Background. Vaccination with DNA encoding tumor antigens can elicit both humoral and cellular immunity specific for DNA-encoding antigens in vaccinated host. However, the immunity elicited by DNA vaccines is not sufficiently strong to eradicate tumors in tumor-bearing hosts. To augment anti-tumor immune responses elicited by DNA vaccination and overcome the established tumor, adaptive as well as innate immune responses are needed to be activated. We previously reported that a sixteen-amino acid peptide analogue derived from pigeon cytochrome c (Pan-IA peptide) can bind a broad range of MHC class II types and activate the helper T function in mice. This peptide analogue is expected to be useful as an adjuvant in cancer immunotherapy. It has recently been reported that dendritic cells can activate the innate arm of the immune system. Purpose. The aim of this study is to determine whether anti-tumor immunity induced by DNA vaccines targeting tumor antigens can be sufficiently augmented to suppress tumor growth in vivo by co-vaccination with mature dendritic cells pulsed with Pan-IA peptide. Materials and Methods. Bone marrow-derived mature dendritic cells pulsed with Pan-IA peptide (DC-IA) was injected into C57BL/6 mice intramuscularly in combination with DNA encoding ovalbumin (OVA), thereafter spleen cells from the immunized mice were examined for their OVA-specific immune responses and NK activity. To test therapeutic efficacy of the combined vaccines, E.G7 (OVA-expressing) tumor-bearing mice were vaccinated with OVA DNA with or without DC-IA and then the size of tumors were monitored. Mice in which E.G7 tumors were eradicated by the combined vaccination were examined for cytokine production and anti-angiogenic abilities by the tumor-infiltrating lymphocytes. Results. In addition to increased NK activity, the tumor-specific proliferative response and cytotoxic activity were observed in mice vaccinated with both OVA DNA and DC-IA. Tumor growth of E.G7 cells was suppressed only by combined vaccination with OVA and DC-IA. An immunohistochemical study revealed that vascularization in the tumor was markedly suppressed only by this vaccine protocol. Many of CD4- and CD8-positive T cells infiltrating the tumors were shown to produce IFN-γ. Conclusions. DC-IA can enhance anti-tumor immunity through the activation of NK cells as well as the induction of antigen-specific CD8-positive T lymphocytes via activation of the helper T function in DNA-vaccinated hosts. Tumor growth was successfully suppressed by both increased cytotoxic activity and decreased vascularization in the tumor in mice that received the combined vaccination. This animal model may contribute to the development of therapeutic DNA vaccines against cancer.
[Proc Amer Assoc Cancer Res, Volume 46, 2005]