Masemann Dörthe, Köther Katharina, Kuhlencord Meike, Varga Georg, Roth Johannes, Lichty Brian Dennis, Rapp Ulf Rüdiger, Wixler Viktor, Ludwig Stephan
Institute of Virology (IMV), Westfaelische-Wilhelms University, Muenster, Germany.
Cluster of Excellence "Cells in Motion", University of Muenster, Muenster, Germany.
Oncoimmunology. 2018 Feb 12;7(5):e1423171. doi: 10.1080/2162402X.2017.1423171. eCollection 2018.
Non-small-cell lung cancer (NSCLC) is the most frequent type of lung cancer and demonstrates high resistance to radiation and chemotherapy. These tumors evade immune system detection by promoting an immunosuppressive tumor microenvironment. Genetic analysis has revealed oncogenic activation of the Ras/Raf/MEK/ERK signaling pathway to be a hallmark of NSCLCs, which promotes influenza A virus (IAV) infection and replication in these cells. Thus, we aimed to unravel the oncolytic properties of IAV infection against NSCLCs in an immunocompetent model . Using transgenic mice that spontaneously develop NSCLCs, we demonstrated that infection with low-pathogenic IAV leads to rapid and efficient oncolysis, eliminating 70% of the initial tumor mass. Interestingly, IAV infection of mice caused a functional reversion of immunosuppressed tumor-associated lung macrophages into a M1-like pro-inflammatory active phenotype that additionally supported virus-induced oncolysis of cancer cells. Altogether, our data demonstrate for the first time in an immunocompetent model that oncolytic IAV infection is capable of restoring and redirecting immune cell functions within the tumor microenvironment of NSCLCs.
非小细胞肺癌（NSCLC）是最常见的肺癌类型，对放疗和化疗具有高度抗性。这些肿瘤通过促进免疫抑制性肿瘤微环境来逃避免疫系统的检测。基因分析显示，Ras/Raf/MEK/ERK信号通路的致癌激活是NSCLC的一个标志，它促进甲型流感病毒（IAV）在这些细胞中的感染和复制。因此，我们旨在阐明在具有免疫活性的模型中IAV感染对NSCLC的溶瘤特性。利用自发发生NSCLC的转基因小鼠，我们证明低致病性IAV感染可导致快速有效的溶瘤作用，消除70%的初始肿瘤块。有趣的是，小鼠的IAV感染导致免疫抑制的肿瘤相关肺巨噬细胞功能逆转，转变为类似M1的促炎活性表型，这进一步支持了病毒诱导的癌细胞溶瘤作用。总之，我们的数据首次在具有免疫活性的模型中证明，溶瘤性IAV感染能够在NSCLC的肿瘤微环境中恢复和重定向免疫细胞功能。
