Investigating how the metastatic niche impairs NK cell cytotoxicity in early lung metastasis from breast cancer

Natural killer (NK) cells are innate lymphocytes with important anti-cancer functions in the tumour microenvironment (TME) of breast cancer. Although NK cells have the capacity to eliminate disseminated cancer cells at the metastatic site, their cytotoxic activity is impaired in successful metastasis. We hypothesise that other components within the TME inhibit NK cell activation and function against cancer cells at the early stage of metastatic colonisation. Therefore, we have used Cherry-niche, an in vivo labelling tool, to characterise how TME cells change and interact with each other in lung micro-metastases from breast cancer. Our single-cell RNA sequencing (scRNA-seq) analysis identified subpopulations of fibroblasts and monocytes that are enriched in the metastatic niche and active signallers to NK cells. Next, we have developed 2D and 3D co-culture systems to study the crosstalk between NK cells, fibroblasts and monocytes. We are currently using these systems to test the role of selected molecular interactions between NK cells and fibroblasts/monocytes that we identified in silico using bioinformatic tools, such as CellChat and NicheNet. This study will reveal novel inter-cellular dynamics occurring in the metastatic niche, as well as molecular targets that may restore NK cell cytotoxicity in early metastasis with immunotherapeutic potential.