The pre-metastatic niche influences neutrophil behaviour, allowing cancer cells to hide in plain site 2309704

Abstract

Abstract Introduction The fatality rate for metastatic cancers remains high, with the lungs being a common and deadly site of metastasis. Before cancer cells arrive, host tissues undergo changes that prepare them for tumour growth. This process forms the pre-metastatic niche, making the lung environment more receptive to colonization. Neutrophils populate the pre-metastatic niche, but their phenotype and whether they support metastasis at this stage remain unclear. Methods A model of E0771-GFP breast cancer cells that metastasize to the lungs was established, where the lung pre-metastatic niche and arrival of cancer cells can be captured using intravital microscopy. Using this model, we observed that not only does neutrophil behaviour change in the pre-metastatic niche from homeostasis, but their responsiveness to arriving cancer cells is compromised. Results The Kubes Lab has previously demonstrated that under healthy conditions, the majority of resident lung neutrophils crawl along the alveolar capillary wall seeking perturbations. Behavioural analysis of neutrophils imaged in pre-metastatic lungs showed reduced crawling and increased adhesion to the endothelium. Further, pre-metastatic neutrophils were imaged in the presence of both intravenously injected and spontaneously arrived cancer cells. In both cases, neutrophils exhibited limited interactions with cancer cells. In contrast, in healthy lungs, numerous neutrophils maintained prolonged contact with intravenously injected cancer cells. Super-resolution microscopy of healthy resident lung neutrophils showed acquisition of GFP+ particles following interaction with GFP+ cancer cells. Conclusion Our findings reveal that neutrophils in the lung pre-metastatic niche adopt a distinct behavioural state compared to healthy resident neutrophils. Such behaviour may contribute to the permissive environment that enables metastatic seeding in the lungs. These findings lay the foundation for therapeutic targeting of neutrophils to prevent metastatic seeding. Funding Source Canadian Research Excellence Chair (CERC), Infrastructure Operating Fund (IOF), Canadian Foundation for Innovation (CFI), and Bruce Mitchell Research Program Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)