HER2/neu-Based Peptide Vaccination-Pulsed with B-Cell Epitope Induced Efficient Prophylactic and Therapeutic Antitumor Activities in TUBO Breast Cancer Mice Model.

Abstract

Simple SummaryRecently, the role of vaccination has been expanded in the management of HER2/neu-positive breast cancer. Data from various clinical trials indicated that an effective breast cancer vaccine must be able to induce both humoral and cellular immune responses. One approach is the use of a multi-epitope peptide vaccine comprising B, T helper and CTL epitopes. In this study, we have successfully developed a vaccine construct based on a chimeric HER2/neu-derived antigenic peptide possessing B- and T-cell epitopes conjugated to the KLH protein as a source of T-helper epitopes. A similar vaccine construct, but without the presence of a B-cell peptide epitope, was also prepared to examine the role of the humoral immune response in antitumor immunity. Multi-epitope peptide vaccine with additional B-cell epitope was found to be superior in inhibiting the tumor growth and prolongation of survival in tumor mice model compared to vaccine construct without the presence of B-cell epitope.Breast cancer is the most common invasive cancer diagnosed among women. A cancer vaccine has been recognized as a form of immunotherapy with a prominent position in the prevention and treatment of breast cancer. The majority of current breast cancer vaccination strategies aim to stimulate antitumor T-cell responses of the HER2/neu oncogene, which is abnormally expressed in breast cancer cells. However, the role of the B-cell humoral response is often underappreciated in the cancer vaccine design. We have advanced this idea by elucidating the role of B-cells in cancer vaccination by designing a chimeric antigenic peptide possessing both cytotoxic T lymphocytes (GP2) and B-cell (P4) peptide epitopes derived from HER2/neu. The chimeric peptide (GP2–P4) was further conjugated to a carrier protein (KLH), forming a KLH–GP2–P4 conjugate. The immunogenicity of KLH–GP2–P4 was compared with KLH–GP2 (lacking the B-cell epitope) in BALB/c mice. Mice immunized with KLH–GP2–P4 elicited more potent antigen-specific neutralizing antibodies against syngeneic TUBO cells (cancer cell line overexpressing HER2/neu) that was governed by a balanced Th1/Th2 polarization in comparison to KLH–GP2. Subsequently, these immune responses led to greater inhibition of tumor growth and longer survival in TUBO tumor-bearing mice in both prophylactic and therapeutic challenge experiments. Overall, our data demonstrated that the B-cell epitope has a profound effect in orchestrating an efficacious antitumor immunity. Thus, a multi-epitope peptide vaccine encompassing cytotoxic T-lymphocytes, T-helper and B-cell epitopes represents a promising strategy in developing cancer vaccines with a preventive and therapeutic modality for the effective management of breast cancer.