Oncolytic influenza virus infection restores immunocompetence of lung tumor-associated alveolar macrophages

Dörthe Masemann; Katharina Köther; Meike Kuhlencord; Georg Varga; Johannes Roth; Brian Dennis Lichty; Ulf Rüdiger Rapp; Viktor Wixler; Stephan Ludwig

doi:10.1080/2162402X.2017.1423171

Oncolytic influenza virus infection restores immunocompetence of lung tumor-associated alveolar macrophages

Oncoimmunology. 2018 Feb 12;7(5):e1423171. doi: 10.1080/2162402X.2017.1423171. eCollection 2018.

Authors

Dörthe Masemann^{1

2}, Katharina Köther^{1

3}, Meike Kuhlencord⁴, Georg Varga⁵, Johannes Roth^{4

2}, Brian Dennis Lichty⁶, Ulf Rüdiger Rapp⁷, Viktor Wixler^{1

2}, Stephan Ludwig^{1

2}

Affiliations

¹ Institute of Virology (IMV), Westfaelische-Wilhelms University, Muenster, Germany.
² Cluster of Excellence "Cells in Motion", University of Muenster, Muenster, Germany.
³ Rentschler Biotechnologie GmbH, Laupheim, Germany.
⁴ Institute of Immunology, Westfaelische-Wilhelms University, Muenster, Germany.
⁵ Department of Pediatric, Rheumatology and Immunology, University Children´s Hospital Muenster, Muenster, Germany.
⁶ Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.
⁷ Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.

Abstract

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 in vivo. Using Raf-BxB 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 Raf-BxB 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 in vivo model that oncolytic IAV infection is capable of restoring and redirecting immune cell functions within the tumor microenvironment of NSCLCs.

Keywords: immune cell polarization; immunotherapy; influenza A viruses; lung cancer; oncolytic viruses; tumor-associated macrophages; virotherapy.

Publication types

Research Support, Non-U.S. Gov't

Grants and funding

This work was supported by the Deutsche Forschungsgemeinschaft (DFG Graduate School GRK1409, DFG Collaborative Research Center SFB1009), the Deutsche Krebshilfe (Grant 70112333), and the Interdisciplinary Center of Clinical Research (IZKF, Lud2/008/17) of the Medical Faculty, University of Münster. Moreover, this work was kindly backed by the COST action BM1404 Mye-EUNITER (www.mye.euniter.de). COST is supported by the EU framework program Horizon 2020.