The temporal progression of immune remodeling during metastasis.

Abstract

Tumor 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-NF{kappa}B 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 involving Igf1 and Ccl6 which 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 abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=85 SRC="FIGDIR/small/539153v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@1333376org.highwire.dtl.DTLVardef@77c937org.highwire.dtl.DTLVardef@3b78b1org.highwire.dtl.DTLVardef@70d497_HPS_FORMAT_FIGEXP M_FIG C_FIG In 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. HighlightsO_LILongitudinal scRNA-seq reveals distinct stages of immune remodeling before, during, and after metastatic colonization in the lungs of PyMT mice. C_LIO_LITLR-NF{kappa}B inflammation correlates with pre-metastatic niche formation and involves both tissue-resident and bone marrow-derived myeloid cell populations. C_LIO_LIInflammatory lung myeloid cells mirror activated primary tumor MDSCs, suggesting that primary tumor-derived cues induce Cd14 expression and TLR-NF{kappa}B inflammation in the lung. C_LIO_LILymphocytes contribute to the inflammatory and immunosuppressive lung metastatic microenvironment, highlighted by enrichment of cytotoxic NK cells in the lung over time. C_LIO_LICell-cell signaling network modeling predicts cell type-specific Ccl6 regulation and IGF1-IGF1R signaling between neutrophils and interstitial macrophages. C_LI