Four-and-a-half LIM domain protein 2 (FHL2) is a multifunctional adaptor protein with fine-tuning adjustment properties. It acts as a regulator of signaling cascades but also as a cofactor of transcription and controls several anti-inflammatory immune responses. Recently, we described FHL2 as a novel regulator of influenza A virus propagation. We have shown that in vitro FHL2 restricts viral replication by accelerating the interferon regulatory factor 3-dependent transcription of the Ifnb1 gene. In this work, we unraveled an ambiguous role of FHL2 during influenza A virus infection in vivo. Although FHL2 restrained viral replication during the first 24 hours of infection, it significantly delayed viral clearance afterward. Comparison of lung immune status of wild-type and FHL2 knockout mice during influenza virus infection did not acknowledge significant differences in the innate host immune response but revealed an improved migration of dendritic cells from infected lungs into draining lymph nodes as well as increased levels of activated CD8 T lymphocytes accumulated in the lungs of FHL2 knockout mice.

Recently, we showed that infection of primary lung tumorbearing 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 in vivo. 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.