Lung mesenchymal stromal cells influenced by Th2 cytokines mobilize neutrophils and facilitate metastasis by producing complement C3

Nat Commun. 2021 Oct 27;12(1):6202. doi: 10.1038/s41467-021-26460-z.


Pre-metastatic niche formation is critical for the colonization of disseminated cancer cells in distant organs. Here we find that lung mesenchymal stromal cells (LMSCs) at pre-metastatic stage possess potent metastasis-promoting activity. RNA-seq reveals an upregulation of complement 3 (C3) in those LMSCs. C3 is found to promote neutrophil recruitment and the formation of neutrophil extracellular traps (NETs), which facilitate cancer cell metastasis to the lungs. C3 expression in LMSCs is induced and sustained by Th2 cytokines in a STAT6-dependent manner. LMSCs-driven lung metastasis is abolished in Th1-skewing Stat6-deficient mice. Blockade of IL-4 by antibody also attenuates LMSCs-driven cancer metastasis to the lungs. Consistently, metastasis is greatly enhanced in Th2-skewing T-bet-deficient mice or in nude mice adoptively transferred with T-bet-deficient T cells. Increased C3 levels are also detected in breast cancer patients. Our results suggest that targeting the Th2-STAT6-C3-NETs cascade may reduce breast cancer metastasis to the lungs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / immunology
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Complement C3 / immunology*
  • Complement C3 / metabolism
  • Cytokines / immunology*
  • Extracellular Traps
  • Female
  • Humans
  • Lung / immunology
  • Lung / pathology*
  • Lung Neoplasms / immunology
  • Lung Neoplasms / secondary
  • Mesenchymal Stem Cells / immunology
  • Mesenchymal Stem Cells / metabolism
  • Mesenchymal Stem Cells / pathology*
  • Mice
  • Mice, Nude
  • Neoplasm Metastasis / immunology*
  • Neutrophil Infiltration
  • Neutrophils / immunology*
  • STAT6 Transcription Factor / immunology
  • Signal Transduction
  • Th2 Cells / immunology*
  • Tumor Microenvironment / immunology


  • Complement C3
  • Cytokines
  • STAT6 Transcription Factor
  • Stat6 protein, mouse