DNA vaccination with a mutated p53 allele induces specific cytolytic T cells and protects against tumor cell growth and the formation of metastasis.

摘要

PURPOSE: Genetic vaccination by expression plasmids that encode mutant p53 was conducted to characterize exogenously induced anti-tumoral immunity in mice. METHODS: Gene transfer was evaluated by reporter gene expression assays. The efficacy of genetic immunization was addressed by analysis of solid tumor outgrowth and the formation of metastases. Cell mediated immunity was determined by (51)Cr-release cytotoxicity assays and adoptive lymphocyte transfer experiments. RESULTS: Genetic vaccination resulted in a persistent protection against the growth and metastasis of transplanted tumor cells. Immunoprotection was based on the induction of cytolytic T cells (CTLs) able to recognize mutant but not wild type p53. Mice were not protected from tumor cell growth when the tumor cells expressed alternate p53 mutations or overexpressed wild type p53. No p53 specific humoral immune response was detected. T-lymphocyte transfer experiments demonstrated that resistance to tumor growth depended both on tumor size and a time-dependent induction of protective immunity. Small tumors (O < 0.4 cm(3)) went into remission or remained stable upon adoptive transfer of T-lymphocytes from mice immunized with mutant p53 DNA; larger tumors progressed. A time course of immunization was evaluated and showed that DNA vaccination must precede tumor cell inoculation in order to induce an efficient anti-tumoral response. CONCLUSION: DNA vaccination against the mutated form of p53 can elicit a specific adaptive immune response and has anti-tumoral activity. Tumor burden and the time necessary to acquire tumor immunity were recognized as critical parameters for immunization; however, tumors may evade specific immunotherapy.