Inhibition of mammary carcinoma development in HER-2/neu transgenic mice through induction of autoimmunity by xenogeneic DNA vaccination.
Plasmid DNA vectors encoding the full-length (VR1012/HER-2-FL) or only the extracellular and transmembrane domains (VR1012/HER-2-ECD-TM) of human (h) HER-2/neu proto-oncogene were used to vaccinate HER-2/neu transgenic mice (N202) engineered to overexpress the rat (r) neu proto-oncogene product (r-p185(neu)). Both the full-length and the deleted vaccines were significantly (P = 0.0001 and P = 0.06, respectively) more active than the empty vector (VR1012/EV) in preventing and delaying HER-2/neu-driven mammary carcinogenesis. A low-level intratumoral infiltrate of dendritic cells, macrophages, CD8 T cells and polymorphonuclear granulocytes in association with low-level cytokine production was observed, which was not detected in tumors from control mice. Morphologic analyses showed that vaccination with VR1012/HER-2-FL or ECD-TM also efficiently hampered the development of terminal ductal lobular units (TDLU). Analyses of sera from vaccinated mice revealed high titers of antihuman HER-2/neu antibodies, which correlated with the delayed time of tumor onset (P = 0.002). These antibodies did not cross-react with r-p185(neu). Nontransgenic mice treated with the vaccines produced autoreactive antibodies targeting mouse (m)-p185(neu) and showed impaired function of the lactating mammary gland and accelerated involution of the gland after weaning. Together, these data indicate that xenogeneic DNA immunization breaks tolerance against the endogenous m-p185(neu), impairing the development of mammary TDLU in which m-p185(neu) expression is concentrated. The reduction in the number of TDLU decreases the number of glandular structures available for r-p185(neu)-dependent mammary carcinogenesis, resulting in a significant inhibition of mammary carcinoma development.
Pupa
Serenella M
SM
Molecular Targeting Unit, Department of Experimental Oncology, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy.
Iezzi
Manuela
M
Di Carlo
Emma
E
Invernizzi
AnnaMaria
A
Cavallo
Federica
F
Meazza
Raffaella
R
Comes
Alberto
A
Ferrini
Silvano
S
Musiani
Piero
P
Ménard
Sylvie
S
D000595:Amino Acid Sequence; D000818:Animals; D015551:Autoimmunity / Q000276:immunology; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000276:immunology*; D017124:Conserved Sequence; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008321:Mammary Glands, Animal / Q000276:immunology / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010957:Plasmids / Q000235:genetics / Q000276:immunology; D011247:Pregnancy; D000090063:Proto-Oncogene Mas; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000276:immunology*; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use
D019496:Cancer Vaccines; D000090063:Proto-Oncogene Mas; D018719:Erb-b2 Receptor Tyrosine Kinases; D019444:Vaccines, DNA; C000715470:MAS1 protein, human