Concordant morphologic and gene expression data show that a vaccine halts HER-2/neu preneoplastic lesions

Abstract

While much experimental data shows that vaccination efficiently inhibits a subsequent challenge by a transplantable tumor, its ability to inhibit the progress of autochthonous preneoplastic lesions is virtually unknown. In this article, we show that a combined DNA and cell vaccine persistently inhibits such lesions in a murine HER-2/neu mammary carcinogenesis model. At 10 weeks of age, all of the ten mammary gland samples from HER-2/neu–transgenic mice displayed foci of hyperplasia that progressed to invasive tumors. Vaccination with plasmids coding for the transmembrane and extracellular domain of rat p185neu followed by a boost with rp185neu+ allogeneic cells secreting IFN-γ kept 48% of mice tumor free. At 22 weeks, their mammary glands were indistinguishable from those of 10-week-old untreated mice. Furthermore, the transcription patterns of the two sets of glands coincided. Of the 12,000 genes analyzed, 17 were differentially expressed and related to the antibody response. The use of B cell knockout mice as well as the concordance of morphologic and gene expression data demonstrated that the Ab response is the main mechanism facilitating tumor growth arrest. This finding suggests that a new way can be found to secure the immunologic control of the progression of HER-2/neu preneoplastic lesions

Antitumor immunization of mothers delays tumor development in cancer-prone offspring

“…16,17,23 Having found specific anti-neu antibodies in ECTM offspring, we investigated whether these antibodies were able to inhibit mammary carcinogenesis in female BALB-neuT pups (neu C offspring). Indeed, neu C ECTM offspring showed significantly extended tumor-free ( Fig.…”

“…This is in line with our previous findings, which demonstrate that ECTM vaccination elicits the activation of T helper cells producing interferon gamma (IFNg), the primary switch factor for IgG2a. 17 IgG2a activate the complement and interact very efficiently with the Fcg receptors on various effector cells. 29 To further elucidate how these passively transferred antibodies induce tumor delay, BALB/c mice KO for the Fc-gamma I/ III receptors (FcgRI/III) (FcgKO mice) 30 were immunized with ECTM or its empty control vector and mated with a BALB-neuT/FcgKO male.…”

“…13,14 Membrane tyrosine kinase Her2, of the epidermal growth factor receptor family, is expressed by many human carcinomas in association with poor prognosis 15 and fulfills the definition of an oncoantigen. We have demonstrated that vaccination with a plasmid that codes for the extracellular and transmembrane (ECTM) domains of rat Her2 (neu) effectively inhibits mammary carcinogenesis [16][17][18] in female BALB/c mice heterozygous for the transforming form of the neu transgene under the transcriptional control of the mouse mammary tumor virus promoter (BALBneuT mice). 19,20 Vaccine-elicited tumor inhibition in these mice is driven by anti-neu antibody generation, 16,17 whereas the T-cell cytotoxic response is marginal as T cells that react against neu with high affinity are wiped out by central tolerance.…”

“…We have demonstrated that vaccination with a plasmid that codes for the extracellular and transmembrane (ECTM) domains of rat Her2 (neu) effectively inhibits mammary carcinogenesis [16][17][18] in female BALB/c mice heterozygous for the transforming form of the neu transgene under the transcriptional control of the mouse mammary tumor virus promoter (BALBneuT mice). 19,20 Vaccine-elicited tumor inhibition in these mice is driven by anti-neu antibody generation, 16,17 whereas the T-cell cytotoxic response is marginal as T cells that react against neu with high affinity are wiped out by central tolerance. 21,22 The induction of high levels of antibodies following vaccination is also the mainstay of the success of maternal immunization strategy against infectious diseases.…”

Anti-HER-2 DNA vaccine protects Syrian hamsters against squamous cell carcinomas

“…Tumour takes were higher in the low-titre hamsters ( Figure 4A). The antitumour effects of antibodies directed against membrane tyrosine kinase receptors such as p185 include the blockade of mitogenic signal transduction through inhibition of receptor dimerisation and induction of internalisation and recycling, along with immunemediated functions, namely complement-mediated cytotoxicity and antibody-dependent cellular cytotoxicity (Rovero et al, 2000;Nanni et al, 2004;Quaglino et al, 2004b). Although transplantable tumours may not reflect a few features of the human cancer, we studied HCPC I cells because the biological and histological characteristics of the tumours they form in hamsters are actually very similar to human SCC.…”