Acute influenza infection drives a transient pro-tumoral state in the lungs

Abstract

Following acute infection, an anti-viral state exists in the immune system that can impact the course of subsequent infections. Since this anti-viral state is broad, we hypothesised that prior infections could alter immune responses to tumours.

Specific pathogen free mice were infected with influenza A virus (IAV). Following viral clearance from the lung, at 28 and 90 days post-infection, mice were subsequently challenged with tumours. 28 days following infection, mice developed more lung tumours in models of both primary (using the carcinogen, urethane) and metastatic disease (through intravenous injection of metastatic cells). However, 90 days post-infection, mice developed fewer lung tumours.

To understand why 28 days post-influenza there is a pro-tumoral state in the lungs, whilst 90 days post-influenza there is an anti-tumoral state, , we explored the immune changes caused by the initial infection. At 28 days post-infection, characterisation of the lung and draining lymph node showed dramatic changes to stroma and immune cells long after viral clearance. This included both pro-tumoral changes indicative of inflammation, and anti-tumoral changes such as increases in cDC1 which remained elevated even 90 days post-infection. The presence of inflammation, and the reduction of tumour burden at 90 days when inflammation is hypothesised to have resolved, suggests that the inflammatory response to the initial infection may be the cause of the increased burden at 28 days. Furthermore, the pro-tumoral state seen 28 days following IAV was also seen following lipopolysaccharide and influenza B virus. This suggested that the pro-tumoral response was not influenza specific, but a response to acute inflammation.

To address this question of inflammation, mice were treated with anti-inflammatories (paracetamol) during influenza A infection, which in preliminary data not only reduced the inflammation caused by the acute stage of flu, but drastically reduced tumour burden compared to the uninfected control. This suggested that the anti-tumoral state seen at day 90 was also underlying the day 28 response and could be exposed with anti-inflammatories.

To investigate this anti-tumoral state, we looked at type-1 conventional dendritic cells (cDC1s), which were increased at 28-, 90- and 180-days post-infection, and were unaffected by paracetamol treatment. To investigate the importance of cDC1s, we increased them experimentally with FLT3L prior to tumour challenge. This treatment resulted in a highly significant decrease in metastatic seeding.