Abstract 4085: Crucial roles of helper and killer epitopes in tumor antigens for developing dendritic cell-mediated cancer immunotherapy

Dendritic cells (DCs), powerful antigen presenting cells, play central role for induction of the antigen-specific immune responses through activation of CD4+T and CD8+T cells. Tumor antigen-pulsed DCs strongly generate helper T cells and cytotoxic T lymphocytes (CTLs), which recognize and kill the target tumor cells in response to the antigens. Thus, proper design of antigen is required for application of DC-mediated cancer immunotherapy. Many investigators have performed clinical trials of cancer immunotherapy. Numerous vaccinations with tumor antigen-derived peptides have been able to induce tumor specific immune responses to eradicate cancer with superior specificity and without severe adverse effects. However, the therapeutic efficacy of cancer vaccine therapy using MHC class I-binding peptides for CTLs have been limited to induce complete regression in cancer patients. To overcome limitation of antitumor effects, strong and persisting activation of tumor specific CTLs are required for eradication of tumor tissues to induce a complete cure in tumor-bearing hosts. Recently, it has been demonstrated that CD4+ helper T cells play a critical role for inducing fully activated antitumor CTLs. Moreover, long peptides composed of both MHC class I- and class II-binding epitopes exhibited superior vaccine efficacy compared with shorter peptides. Thus, the existence of helper epitopes and the length of peptides appeared to be key factors for designing a promising peptide for DC-mediated immunotherapy. In this work, we focused natural tumor antigens such as Birc5, a member of the inhibitor of apoptosis gene family, which was abundantly expressed in the majority of cancer cells. We first prepared a Birc5 long peptide containing helper and killer epitopes and the shorter peptides containing helper and/or killer epitope. The long peptide was injected alone or with bone marrow-derived DCs into several types of tumor-bearing mice. The tumor growth was remarkably decreased by in vivo injection of the long peptide compared with the short peptide. In addition, we confirmed that long peptides were superior to the short peptides for inducing antigen-specific immune responses in vivo. These data indicated that long peptides containing helper and killer epitopes might be critical for inducing effective antitumor immunity in cancer immunotherapy, suggesting that long peptide vaccination containing helper and killer epitope would become a promising therapeutic vaccine strategy