主因子作为潜在生物标志物。与经典分子亚型相比，发现PDAC的准间充质或基底样亚型对H-1PV更敏感，jin-3和T-VEC。一般来说,病毒进入受体的表达与OV治疗的敏感性无关，有一个例外：半乳糖凝集素-1（LGALS1）的表达，参与H-1PV进入的一个因素，与H-1PV诱导的细胞杀伤呈正相关。相反，细胞途径控制免疫学，代谢和增殖信号似乎决定了结局.例如,干扰素刺激基因（ISGs）的高基线表达与溶瘤麻疹病毒的相对抗性相关，而低环状GMP-AMP合酶（cGAS）表达与异常反应相关。MV-NIS与cGAS抑制剂的组合治疗可改善几种PDAC培养物中的肿瘤细胞杀伤，并且发现过表达cGAS的细胞对MV溶瘤的敏感性较低。
结论：考虑到PDAC的异质性和OVs等生物疗法的复杂性，没有单一的生物标志物可以解释反应模式的频谱.为了选择特定的OV，PDAC分子亚型,应考虑ISG表达以及不同信号传导和代谢途径的激活。组合疗法可以克服特定星座中的抗性。总的来说,溶瘤病毒疗法是PDAC的可行治疗选择，这需要进一步发展。这项研究强调了OVT个性化治疗的必要性。通过提供所有主要数据，这项研究为正在进行的发展提供了丰富的资源和指导。
背景：德国国家科学基金会（DeutscheForschungsgemeinschaft，DFG），德国癌症援助组织（DeutscheKrebshilfe），德国国家学术奖学金基金会（StudienstiftungdesdeutschenVolkes），胰腺癌基金会的生存。
