The temporal progression of lung immune remodeling during breast cancer metastasis

Cancer Cell. 2024 Jun 10;42(6):1018-1031.e6. doi: 10.1016/j.ccell.2024.05.004. Epub 2024 May 30.


Tumor metastasis requires systemic remodeling of distant organ microenvironments that impacts immune cell phenotypes, population structure, and intercellular communication. However, our understanding of immune phenotypic dynamics in the metastatic niche remains incomplete. Here, we longitudinally assayed lung immune transcriptional profiles in the polyomavirus middle T antigen (PyMT) and 4T1 metastatic breast cancer models from primary tumorigenesis, through pre-metastatic niche formation, to the final stages of metastatic outgrowth at single-cell resolution. Computational analyses of these data revealed a TLR-NFκB inflammatory program enacted by both peripherally derived and tissue-resident myeloid cells that correlated with pre-metastatic niche formation and mirrored CD14+ "activated" myeloid cells in the primary tumor. Moreover, we observed that primary tumor and metastatic niche natural killer (NK) cells are differentially regulated in mice and human patient samples, with the metastatic niche featuring elevated cytotoxic NK cell proportions. Finally, we identified cell-type-specific dynamic regulation of IGF1 and CCL6 signaling during metastatic progression that represents anti-metastatic immunotherapy candidate pathways.

Keywords: NF-κB; TLR; cancer immunology; immunosuppression; inflammation; metastasis; myeloid; natural killer cells; single-cell genomics.

MeSH terms

  • Animals
  • Breast Neoplasms* / genetics
  • Breast Neoplasms* / immunology
  • Breast Neoplasms* / pathology
  • Cell Line, Tumor
  • Chemokines, CC / genetics
  • Chemokines, CC / metabolism
  • Disease Progression
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Insulin-Like Growth Factor I / metabolism
  • Killer Cells, Natural* / immunology
  • Lung / immunology
  • Lung / pathology
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / immunology
  • Lung Neoplasms* / pathology
  • Lung Neoplasms* / secondary
  • Mice
  • Mice, Inbred BALB C
  • Myeloid Cells / immunology
  • Myeloid Cells / metabolism
  • Neoplasm Metastasis
  • Signal Transduction
  • Tumor Microenvironment* / immunology


  • Insulin-Like Growth Factor I
  • Chemokines, CC