title: Interleukin-15 is required for immunosurveillance and immunoprevention of HER2/neu-driven mammary carcinogenesis.
abstract: BACKGROUND
  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.
authors.affiliation: 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.|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.
authors.forename: Stefania
authors.initials: S
authors.lastname: Croci
authors.affiliation: 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.|Interdepartmental Centre for Cancer Research "Giorgio Prodi", University of Bologna, Via Massarenti 9, Bologna, 40138, Italy. patrizia.nanni@unibo.it.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Nanni
authors.affiliation: 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.
authors.forename: Arianna
authors.initials: A
authors.lastname: Palladini
authors.affiliation: Laboratory of Experimental Oncology, Rizzoli Orthopedic Institute, Via di Barbiano 1/10, Bologna, 40136, Italy. giordano.nicoletti@ior.it.
authors.forename: Giordano
authors.initials: G
authors.lastname: Nicoletti
authors.affiliation: 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.
authors.forename: Valentina
authors.initials: V
authors.lastname: Grosso
authors.affiliation: 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.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Benegiamo
authors.affiliation: Laboratory of Experimental Oncology, Rizzoli Orthopedic Institute, Via di Barbiano 1/10, Bologna, 40136, Italy. lorena.landuzzi@ior.it.
authors.forename: Lorena
authors.initials: L
authors.lastname: Landuzzi
authors.affiliation: CESI Aging Research Center, G. D'Annunzio University, Via Colle dell'Ara, Chieti Scalo, Chieti, 66013, Italy. alessia.lamolinara@gmail.com.
authors.forename: Alessia
authors.initials: A
authors.lastname: Lamolinara
authors.affiliation: 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.
authors.forename: Marianna L
authors.initials: ML
authors.lastname: Ianzano
authors.affiliation: 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.
authors.forename: Dario
authors.initials: D
authors.lastname: Ranieri
authors.affiliation: 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.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Dall'Ora
authors.affiliation: CESI Aging Research Center, G. D'Annunzio University, Via Colle dell'Ara, Chieti Scalo, Chieti, 66013, Italy. miezzi@unich.it.
authors.forename: Manuela
authors.initials: M
authors.lastname: Iezzi
authors.affiliation: 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.|Interdepartmental Centre for Cancer Research "Giorgio Prodi", University of Bologna, Via Massarenti 9, Bologna, 40138, Italy. carla.degiovanni@unibo.it.
authors.forename: Carla
authors.initials: C
authors.lastname: De Giovanni
authors.affiliation: 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.|Interdepartmental Centre for Cancer Research "Giorgio Prodi", University of Bologna, Via Massarenti 9, Bologna, 40138, Italy. pierluigi.lollini@unibo.it.
authors.forename: Pier-Luigi
authors.initials: PL
authors.lastname: Lollini
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D019496:Cancer Vaccines / Q000276:immunology; D002471:Cell Transformation, Neoplastic / Q000276:immunology* / Q000378:metabolism*; D002633:Chemotaxis / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006801:Humans; D019409:Interleukin-15 / Q000235:genetics / Q000378:metabolism*; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015166:Monitoring, Immunologic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D019496:Cancer Vaccines; D019409:Interleukin-15; D018719:Erb-b2 Receptor Tyrosine Kinases