Heterologous human/rat HER2-specific exosome-targeted T cell vaccine stimulates potent humoral and CTL responses leading to enhanced circumvention of HER2 tolerance in double transgenic HLA-A2/HER2 mice

摘要

DNA vaccines composed of heterologous human HER2 and rat neu sequences induce stronger antibody response and protective antitumor immunity than either HER2 or neu DNA vaccines in transgenic mice. We previously developed HER2-specific exosome-targeted T-cell vaccine HER2-T-EXO capable of stimulating HER2-specific CD8(+) T-cell responses, but only leading to partial protective immunity in double-transgenic HLA-A2/HER2 mice with self-immune tolerance to HER2. Here, we constructed an adenoviral vector AdV(HuRt) expressing HuRt fusion protein composed of NH2-HER2(1-407) (Hu) and COOH-neu(408-690) (Rt) fragments, and developed a heterologous human/rat HER2-specific exosome-targeted T-cell vaccine HuRt-T-EXO using polyclonal CD4(+) T-cells uptaking exosomes released by AdV(HuRt)-transfected dendritic cells. We found that the HuRt-T-EXO vaccine stimulates enhanced CD4+ T-cell responses leading to increased induction of HER2-specific antibody (similar to 70 g/ml) compared to that (similar to 40 mu g/ml) triggered by the homologous HER2-T-EXO vaccine. By using PE-H-2K(d)/HER2(23-71) tetramer, we determined that HuRt-T-EXO stimulates stronger HER2-specific CD8(+) T-cell responses eradicating 90% of HER2-specific target cells, while HER2-T-EXO-induced CD8(+) T-cell responses only eliminating 53% targets. Furthermore, HuRt-T-EXO but not HER2-T-EXO vaccination, is capable of suppressing early stage-established HER2-expressing 4T1(HER2) breast cancer in its lung metastasis or subcutaneous form in BALB/c mice, and of completely protecting transgenic HLA-A2/HER2 mice from growth of HLA-A2/HER2-expressing BL6-10(A2/HEx2) melanoma. HuRt-T-EXO-stimulated HER2-specific CD8(+) T-cells not only are cytolytic to trastuzumab-resistant HLA-A2/HER2-expressing BT474/A2 breast tumor cells in vitro but also eradicates pre-established BT474/A2 tumors in athymic nude mice. Therefore, our novel heterologous human/rat HER2-specific T-cell vaccine HuRt-T-EXO, circumventing HER2 tolerance, may provide a new therapeutic alternative for patients with trastuzumab-resistant HER2(+) breast tumor. (C) 2018 Elsevier Ltd. All rights reserved.