One of the major obstacles in human
epidermal growth factor receptor (HER)-2/neu-specific
trastuzumab immunotherapy of HER2/neu-positive
breast cancer is the development of
trastuzumab resistance, warranting the search for other therapeutic strategies. Although dendritic cell (DC)
vaccines have been extensively applied in clinical trials for
cancer treatment, the vaccination efficacy is still limited, mostly because DC
vaccines are not sufficient to break
tumor-associated
antigen-specific self-immune tolerance in
cancer patients. P30 (FNNFTVSFWLRVPKVSASHLE) derived from
tetanus toxin is a universally potent CD4(+) T helper
epitope capable of enhancing CD8(+) cytotoxic T-lymphocyte (CTL) responses. In this study, we constructed two recombinant adenoviral vectors (AdVs), AdVOVA-P30 and AdVHER2/neu-P30, expressing
ovalbumin (OVA)-P30 and HER2/neu-P30. In order to enhance DC
vaccine efficacy, we transfected mouse bone marrow (BM)-derived DCs with AdVOVA-P30 and AdVHER2/neu-P30 to generate engineered DCOVA-P30 and DCHER2/neu-P30
vaccines, respectively. We, then, compared CD4(+) and CD8(+) T-cell responses and antitumor immunity derived from DCOVA-P30 and DCHER2/neu-P30 vaccination in wild-type C57BL/6 and transgenic FVBneuN mice, respectively. We demonstrate that engineered DCOVA-P30
vaccine stimulates more efficient CD4(+) and CD8(+) T-cell responses than DCOVA in C57BL/6 mice. Interestingly, the increased DCOVA-P30-induced CTL responses are mainly contributed by enhanced CD4(+) T-cell-stimulated CTL proliferation. We show that DCOVA-P30
vaccine also stimulates more efficient therapeutic immunity against OVA-expressing BL6-10OVA
melanoma than DCOVA in C57BL/6 mice. In addition, we demonstrate that DCHER2/neu-P30
vaccine stimulates more efficient CD4(+) and CD8(+) T-cell responses and protective immunity against HER2/neu-expressing Tg1-1
breast cancer than DCHER2/neu in transgenic FVBneuN mice with HER2/neu-specific self-immune tolerance. Therefore, the engineered DCHER2/neu-P30
vaccine may provide a new
immunotherapy alternative for women with HER2/neu(+)
breast cancer, especially for
trastuzumab-resistant HER2/neu(+)
breast cancer patients.