abstract
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IL-15 is a cytokine that has effects on both innate and adaptive immune cells, including NK and CD8 T cells. The involvement of these cell types in tumor immunosurveillance and eradication has led to interest in IL-15 as an immunotherapy. Its role in spontaneous solid cancers has not been studied thoroughly. Here, we have shown for the first time that IL-15 overexpression in a spontaneous breast cancer model, MMTV-polyoma Middle T antigen (MT), leads to increased survival, tumor destruction, and decreased metastasis (IL-15 TG/MT). In contrast, lack of IL-15 led to decreased survival (IL-15 KO/MT) and increased metastasis. Protection in IL-15 TG/MT mice was dependent upon the presence of highly activated NK1.1+ cells, but not dependent upon CD8 T cells. The cytokine environment in IL-15 TG/MT tumors was capable of activating human NK cells to kill human triple negative breast cancer cells. In a model of metastasis, we found that overexpression of IL-15 protected from metastasis in a NK cell dependent manner. Lack of IL-15 promoted the polarization of CD4 T cells to a Th2 phenotype and they influenced polarization of macrophages to an M2 phenotype. M2 macrophages help establish tumors at the metastatic site. Here we found that M1 polarized macrophages could prevent engrafted breast tumor formation, whereas M2 macrophages promoted it. Overall, IL-15 is an extremely promising immunotherapy that has more anti-tumor effects on the immune system than were previously appreciated. Additionally, our data argues that it could generate immune responses against both primary breast cancer and metastasis.