The absence or overexpression of IL-15 drastically alters breast cancer metastasis via effects on NK cells, CD4 T cells, and macrophages

J Immunol. 2014 Dec 15;193(12):6184-91. doi: 10.4049/jimmunol.1303175. Epub 2014 Oct 29.


IL-15 is a cytokine that can affect many immune cells, including NK cells and CD8 T cells. In several tumor models, IL-15 delays primary tumor formation and can prevent or reduce metastasis. In this study, we have employed a model of breast cancer metastasis to examine the mechanism by which IL-15 affects metastasis. When breast tumor cells were injected i.v. into IL-15(-/-), C57BL/6, IL-15 transgenic (TG) and IL-15/IL-15Rα-treated C57BL/6 mice, there were high levels of metastasis in IL-15(-/-) mice and virtually no metastasis in IL-15 TG or IL-15-treated mice. In fact, IL-15(-/-) mice were 10 times more susceptible to metastasis, whereas IL-15 TG mice were at least 10 times more resistant to metastasis when compared with control C57BL/6 mice. Depletion of NK cells from IL-15 TG mice revealed that these cells were important for protection from metastasis. When NK cells were depleted from control C57BL/6 mice, these mice did not form as many metastatic foci as IL-15(-/-) mice, suggesting that other cell types may be contributing to metastasis in the absence of IL-15. We then examined the role of CD4 T cells and macrophages. In IL-15(-/-) mice, in vivo depletion of CD4 T cells decreased metastasis. The lack of IL-15 in IL-15(-/-) mice, and possibly the Th2-polarized CD4 T cells, was found to promote the formation of M2 macrophages that are thought to contribute to metastasis formation. This study reveals that whereas IL-15 effects on NK cells are important, it also has effects on other immune cells that contribute to metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / immunology
  • Breast Neoplasms / pathology*
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism*
  • Disease Models, Animal
  • Female
  • Gene Expression*
  • Interleukin-15 / administration & dosage
  • Interleukin-15 / genetics*
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • Lung Neoplasms / secondary
  • Macrophages / immunology
  • Macrophages / metabolism*
  • Mammary Neoplasms, Experimental
  • Melanoma, Experimental
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Neoplasm Metastasis


  • Interleukin-15

Associated data

  • GEO/GSE61858