DNA vaccines targeting the encoded antigens to dendritic cells induce potent antitumor immunity in mice.
BACKGROUND
Although DNA vaccine holds a great potential for cancer immunotherapy, effective long-lasting antitumoral immunity sufficient to induce durable responses in cancer patients remains to be achieved. Considering the pivotal role of dendritic cells (DC) in the antigen processing and presentation, we prepared DC-targeting DNA vaccines by fusing tumor-associated antigen HER2/neu ectodomain to single chain antibody fragment (scFv) from NLDC-145 antibody specific for DC-restricted surface molecule DEC-205 (scFvNLDC-145), and explored its antitumoral efficacy and underlying mechanisms in mouse breast cancer models.


RESULTS
In vivo targeting assay demonstrated that scFvNLDC-145 specifically delivered DNA vaccine-encoded antigen to DC. Compared with untargeted HER2/neu DNA vaccines, vaccination with scFvNLDC-145-HER2/neu markedly promoted the HER2/neu-specific cellular and humoral immune responses with long-lasting immune memory, resulting in effective protection against challenge of HER2/neu-positive D2F2/E2 breast tumor while ineffective in parental HER2/neu-negative D2F2 breast tumor. More importantly, in combination with temporary depletion of regulatory T cells (Treg) by low-dose cyclophosphamide, vaccination with scFvNLDC-145-HER2/neu induced the regression of established D2F2/E2 breast tumor and significantly retarded the development of spontaneous mammary carcinomas in transgenic BALB-neuT mice.


CONCLUSIONS
Our findings demonstrate that DC-targeted DNA vaccines for in vivo direct delivery of tumor antigens to DC could induce potent antigen-specific cellular and humoral immune responses and, if additional combination with systemic Treg depletion, was able to elicit an impressively therapeutic antitumoral activity, providing a rationale for further development of this approach for cancer treatment.
Interventional Oncology, Dahua Hospital, Xuhui District, Shanghai 200237, China.
Jun
J
Cao
Yiqi
Y
Jin
Wei
W
Li
Bin
B
Zhang
Yang
Y
He
Hongqiang
H
Liu
Ning
N
Xia
Huafeng
H
Wei
Jian
J
Yan
D000818:Animals; D000912:Antibodies, Neoplasm / Q000276:immunology; D000918:Antibody Specificity / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D007108:Immune Tolerance / Q000276:immunology; D007109:Immunity / Q000276:immunology*; D007156:Immunologic Memory / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D057127:Single-Chain Antibodies / Q000276:immunology; D016896:Treatment Outcome; D014611:Vaccination; D019444:Vaccines, DNA / Q000276:immunology*
D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D018719:Erb-b2 Receptor Tyrosine Kinases; D057127:Single-Chain Antibodies; D019444:Vaccines, DNA