Potent CD4+ T-cell epitope P30 enhances HER2/neu-engineered dendritic cell-induced immunity against Tg1-1 breast cancer in transgenic FVBneuN mice by enhanced CD4+ T-cell-stimulated CTL responses

Abstract

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.

Therapeutic vaccines for breast cancer: Has the time finally come?

“…To date, although multiple approaches, such as selection of suitable DC subsets, adjuvants and different DC engineering methods, are being developed to improve the efficiency of DC-based vaccines, their clinical benefit is still limited [ [75] , [76] , [77] ].…”

HER2-Positive Breast Cancer Immunotherapy: A Focus on Vaccine Development

“…The result of in vivo depletion studies also established the role of both CD4 + and CD8 + T cells in inducing anti-tumor immunity (Chen et al 2001). Xie et al (2013) engineered DCs with two cancer antigens including the P30 peptide-derived from tetanus toxin (FNNFTVSFWLRVPKVSASHLE) and HER2derived peptides to generate highly efficient CD4 + and CD8 + T cell responses toward HER2-positive breast cancer. In another report, Viehl et al (2005) indicated that administration of DCs transfected with HER2 fused to Tat protein led to protection effects against tumor in FVB/N mice challenged with syngeneic HER2 overexpressing breast cancer cells.…”

MUC1 Glycopeptide Vaccine Modified with a GalNAc Glycocluster Targets the Macrophage Galactose C-type Lectin on Dendritic Cells to Elicit an Improved Humoral Response

“…In the second peptides set (Figure 1, peptides 15 and 16), w e i n t r o d u c e d t h e T h e l p e r e p i t o p e P 3 0 (FNNFTVSFWLRVPKVSASHLE), derived from tetanus toxoid, to improve the presentation of exogenous glycopeptides on the MHC complex and activate T cells for in vivo testing. 44 The tripartite vaccine 16 contains the Tn-modified MUC1 glycopeptide, the T helper epitope P30, and the high-affinity ligand 1 to enhance endocytosis by the C-type lectin MGL. Additionally, a corresponding control glycopeptide 15 lacking the MGL glycocluster ligand 1 was prepared.…”