Sitnik Siarhei, Masemann Dörthe, Leite Dantas Rafael, Wixler Viktor, Ludwig Stephan
Institute of Molecular Virology (IMV), Centre for Molecular Biology of Inflammation (ZMBE), Westfaelische Wilhelms University, 48149 Muenster, Germany.
Mol Ther Oncolytics. 2020 Apr 8;17:190-204. doi: 10.1016/j.omto.2020.03.023. eCollection 2020 Jun 26.
Recently, we showed that infection of primary lung tumor-bearing mice with oncolytic influenza A viruses (IAVs) led to strong virus-induced tumor cell lysis but also to restoration of immune competence of innate immune cells. Murine B16-F10 melanoma cells are known for their high lung tropism and progressive growth. As these cells are also highly permissive for IAVs, we analyzed their oncolytic and immunomodulatory efficiency against pulmonary B16-F10 lung metastases . IAV infection abrogated the melanoma-mediated immune suppression in the lung and induced a more than 50% cancer cell lysis. The oncolytic effect reached maximal efficacy 3 days post-infection, but it was not sustained over time. In order to maintain the virus-induced anti-tumor effect, mice with melanoma-derived lung cancers were treated in addition to influenza virus infection with an immune checkpoint inhibitor against programmed death-1 receptor (PD-1). The combined IAV and immune checkpoint inhibition (ICI) therapy resulted in a sustained anti-tumor efficacy, keeping the lung melanoma mass at day 12 of IAV infection still reduced by 50% over the control mice. In conclusion, ICI treatment strongly enhanced the oncolytic effect of influenza virus infection, suggesting that combined treatment is a promising approach against metastatic pulmonary melanoma.
最近，我们发现用溶瘤性甲型流感病毒（IAV）感染原发性肺肿瘤荷瘤小鼠，不仅会导致强烈的病毒诱导的肿瘤细胞裂解，还会使先天免疫细胞的免疫能力得以恢复。小鼠B16-F10黑色素瘤细胞以其高肺嗜性和进行性生长而闻名。由于这些细胞对IAV也具有高度敏感性，我们分析了它们对肺部B16-F10肺转移瘤的溶瘤和免疫调节效率。IAV感染消除了黑色素瘤介导的肺部免疫抑制，并诱导了超过50%的癌细胞裂解。溶瘤作用在感染后3天达到最大疗效，但随着时间的推移并未持续。为了维持病毒诱导的抗肿瘤作用，除了用流感病毒感染黑色素瘤衍生的肺癌小鼠外，还使用了针对程序性死亡-1受体（PD-1）的免疫检查点抑制剂进行治疗。IAV与免疫检查点抑制（ICI）联合治疗产生了持续的抗肿瘤疗效，在IAV感染第12天时，肺部黑色素瘤肿块仍比对照小鼠减少了50%。总之，ICI治疗显著增强了流感病毒感染的溶瘤作用，表明联合治疗是对抗转移性肺黑色素瘤的一种有前景的方法。
