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

• DOI: 10.1007/s00262-004-0619-4
• Publication Date: 2004-11-15T21:28:19Z
• Authors: Zheng-Cai Jia; Li-Yun Zou; Bing Ni; Ying Wan; Wei Zhou; Yan-Bo Lv; Miao Geng; Yu-Zhang Wu
• Keywords: CD4-Positive T-Lymphocytes; Melanoma, Experimental; Membrane Proteins; CD8-Positive T-Lymphocytes; Xenopus Proteins; Cancer Vaccines; Peptide Fragments; 3. Good health; Intramolecular Oxidoreductases; Mice, Inbred C57BL; Transforming Growth Factor beta1; Mice; 03 medical and health sciences; 0302 clinical medicine; Transforming Growth Factor beta; Immune Tolerance; Vaccines, DNA; Animals; Female; Plasmids; T-Lymphocytes, Cytotoxic

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.