The effect of type I interferons in preventing breast cancer metastasis to the lung

Cancer is the second leading cause of death globally. The problem with cancer is not so much the primary tumour, which in many cases can be surgically removed, but the ability of cancer cells to spread away from that primary tumour and seed themselves in other parts of the body where they establish secondary tumours. This is called metastasis and often involves spread to the lungs. There is a need to understand how metastatic cells are received in the lungs and how their seeding and growth can be restricted to reduce cancer spread and thereby increase cancer patient survival. We have found that the milieu of the lung in mice can be altered to make it hostile to cancer metastases by giving the animals type I interferons, an important group of cytokines that help fight viral infections but also have a role in anti-cancer immune responses. We will investigate how different types of interferons or interferon-inducing agents can stop metastasising breast cancer cells from entering the lungs and/or to successfully start growing in the lung. To address our questions, we will use well-established mouse models of lung metastatic mammary tumours as these type of studies are impossible to do in humans. However, we will also test different types of interferons on healthy human lung tissue to confirm the results from the mouse models and inform for future translational studies. The project will shed light on host mechanisms that can restrict cancer metastatic growth, especially in the lung, and contribute to finding targets for the development of future cancer therapies.

Type I interferons (IFNs) are important drivers of anti-viral responses and inflammation, but they can also contribute to anti-tumour responses. We have preliminary data that type I interferons alter the lung microenvironment to impair the seeding and/or growth of metastatic breast cancer cells. Here, we propose to extend those observations and elucidate the mechanism underlying IFN-inducible lung metastatic restriction. We will use well-established mouse models of primary lung metastatic mammary tumours combined with interferon treatment via different routes and at different time points. Tumour growth and immune response parameters will be monitored and assessed. The lung metastatic microenvironment will be characterised by single cell and bulk RNAseq and changes induced by interferon treatment will be uncovered. We will build on the latter to determine which key cell types and their gene products drive the IFN-inducible anti-metastatic response using chimeric, transgenic and knockout mouse models and in vitro culture. Finally, the effects of interferons on human lung will be investigated as a start for translating the findings from the mouse studies and direct future therapeutic application. Overall, the project will provide mechanistic dissection of how the lung microenvironment can be manipulated to become more resistant to seeding of metastatic cells, findings that are important for future targeted therapies.