Combined allogeneic tumor cell vaccination and systematic interleukin 12 prevents mammary carcinogenesis in HER-2/neu transgenic mice

Patrizia Nanni, Giordano Nicoletti, Carla De Giovanni, Lorena Landuzzi, Emma Di Carlo, Federica Cavallo, Serenella M. Pupa, Ilaria Rossi, Mario P. Colombo, Cinzia Ricci, Annalisa Astolfi, Piero Musiani, Guido Forni, Pier Luigi Lollini

Research output: Contribution to journalArticle

Abstract

Transgenic Balb/c mice expressing the transforming rat HER-2/neu oncogene develop early and multifocal mammary carcinomas. Within the first 5 months of life the tissue-specific expression of HER-2/neu causes a progression in all their 10 mammry glands from atypical hyperplasia to invasive carcinoma. It was previously observed that chronic administration of interleukin (IL)-12 increased tumor latency, but every mouse eventually succumbed to multiple carcinomas. A significant improvement in tumor prevention was sought by administering allogeneic mammary carcinoma cells expressing HER-2/neu combined with systematic IL-12. This treatment reduced tumor incidence by 90% and more than doubled mouse lifetime. For the maximum prevention p185neu antigen must be expressed by allogeneic cells. IL-12 treatment strongly increased the cell vaccine efficacy. The mammary glands of mice receiving the combined treatment displayed a markedly reduced epithelial cell proliferation, angiogenesis, and HER-2/neu expression, while the few hyperplastic foci were heavily infiltrated by granulocytes, macrophages, and CD8+ lymphocytes. Specific anti-HER-2/neu antibodies were produced and a nonpolarized activation of CD4+ and CD8+ cells secreting IL-4 and interferon (IFN)-γ were evident. A central role for IFN-γ in the preventive effect was proven by the lack of efficacy of vaccination in IFN-γ gene knockout HER-2/neu trangenic Balb/c mice. A possible requirement of IFN-gamma; is related to its effect on antibody production, in particular on IgG2a and IgG2b subclasses, that were not induced in IFN-γ knockout HER-2/neu mice. In conclusion, our data show that an aloogeneic HER-2/neu-expressing cell vaccine combined with IL-12 systematic treatment can prevent the onset of genetically determined tumors.

Original languageEnglish
Pages (from-to)1195-1205
Number of pages11
JournalJournal of Experimental Medicine
Volume194
Issue number9
DOIs
Publication statusPublished - 2001

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Keywords

  • Allogeneic vaccine
  • HER-2/neu
  • IL-12
  • Mammary carcinoma

ASJC Scopus subject areas

  • Immunology

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