Successful tumor eradication was achieved by collaboration of augmented cytotoxic activity and anti-angiogenic effects following therapeutic vaccines containing helper-activating analog-loaded dendritic cells and tumor antigen DNA.
We reported previously that pigeon cytochrome c-derived peptides (Pan-IA), which bind broad ranges of MHC class II molecules efficiently, activate T helper (Th) function in mice. In an experimental model, Pan-IA DNA vaccines augmented antitumor immunity in tumor antigen-immunized mice. To elicit more potent antitumor immunity and to eradicate tumors in a therapeutic setting, Pan-IA-loaded dendritic cells (DCs) were inoculated in combination with vaccines including ovalbumin (OVA) antigen DNA in tumor-bearing mice. Seventy percent of the immunized mice survived tumor-free for at least 4 months after treatment. In contrast, mice vaccinated with OVA DNA, either with or without naïve DCs, did not eliminate the tumors and died within 5 weeks. Only in mice vaccinated with OVA DNA and Pan-IA-loaded DCs were both cytotoxic and helper responses specific for OVA induced at the spleen and tumor sites as well as at the vaccination sites. Furthermore, accumulation of OVA-specific CD4(+) and CD8(+) T lymphocytes and interferon-gamma-mediated anti-angiogenesis were observed in the tumors of these mice. Thus, the combined vaccination primed both tumor-specific cytotoxicity and helper immunity resulting in augmented tumor lysis ability and anti-angiogenic effects. This is the first report to show that most established tumors were successfully eradicated by collaboration of potent antitumor immunity and anti-angiogenic effects by vaccination with tumor antigens and helper-activating analogs. This novel vaccination strategy is broadly applicable, regardless of identifying helper epitopes in target molecules, and contributes to the development of therapeutic cancer vaccines.
Teramoto
Koji
K
Department of Surgery, Shiga University of Medical Science, Seta-tsukinowa, Otsu 520-2192, Japan.
Kontani
Keiichi
K
Fujita
Takuya
T
Ozaki
Yoshitomo
Y
Sawai
Satoru
S
Tezuka
Noriaki
N
Fujino
Shozo
S
Itoh
Yasushi
Y
Taguchi
Osamu
O
Kannagi
Reiji
R
Ogasawara
Kazumasa
K
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D010856:Columbidae; D045304:Cytochromes c / Q000276:immunology; D004273:DNA, Neoplasm / Q000276:immunology*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000637:transplantation*; D004195:Disease Models, Animal; D000939:Epitopes / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000032:analysis; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D013154:Spleen / Q000276:immunology
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D004273:DNA, Neoplasm; D000939:Epitopes; D010446:Peptide Fragments; D007371:Interferon-gamma; D010047:Ovalbumin; D045304:Cytochromes c