Pulmonary alveolar macrophages contribute to the premetastatic niche by suppressing antitumor T cell responses in the lungs

J Immunol. 2015 Jun 1;194(11):5529-38. doi: 10.4049/jimmunol.1403215. Epub 2015 Apr 24.


In contrast to tumor-associated macrophages, myeloid-derived suppressor cells, or inflammatory monocytes, functions of tissue resident macrophages, including alveolar macrophages (AM), in cancer were not well studied. Using a mouse model of breast cancer, we show that AM promote cancer metastasis to the lungs by suppressing antitumor T cells in this organ. AM accumulated in the premetastatic lungs through complement C5a receptor-mediated proliferation but not through recruitment from the circulation. AM preconditioned by breast tumors inhibited Th1 and favored generation of Th2 cells that had lower tumoricidal activity than Th1 cells. In addition, AM reduced the number and maturation of lung dendritic cells by regulating TGF-β in the lung environment. Depletion of AM reversed immunosuppression imposed by these cells and strengthened local Th1 responses, which significantly reduced lung metastatic burden. C5a receptor deficiency, which also lessens myeloid-derived suppressor cells in the premetastatic niche, synergized with the depletion of AM in preventing metastasis, leading to protection of mice from lung metastases. This study identifies AM as a new component of the premetastatic niche, which is harnessed by tumors to impose immunosuppression, and as a new target for cancer immunotherapies to eliminate or reduce metastasis. Because the lungs are the most common target for hematogenous metastasis, this research offers a plausible explanation for susceptibility of the lungs to cancer metastasis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Line
  • Cell Proliferation
  • Dendritic Cells / immunology
  • Female
  • Humans
  • Lung / immunology
  • Lung Neoplasms / immunology*
  • Lung Neoplasms / secondary*
  • Macrophages, Alveolar / cytology
  • Macrophages, Alveolar / immunology*
  • Mammary Neoplasms, Experimental / pathology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptor, Anaphylatoxin C5a / immunology
  • Th1 Cells / immunology*
  • Th2 Cells / immunology*
  • Transforming Growth Factor beta / biosynthesis
  • Tumor Microenvironment / immunology


  • Receptor, Anaphylatoxin C5a
  • Transforming Growth Factor beta