An Autologous Oral DNA Vaccine Protects against Murine Melanoma

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 97; no. 10; pp. 5492 - 5497
• Main Authors: Xiang, Rong, Lode, Holger N., Chao, Ta-Hsiang, Ruehlmann, J. Michael, Dolman, Carrie S., Rodriguez, Fernando, Whitton, J. Lindsay, Overwijk, Willem W., Restifo, Nicholas P., Reisfeld, Ralph A.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 09-05-2000; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences
• Subjects: Administration, Oral; AIDS/HIV; Animals; Antigens, Neoplasm - immunology; Biological Sciences; Cancer Vaccines - administration & dosage; Cancer Vaccines - therapeutic use; CD8-Positive T-Lymphocytes - immunology; Cell lines; Cellular immunity; Cytokines - biosynthesis; Cytotoxicity, Immunologic; Deoxyribonucleic acid; DNA; DNA vaccines; Epitopes; Female; Histocompatibility Antigens Class I - immunology; Humans; Immunity; Male; Medical research; Melanoma; Melanoma, Experimental - immunology; Melanoma, Experimental - prevention & control; Mice; Mice, Inbred C57BL; Mice, SCID; Prostatic Neoplasms - immunology; Salmonella typhimurium - immunology; Skin cancer; T lymphocytes; Ubiquitins; Ubiquitins - genetics; Vaccination; Vaccines; Vaccines, DNA - administration & dosage; Vaccines, DNA - therapeutic use
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.090097697

We demonstrated that peripheral T cell tolerance toward murine melanoma self-antigens gp 100 and TRP-2 can be broken by an autologous oral DNA vaccine containing the murine ubiquitin gene fused to minigenes encoding peptide epitopes gp10025-33and TRP-2181-188. These epitopes contain dominant anchor residues for MHC class I antigen alleles H-2Dband H-2Kb, 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 TH1 cytokine IFN-γ 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 gp10025-33peptide, which differs in its three NH2-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.