We demonstrated that peripheral T cell tolerance toward murine
melanoma self-antigens gp100 and TRP-2 can be broken by an autologous oral
DNA vaccine containing the murine
ubiquitin gene fused to minigenes encoding
peptide epitopes gp100(25-33) and TRP-2(181-188). These
epitopes contain dominant anchor residues for MHC
class I antigen alleles H-2D(b) and H-2K(b), respectively. The
DNA vaccine was delivered by oral gavage by using an attenuated strain of Salmonella typhimurium as carrier.
Tumor-protective immunity was mediated by MHC
class I antigen-restricted CD8(+) T cells that secreted T(H)1
cytokine IFN-gamma and induced
tumor rejection and growth suppression after a lethal challenge with B16G3. 26 murine
melanoma cells. Importantly, the protective immunity induced by this autologous
DNA vaccine against murine
melanoma cells was at least equal to that achieved through xenoimmunization with the human gp100(25-33)
peptide, which differs in its three NH(2)-terminal
amino acid residues from its murine counterpart and was previously reported to be clearly superior to an autologous
vaccine in inducing protective immunity. The presence of
ubiquitin upstream of the minigene proved to be essential for achieving this
tumor-protective immunity, suggesting that effective antigen processing and presentation may make it possible to break peripheral T cell tolerance to a
self-antigen. This
vaccine design might prove useful for future rational designs of other
recombinant DNA vaccines targeting tissue
differentiation antigens expressed by
tumors.