Enhancement of DNA vaccine potency by sandwiching antigen-coding gene between secondary lymphoid tissue chemokine (SLC) and IgG Fc fragment genes.
DNA vaccine has become an attractive approach for generating antigen-specific immunity. Targeting antigens to FcRs for IgG (FcgammaRs) on dendritic cells (DCs) has been demonstrated to enhance antigen presentation. Secondary lymphoid tissue chemokine (SLC) has been shown to increase immune responses not only by promoting coclustering of T cells and DCs in the lymph nodes and spleen but also by regulating their immunogenic potential for the induction of T cell responses. In this study, using HPV 16 E7 as a model antigen, we constructed a chemotactic-antigen plasmid DNA vaccine (pSLC-E7-Fc) by linking SLC and Fc gene sequences to each end of E7 and evaluated its potency of eliciting specific immune response. We found that immunization with pSLC-E7-Fc generated much stronger E7-specific lymphocyte proliferative and cytotoxic T lymphocyte (CTL) responses than control DNA. All the mice receiving pSLC-E7-Fc prophylactic vaccination remained tumor free upon subcutaneous inoculation of TC-1 cells, while those given control DNA all developed tumors. These tumor-free mice were also protected against TC-1 rechallenge. Complete tumor regression with long-term survival occurred in 72% of mice given pSLC-E7-Fc as therapeutic vaccination. In experimental lung metastasis model wherein TC-1 cells were intravenously injected, therapeutic vaccination with pSLC-E7-Fc significantly reduced the number of tumor nodules in the lung. In vivo depletion with antibodies against CD4+or CD8+ T cells both resulted in complete abrogation of the pSLC-E7-Fc-induced immunotherapeutic effect. Our data indicate that the DNA vaccine constructed by the fusion of SLC and IgG Fc fragment genes to antigen-coding gene is an effective approach to induce potent anti-tumor immune response via both CD4+ and CD8+ T cells dependent pathways.
Department of Immunology, Cancer Hospital & Institute, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
Rongzhi
R
Liu
Chunxia
C
Zhou
Dongmei
D
Wang
Wenbo
W
Ma
Chen
C
Lin
Yongquan
Y
Wang
Xiao
X
Liang
Jie
J
Li
Sujuan
S
Guo
Yihua
Y
Wang
Youhui
Y
Zhang
Shuren
S
Zhang
D000818:Animals; D000941:Antigens / Q000737:chemistry*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D054421:Chemokine CCL21; D019742:Chemokines, CC / Q000378:metabolism*; D005260:Female; D006801:Humans; D007128:Immunoglobulin Fragments / Q000378:metabolism; D007074:Immunoglobulin G / Q000737:chemistry; D008198:Lymph Nodes / Q000473:pathology; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D019444:Vaccines, DNA
D000941:Antigens; C515478:CCL21 protein, human; C515479:Ccl21c protein, mouse; D054421:Chemokine CCL21; D019742:Chemokines, CC; D007128:Immunoglobulin Fragments; D007074:Immunoglobulin G; D019444:Vaccines, DNA