The temporal progression of immune remodeling during metastasis

Abstract

SUMMARYTumor metastasis requires systemic remodeling of distant organ microenvironments which impacts immune cell phenotypes, population structure, and intercellular communication networks. However, our understanding of immune phenotypic dynamics in the metastatic niche remains incomplete. Here, we longitudinally assayed lung immune cell gene expression profiles in mice bearing PyMT-driven metastatic breast tumors from the onset of primary tumorigenesis, through formation of the pre-metastatic niche, to the final stages of metastatic outgrowth. Computational analysis of these data revealed an ordered series of immunological changes that correspond to metastatic progression. Specifically, we uncovered a TLR-NFκB myeloid inflammatory program which correlates with pre-metastatic niche formation and mirrors described signatures of CD14+ ‘activated’ MDSCs in the primary tumor. Moreover, we observed that cytotoxic NK cell proportions increased over time which illustrates how the PyMT lung metastatic niche is both inflammatory and immunosuppressive. Finally, we predicted metastasis-associated immune intercellular signaling interactions involvingIgf1andCcl6which may organize the metastatic niche. In summary, this work identifies novel immunological signatures of metastasis and discovers new details about established mechanisms that drive metastatic progression.Graphical abstractIn briefMcGinnis et al. report a longitudinal scRNA-seq atlas of lung immune cells in mice bearing PyMT-driven metastatic breast tumors and identify immune cell transcriptional states, shifts in population structure, and rewiring of cell-cell signaling networks which correlate with metastatic progression.HighlightsLongitudinal scRNA-seq reveals distinct stages of immune remodeling before, during, and after metastatic colonization in the lungs of PyMT mice.TLR-NFκB inflammation correlates with pre-metastatic niche formation and involves both tissue-resident and bone marrow-derived myeloid cell populations.Inflammatory lung myeloid cells mirror ‘activated’ primary tumor MDSCs, suggesting that primary tumor-derived cues induceCd14expression and TLR-NFκB inflammation in the lung.Lymphocytes contribute to the inflammatory and immunosuppressive lung metastatic microenvironment, highlighted by enrichment of cytotoxic NK cells in the lung over time.Cell-cell signaling network modeling predicts cell type-specificCcl6regulation and IGF1-IGF1R signaling between neutrophils and interstitial macrophages.