Effective induction of antitumor immunity by immunization with plasmid DNA encoding TRP-2 plus neutralization of TGF-beta.
Plasmid DNA vaccine is an appealing cancer immunotherapy. However, it is a weak immunogen and immunization with plasmid DNA encoding self-antigens, such as melanoma-associated antigens, could not induce antitumor immunity because of tolerance. In this study, we investigated the feasibility of using a plasmid DNA encoding Xenopus laevis transforming growth factor-beta 5 (aTGF-beta5) as an immunogen to induce neutralizing antibodies against murine TGF-beta1 (mTGF-beta1) and thus enhance the efficacy of plasmid DNA vaccine encoding murine tyrosinase-related protein 2 (mTRP-2) through neutralization of TGF-beta. The results showed that immunization with aTGF-beta5 resulted in the generation of mTGF-beta1-neutralizing antibodies, and immunization with a combination of aTGF-beta5 and mTRP-2 induced specific cytotoxic T lymphocytes (CTLs). On the contrary, immunization with mTRP-2 alone could not elicit the CTL response. Moreover, immunization of C57BL/6 wild-type mice with a combination of aTGF-beta5 and mTRP-2 induced the protective and therapeutic antitumor immunity to B16F10 melanoma, whereas the antitumor activity was abrogated in both CD4-deficient mice and CD8-deficient mice on the C57BL/6 background. Our results indicate that immunization with aTGF-beta5 is capable of breaking immune tolerance and induces mTGF-beta1-neutralizing antibodies. Neutralization of TGF-beta can enhance the efficacy of DNA vaccine encoding mTRP-2 and the induction of antitumor immunity by this immunization strategy is associated with CD4+ and CD8+ T cells.
Jia
Zheng-Cai
ZC
Institute of Immunology, Third Military Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing, 400038, China.
Zou
Li-Yun
LY
Ni
Bing
B
Wan
Ying
Y
Zhou
Wei
W
Lv
Yan-Bo
YB
Geng
Miao
M
Wu
Yu-Zhang
YZ
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D005260:Female; D007108:Immune Tolerance / Q000276:immunology; D019746:Intramolecular Oxidoreductases / Q000276:immunology; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000517:prevention & control; D008565:Membrane Proteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000276:immunology*; D010957:Plasmids / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000276:immunology*; D053773:Transforming Growth Factor beta1; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D029867:Xenopus Proteins
D019496:Cancer Vaccines; D008565:Membrane Proteins; D010446:Peptide Fragments; C404602:TGF-beta5 protein, Xenopus laevis; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D019444:Vaccines, DNA; D029867:Xenopus Proteins; C500290:peptide SVYDFFVWL; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase