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FREQUENT HOMOZYGOUS DELETIONS OF TYPE I INTERFERON GENES IN PLEURAL MESOTHELIOMA CONFER SENSITIVITY TO ONCOLYTIC MEASLES VIRUS
Journal of Thoracic Oncology ( IF 21.0 ) Pub Date : 2020-05-01 , DOI: 10.1016/j.jtho.2019.12.128
Tiphaine Delaunay 1 , Carole Achard 1 , Nicolas Boisgerault 1 , Marion Grard 1 , Tacien Petithomme 1 , Camille Chatelain 1 , Soizic Dutoit 1 , Christophe Blanquart 1 , Pierre-Joseph Royer 2 , Stéphane Minvielle 3 , Lisa Quetel 4 , Clément Meiller 4 , Didier Jean 4 , Delphine Fradin 1 , Jaafar Bennouna 5 , Antoine Magnan 6 , Laurent Cellerin 7 , Frédéric Tangy 8 , Marc Grégoire 1 , Jean-François Fonteneau 1
Affiliation  

Oncolytic immunotherapy is based on the use of non-pathogenic replicative oncolytic viruses (OV) that infect and kill exclusively tumor cells. Recently, we showed that the spontaneous oncolytic activity of the Schwarz strain of measles virus (MV) against human malignant pleural mesothelioma (MPM) depends on defects in the antiviral type I interferon (IFN I) response in tumor cells. In this study, we identify the most frequent defect as the homozygous deletions (HD) of all fourteen IFN I genes (IFN-α and IFN-β) that we found in more than half of MV-sensitive MPM cell lines. These HD occur together with the HD of the tumor suppressor gene CDKN2A also located in the 9p21.3 chromosome region. Therefore, the IFN I-/- MPM cell lines develop a partial and weak IFN I response when they are exposed to the virus compared to normal cells and MV-resistant MPM cell lines. This response consists in the expression of a restricted number of IFN-stimulated genes that do not depend on the presence of IFN I. In addition, the IFN I-/- MPM cell lines infected by MV also develop a pro-inflammatory response associated with a stress of the endoplasmic reticulum. Our study emphasizes the link between HD of IFN I encoding genes and CDKN2A gene in MPM and sensitivity to MV oncolytic immunotherapy.

中文翻译:

胸膜间皮瘤中 I 型干扰素基因的频繁纯合缺失导致对溶瘤性麻疹病毒的敏感性

溶瘤免疫疗法是基于使用非致病性复制溶瘤病毒 (OV) 来感染和杀死专门的肿瘤细胞。最近,我们发现麻疹病毒 (MV) 施瓦茨株对人恶性胸膜间皮瘤 (MPM) 的自发溶瘤活性取决于肿瘤细胞中抗病毒 I 型干扰素 (IFN I) 反应的缺陷。在这项研究中,我们将最常见的缺陷确定为我们在超过一半的 MV 敏感 MPM 细胞系中发现的所有 14 个 IFN I 基因(IFN-α 和 IFN-β)的纯合缺失 (HD)。这些 HD 与同样位于 9p21.3 染色体区域的肿瘤抑制基因 CDKN2A 的 HD 一起发生。所以,与正常细胞和 MV 抗性 MPM 细胞系相比,IFN I-/- MPM 细胞系在暴露于病毒时会产生部分和弱的 IFN I 反应。这种反应包括有限数量的 IFN 刺激基因的表达,这些基因不依赖于 IFN I 的存在。此外,被 MV 感染的 IFN I-/- MPM 细胞系也会产生与内质网应激。我们的研究强调了 MPM 中 IFN I 编码基因和 CDKN2A 基因的 HD 与对 MV 溶瘤免疫疗法的敏感性之间的联系。被 MV 感染的 IFN I-/- MPM 细胞系也会产生与内质网应激相关的促炎反应。我们的研究强调了 MPM 中 IFN I 编码基因和 CDKN2A 基因的 HD 与对 MV 溶瘤免疫疗法的敏感性之间的联系。被 MV 感染的 IFN I-/- MPM 细胞系也会产生与内质网应激相关的促炎反应。我们的研究强调了 MPM 中 IFN I 编码基因和 CDKN2A 基因的 HD 与对 MV 溶瘤免疫疗法的敏感性之间的联系。
更新日期:2020-05-01
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