Targeting suppressive TGF-βR, IL-10R and A2AR pathways in natural killer cells: enhancing the innate anti-metastatic response against breast cancer progression

Despite advances in treatment and earlier detection, breast cancer is still the most common non-skin metastatic cancer in women and the fifth cause of cancer death worldwide. Natural killer (NK) cells are circulating innate lymphocytes that naturally protect against tumour spread (metastasis). Our group recently showed that these cells are dysfunctional in environments (niche) established by breast cancers at distant organs for future metastatic spread. Despite knowing that NK cells do control cancer metastasis, our knowledge of how breast cancers evade NK cell control remains poor. This project aims to examine several immune suppressive pathways that breast cancers probably manipulate to avoid NK cells and spread. These include factors such as adenosine, transforming growth factor (TGF)-β and interleukin-10 that are elevated in the tumour environment. These molecules have great potential to suppress the normally high killing and anti-metastatic activity mediated by NK cells, but we currently lack a clinical understanding of the relatively importance of each pathway might be. This project will use mouse models of metastatic breast cancer to assess the relative importance of these pathways in NK cells. The project will also apply methods to selectively delete NK cell response to each of these suppressive pathways in mice. These experimental tools will determine which is the most important suppressive pathway in inhibiting NK cell control of breast cancer. The information obtained from this research will inform the design of medical approaches to increase NK cell anti-metastatic function and potentially prevent breast cancer spread in humans.