Abstract
BALB/c mice transgenic (Tg) for the transforming rat neu oncogene (BALB-neuT) are genetically predestined to develop mammary carcinogenesis in a process similar to that in humans. We crossed HLA-A2.1/HLA-DR1 (A2.1/DR1) Tg mice with BALB-neuT mice to generate A2.1/DR1 x BALB-neuT triple Tg (A2.1/DR1 x neuT(+)) mice, which represent an improvement over BALB-neuT mice for evaluating vaccination regimens to overcome tolerance against HER-2/neu. A vaccine formulation strategy, consisting of synthetic peptides from the rat HER-2/neu oncogene combined with granulocyte macrophage colony-stimulating factor, was highly effective in preventing the growth of established transplantable tumors in male A2.1/DR1 x neuT(+) mice. Vaccination with HER-2(435-443) (p435) CTL peptide alone induced weak antitumor responses, which were characterized by increased numbers of regulatory T cells (Treg) and low numbers of vaccine-specific CD8(+) CTL and helper T cells (Th). The administration of p435 plus HER-2(776-790) (p776; helper peptide) reversed this situation, inducing functionally active, peptide-specific CTL and Th. There was a striking change in the intratumoral balance of Tregs (decrease) and vaccine-specific Th (increase) that directly correlated with tumor rejection. Intratumoral administration of anti-FasL antibody promoted tumor growth. The decrease in Tregs (Fas(+)) was due to apoptosis induced by cell contact with Fas ligand(+) (L)(+) Th. Mice vaccinated with p435 plus p776 exhibited long-lasting antitumor immunity. Our vaccine regimen also significantly delayed the outgrowth of mammary carcinomas in female A2.1/DR1 x neuT(+) animals. We provide a mechanism to overcome tolerance against HER-2/neu, which proposes a combined vaccination with two (Th and CTL) HER-2 peptides against HER-2/neu-expressing tumors.
Highlights
HER-2/neu oncoprotein is overexpressed by a significant percentage of human carcinomas [1], and this, at least in breast cancer, is associated with aggressive disease and enhanced metastatic potential [2]
Our first task was to determine the immunogenicity of p435 in our HER-2/ neu tolerant male A2.1/DR1 × neuT+ triple Tg versus their HER-2/neu nontolerant littermates (A2.1/DR1 × neuT−; hereinafter called neuT− littermates) given either alone or in combination with p776
Two major findings emerged from these studies (Fig. 1Aa): firstly, only marginal levels of cytotoxicity could be detected in neuT+ triple Tg when p435 was given alone
Summary
HER-2/neu oncoprotein is overexpressed by a significant percentage of human carcinomas [1], and this, at least in breast cancer, is associated with aggressive disease and enhanced metastatic potential [2]. Based on HER-2/neu transgenic (Tg) mouse models [3, 4], we know that T cells recognizing an immunodominant epitope from the transgene (self) are rare and of lower avidity [4, 5]. We evaluate the use of a vaccine mixture consisting of two immunogenic peptides corresponding to the HER-2 [776–790] (p776) CTL epitope [12,13,14,15,16] and the promiscuous p776 helper T cells (Th) epitope [17,18,19,20,21] This is the first study, to our knowledge, defining the in vivo effect of combined vaccination with two HER-2/neu peptides representing CTL and Th epitopes on the dynamic relationship between vaccine-specific CTL and Th/Tregs in HER-2/neu tolerant A2.1/DR1 × neuT+ and nontolerant A2.1/DR1 × neuT− littermates. The data show that our vaccination schedule induces memory antitumor immunity, which is important considering the use of this peptide combination in clinical studies
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