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

196 Citations (Scopus)

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

Fingerprint

Interleukin-12
Transgenic Mice
Carcinogenesis
Vaccination
Breast
Interferons
Neoplasms
Breast Neoplasms
Carcinoma
Combined Vaccines
Gene Knockout Techniques
Therapeutics
Human Mammary Glands
Oncogenes
Granulocytes
Interleukin-4
Interferon-gamma
Antibody Formation
Hyperplasia
Vaccines

Keywords

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

ASJC Scopus subject areas

  • Immunology

Cite this

Combined allogeneic tumor cell vaccination and systematic interleukin 12 prevents mammary carcinogenesis in HER-2/neu transgenic mice. / Nanni, Patrizia; Nicoletti, Giordano; De Giovanni, Carla; Landuzzi, Lorena; Di Carlo, Emma; Cavallo, Federica; Pupa, Serenella M.; Rossi, Ilaria; Colombo, Mario P.; Ricci, Cinzia; Astolfi, Annalisa; Musiani, Piero; Forni, Guido; Lollini, Pier Luigi.

In: Journal of Experimental Medicine, Vol. 194, No. 9, 2001, p. 1195-1205.

Research output: Contribution to journalArticle

Nanni, Patrizia ; Nicoletti, Giordano ; De Giovanni, Carla ; Landuzzi, Lorena ; Di Carlo, Emma ; Cavallo, Federica ; Pupa, Serenella M. ; Rossi, Ilaria ; Colombo, Mario P. ; Ricci, Cinzia ; Astolfi, Annalisa ; Musiani, Piero ; Forni, Guido ; Lollini, Pier Luigi. / Combined allogeneic tumor cell vaccination and systematic interleukin 12 prevents mammary carcinogenesis in HER-2/neu transgenic mice. In: Journal of Experimental Medicine. 2001 ; Vol. 194, No. 9. pp. 1195-1205.
@article{a75bca27b10a41f2b8683a63437e5ee2,
title = "Combined allogeneic tumor cell vaccination and systematic interleukin 12 prevents mammary carcinogenesis in HER-2/neu transgenic mice",
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.",
keywords = "Allogeneic vaccine, HER-2/neu, IL-12, Mammary carcinoma",
author = "Patrizia Nanni and Giordano Nicoletti and {De Giovanni}, Carla and Lorena Landuzzi and {Di Carlo}, Emma and Federica Cavallo and Pupa, {Serenella M.} and Ilaria Rossi and Colombo, {Mario P.} and Cinzia Ricci and Annalisa Astolfi and Piero Musiani and Guido Forni and Lollini, {Pier Luigi}",
year = "2001",
doi = "10.1084/jem.194.9.1195",
language = "English",
volume = "194",
pages = "1195--1205",
journal = "Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "9",

}

TY - JOUR

T1 - Combined allogeneic tumor cell vaccination and systematic interleukin 12 prevents mammary carcinogenesis in HER-2/neu transgenic mice

AU - Nanni, Patrizia

AU - Nicoletti, Giordano

AU - De Giovanni, Carla

AU - Landuzzi, Lorena

AU - Di Carlo, Emma

AU - Cavallo, Federica

AU - Pupa, Serenella M.

AU - Rossi, Ilaria

AU - Colombo, Mario P.

AU - Ricci, Cinzia

AU - Astolfi, Annalisa

AU - Musiani, Piero

AU - Forni, Guido

AU - Lollini, Pier Luigi

PY - 2001

Y1 - 2001

N2 - 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.

AB - 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.

KW - Allogeneic vaccine

KW - HER-2/neu

KW - IL-12

KW - Mammary carcinoma

UR - http://www.scopus.com/inward/record.url?scp=0035163903&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035163903&partnerID=8YFLogxK

U2 - 10.1084/jem.194.9.1195

DO - 10.1084/jem.194.9.1195

M3 - Article

VL - 194

SP - 1195

EP - 1205

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

IS - 9

ER -