Abstract
IntroductionWe previously demonstrated that HER2/neu-driven mammary carcinogenesis can be prevented by an interleukin-12 (IL-12)-adjuvanted allogeneic HER2/neu-expressing cell vaccine. Since IL-12 can induce the release of interleukin-15 (IL-15), in the present study we investigated the role played by IL-15 in HER2/neu driven mammary carcinogenesis and in its immunoprevention.MethodsHER2/neu transgenic mice with homozygous knockout of IL-15 (here referred to as IL15KO/NeuT mice) were compared to IL-15 wild-type HER2/neu transgenic mice (NeuT) regarding mammary carcinogenesis, profile of peripheral blood lymphocytes and splenocytes and humoral and cellular responses induced by the vaccine.ResultsIL15KO/NeuT mice showed a significantly earlier mammary cancer onset than NeuT mice, with median latency times of 16 and 20 weeks respectively, suggesting a role for IL-15 in cancer immunosurveillance. Natural killer (NK) and CD8+ lymphocytes were significantly lower in IL15KO/NeuT mice compared to mice with wild-type IL-15. The IL-12-adjuvanted allogeneic HER2/neu-expressing cell vaccine was still able to delay mammary cancer onset but efficacy in IL-15-lacking mice vanished earlier: all vaccinated IL15KO/NeuT mice developed tumors within 80 weeks of age (median latency of 53 weeks), whereas more than 70 % of vaccinated NeuT mice remained tumor-free up to 80 weeks of age. Vaccinated IL15KO/NeuT mice showed less necrotic tumors with fewer CD3+ lymphocyes and lacked perforin-positive infiltrating cells compared to NeuT mice. Concerning the anti-vaccine antibody response, antibody titer was unaffected by the lack of IL-15, but less antibodies of IgM and IgG1 isotypes were found in IL15KO/NeuT mice. A lower induction by vaccine of systemic interferon-gamma (IFN-γ) and interleukin-5 (IL-5) was also observed in IL15KO/NeuT mice when compared to NeuT mice. Finally, we found a lower level of CD8+ memory cells in the peripheral blood of vaccinated IL15KO/NeuT mice compared to NeuT mice.ConclusionsWe demonstrated that IL-15 has a role in mammary cancer immunosurveillance and that IL-15-regulated NK and CD8+ memory cells play a role in long-lasting immunoprevention, further supporting the potential use of IL-15 as adjuvant in immunological strategies against tumors.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0588-x) contains supplementary material, which is available to authorized users.
Highlights
We previously demonstrated that HER2/neu-driven mammary carcinogenesis can be prevented by an interleukin-12 (IL-12)-adjuvanted allogeneic HER2/neu-expressing cell vaccine
Vaccination of BALB/c mice transgenic for rat HER2/neu (NeuT mice) with an interleukin-12 (IL-12)adjuvanted allogeneic HER2/neu-expressing cell vaccine gave an effective and long-lasting prevention of mammary carcinogenesis, provided that vaccinations started at the preneoplastic stage and were repeated cyclically for the mouse’s lifetime [2, 3]
Lack of IL-15 hastens HER2/neu-driven mammary carcinogenesis Mice knocked out for IL-15 and transgenic for HER2/ neu oncogene (IL15KO/BALB/c mice transgenic for rat HER2/neu oncogene (NeuT) mice) developed mammary carcinomas with a median latency of 16 weeks, significantly shorter than the median latency of 20 weeks displayed by HER2/neu transgenic mice with wild-type IL-15 (NeuT mice) (Fig. 1a)
Summary
HER2/neu transgenic mice with homozygous knockout of IL-15 (here referred to as IL15KO/NeuT mice) were compared to IL-15 wild-type HER2/neu transgenic mice (NeuT) regarding mammary carcinogenesis, profile of peripheral blood lymphocytes and splenocytes and humoral and cellular responses induced by the vaccine. Mice Mice knocked out for the IL-15 gene and transgenic for the transforming activated rat HER2/neu oncogene driven by the mouse mammary tumor virus promoter, on a BALB/c background (throughout referred to as IL15KO/NeuT mice) were kindly provided by Dr Silvia Bulfone Paus (Faculty of Human and Medical Sciences, University of Manchester, Manchester, UK and Department of Immunology and Cell Biology, Research Center Borstel, Borstel, Germany). Mammary pads were inspected weekly: masses with a mean diameter exceeding 3 mm were considered tumors. Mice were sacrificed when tumors were present in all mammary glands or when a single mass exceeded a mean diameter of 1.5 cm. Tumor progression of control mice was equal to that of untreated mice
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