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Breast Cancer Res. 2015 May 22;17:70. doi: 10.1186/s13058-015-0588-x.

Interleukin-15 is required for immunosurveillance and immunoprevention of HER2/neu-driven mammary carcinogenesis.

Author information

1
Laboratory of Immunology and Biology of Metastases, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Viale Filopanti 22, Bologna, 40126, Italy. stefania.croci@asmn.re.it.
2
Present address: Unit of Clinical Immunology, Allergy and Advanced Biotechnologies, Arcispedale Santa Maria Nuova-IRCCS, Viale Risorgimento 80, Reggio Emilia, 42123, Italy. stefania.croci@asmn.re.it.
3
Laboratory of Immunology and Biology of Metastases, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Viale Filopanti 22, Bologna, 40126, Italy. patrizia.nanni@unibo.it.
4
Interdepartmental Centre for Cancer Research "Giorgio Prodi", University of Bologna, Via Massarenti 9, Bologna, 40138, Italy. patrizia.nanni@unibo.it.
5
Laboratory of Immunology and Biology of Metastases, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Viale Filopanti 22, Bologna, 40126, Italy. arianna.palladini@unibo.it.
6
Laboratory of Experimental Oncology, Rizzoli Orthopedic Institute, Via di Barbiano 1/10, Bologna, 40136, Italy. giordano.nicoletti@ior.it.
7
Laboratory of Immunology and Biology of Metastases, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Viale Filopanti 22, Bologna, 40126, Italy. valentina.grosso@unibo.it.
8
Laboratory of Immunology and Biology of Metastases, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Viale Filopanti 22, Bologna, 40126, Italy. gbenegiamo@salk.edu.
9
Laboratory of Experimental Oncology, Rizzoli Orthopedic Institute, Via di Barbiano 1/10, Bologna, 40136, Italy. lorena.landuzzi@ior.it.
10
CESI Aging Research Center, G. D'Annunzio University, Via Colle dell'Ara, Chieti Scalo, Chieti, 66013, Italy. alessia.lamolinara@gmail.com.
11
Laboratory of Immunology and Biology of Metastases, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Viale Filopanti 22, Bologna, 40126, Italy. marianna.ianzano@unibo.it.
12
Laboratory of Immunology and Biology of Metastases, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Viale Filopanti 22, Bologna, 40126, Italy. dario.ranieri@unibo.it.
13
Laboratory of Immunology and Biology of Metastases, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Viale Filopanti 22, Bologna, 40126, Italy. massimiliano.dallora@unibo.it.
14
CESI Aging Research Center, G. D'Annunzio University, Via Colle dell'Ara, Chieti Scalo, Chieti, 66013, Italy. miezzi@unich.it.
15
Laboratory of Immunology and Biology of Metastases, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Viale Filopanti 22, Bologna, 40126, Italy. carla.degiovanni@unibo.it.
16
Interdepartmental Centre for Cancer Research "Giorgio Prodi", University of Bologna, Via Massarenti 9, Bologna, 40138, Italy. carla.degiovanni@unibo.it.
17
Laboratory of Immunology and Biology of Metastases, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Viale Filopanti 22, Bologna, 40126, Italy. pierluigi.lollini@unibo.it.
18
Interdepartmental Centre for Cancer Research "Giorgio Prodi", University of Bologna, Via Massarenti 9, Bologna, 40138, Italy. pierluigi.lollini@unibo.it.

Abstract

INTRODUCTION:

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. 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.

METHODS:

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.

RESULTS:

IL15KO/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.

CONCLUSIONS:

We 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.

PMID:
25997501
PMCID:
PMC4462012
DOI:
10.1186/s13058-015-0588-x
[Indexed for MEDLINE]
Free PMC Article

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