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.