Effective induction of antitumor immunity by immunization with plasmid DNA encoding TRP-2 plus neutralization of TGF-ß.

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 encodingXenopus laevistransforming growth factor-beta 5 (aTGF-ß5) as an immunogen to induce neutralizing antibodies against murine TGF-ß1 (mTGF-ß1) and thus enhance the efficacy of plasmid DNA vaccine encoding murine tyrosinase-related protein 2 (mTRP-2) through neutralization of TGF-ß. The results showed that immunization with aTGF-ß5 resulted in the generation of mTGF-ß1-neutralizing antibodies, and immunization with a combination of aTGF-ß5 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-ß5 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-ß5 is capable of breaking immune tolerance and induces mTGF-ß1-neutralizing antibodies. Neutralization of TGF-ß 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. [ABSTRACT FROM AUTHOR]