Dynamic Immune Cell Composition, Phenotypes, and Signaling in an Engineered Metastatic Niche

In breast cancer patients, metastasis is the stage of disease where prognosis significantly worsens. However, the timing at which metastasis initiates and the location of metastatic lesions in an organ are stochastic, limiting the timely identification of disease and the administration of treatments. Herein, we employ a synthetic metastatic niche comprised of a microporous scaffold to investigate the dynamic immune processes associated with metastatic progression. Upon implantation, the porous scaffold is infiltrated with immune cells and recruits tumor cells. We have previously reported stable tumor cell numbers in the scaffold, suggesting a state of metastatic dormancy. Towards understanding dormancy, we investigated the immune cell dynamics at the scaffold, including neutrophils, monocytes, and dendritic cells, and compared these changes to the lungs, the native metastatic niche in this model. The cell phenotypes within the scaffold microenvironment are initially polarized toward an anti-tumor phenotype and become progressively more pro-tumor with disease progression, similar to the lung microenvironment. However, the phenotypes at the scaffold are consistently less pro-tumor than the phenotypes in the lung, consistent with the lung supporting tumor cell expansion and the scaffold exhibiting dormancy. Signaling pathways identified from the analysis are consistent with the changing innate cell phenotypes, with macrophages having a significant role during the early responses and neutrophils dominating the latter stages of disease. Collectively, the scaffold captures the immune dynamics during disease progression and the signaling that underlies stable tumor cell numbers, providing a tool for investigating the mechanisms of disease progression.