The lungs serve as a boundary between the body and the external environment—they are constantly exposed to air and, therefore, to microbes, allergens, and pollutants. To prevent excessive inflammatory responses, the pulmonary immune system does not activate immediately. However, this feature makes the lungs vulnerable, providing a favourable site for metastasis, which explains why the lungs are the second most common metastatic site for cancers such as breast cancer, colorectal cancer, and melanoma.
At the same time, the lungs are frequently targeted by viral and bacterial infections, which often lead to severe complications, especially in the elderly. One such virus is respiratory syncytial virus (RSV), which can cause severe bronchiolitis or pneumonia. Some studies have suggested a possible link between bronchiolitis, pneumonia, and lung cancer development, but this connection remains poorly understood and requires further research.
Many respiratory viruses infect lung epithelial cells and rapidly trigger a pro-inflammatory response, activating lung immune cells and attracting innate immune system cells. These immune responses are crucial for fighting viral infections but also alter the pulmonary environment and may influence cancer progression and metastasis.
Research findings on the impact of respiratory infections on metastasis are mixed. Some studies suggest that influenza enhances metastasis, while others indicate that influenza suppresses it. The outcome may depend on whether the viral infection occurs before or after tumor cells reach the lungs.
Type I interferons (IFNs) are antiviral cytokines that play a key role in immune cell activation and recruitment. UK researchers demonstrated that RSV infection one day before tumor cell introduction significantly reduces the number of metastases. This effect is attributed to IFN-I, which alters the lung environment, making it less conducive to metastasis.
RSV Infection Influences All Lung Cell Types via Interferon
The body rapidly produces type I IFNs during viral infections, including RSV. In the lungs, the primary source of interferons is alveolar macrophages. Since IFN-I receptors are present in nearly all cells, IFN signaling affects all lung cell types. The activation of IFN-I receptors induces the production of IFN-I itself and the expression of interferon-stimulated genes (ISGs), which can restrict viral replication. IFN-I also activates neutrophils, inflammatory monocytes, NK cells, dendritic cells, and macrophages.
IFN-I Signaling Creates an Unfavorable Environment for Metastases
Intranasal administration of IFN-α can reproduce the effect of RSV infection, reducing the number of lung metastases in breast cancer. A similar effect has been observed in other cancer models, including melanoma and fibrosarcoma, where intramuscular IFN-α administration reduced lung metastases. Additionally, subcutaneous IFN-α treatment altered the lung environment in hepatocellular carcinoma, decreasing the number of metastatic nodules independent of the primary tumor.
A breast cancer model experiment showed that interferon does not act directly on tumor cells but instead modifies lung tissue, creating unfavorable conditions for metastasis. Intranasal IFN-α administration in mice whose tumor cells expressed IFN-I receptors had no impact on metastasis, confirming that IFN’s effects are mediated through the lung environment rather than direct tumor cell interaction.
The anti-metastatic effect of type I interferons and RSV infection is not dependent on a specific immune cell type. Due to the complexity of the lung environment during RSV infection, multiple immune cell types may work together or redundantly to reduce metastatic burden.
Lung epithelial cells play the most crucial role in this process. They undergo significant changes in response to RSV infection or interferon signaling and no longer support the proliferation of tumor cells. This finding suggests that key alterations occur not within the immune system but within the lung tissue.
Conclusion
The impact of respiratory viral infections on metastasis may depend on the stage of cancer progression. When the primary tumor has not yet metastasized to the lungs, RSV infection triggers a type I interferon response that modifies the lung environment and suppresses metastasis. Intranasal IFN-α administration can replicate the anti-metastatic effects of RSV infection. These findings may help identify targets for making lung tissue less susceptible to metastatic cancer cells.
Useful article, necessary information? Share it!
Someone will also find it useful and necessary:
Reference
Type I interferons induced upon respiratory viral infection impair lung metastatic initiation
