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Consequences of cell death: exposure to necrotic tumor cells
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 mammary 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 systemic IL-12. This treatment reduced tumor incidence by 90% and more than doubled mouse lifetime. For the maximum prevention p185 neu 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 transgenic Balb/c mice. A possible requirement for IFN-γ 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 allogeneic HER-2/neu–expressing cell vaccine combined with IL-12 systemic treatment can prevent the onset of genetically determined tumors. IL-12 allogeneic vaccine HER-2/neu mammary carcinoma immunoprevention Footnotes ↵ * Abbreviations used in this paper: IP, IFN-γ–inducible protein; MIG, monokine induced by IFN-γ; MIP, macrophage inflammatory protein; MitC, mitomycin C; MMP, matrix metalloproteinase; MSA, mouse serum albumin; PCNA, proliferating cell nuclear antigen; TEB, terminal ductal end bud. Submitted: 19 October 2000 Accepted: 10 September 2001 Revision received 21 August 2001
The Journal of Experimental Medicine – Rockefeller University Press
Published: Nov 5, 2001
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