Tumor agonist peptides break tolerance and elicit effective CTL responses in an inducible mouse model of hepatocellular carcinoma.
Tumors often induce tolerance in the immune system, which may contribute to the limited success of clinical vaccination against tumors. In order to develop strategies for overcoming tumor tolerance we have developed an inducible mouse model of autochthonus hepatocellular carcinoma growth, which relates more closely to the clinical situation than transplantation tumors. These so-called AST mice harbour a construct consisting of the hepatocyte-specific albumin promoter, a loxP flanked stop-cassette, and the oncogene SV40 large T antigen (Tag). By intravenous application of an adenovirus encoding Cre recombinase the stop cassette was excised, thereby inducing Tag expression and formation of hepatoma nodules in a dose-dependent fashion in about 3 months. Non-induced AST mice showed tumor tolerance, as demonstrated by the failure to reject Tag-positive transplantation tumors and the inability to mount CTL following Tag immunization. Dendritic cell-based immunization with an agonist Tag peptide was able to overcome tolerance and resulted in marked CTL activity against naturally occurring Tag epitopes. Importantly, vaccination with the agonist peptide prevented growth of the autochthonous liver tumors and significantly prolonged survival of the animals. Our findings demonstrate that agonist peptides can be used in immunization protocols for breaking of tolerance and induction of CTL that mediate effective anti-tumor responses. In addition, the inducible hepatoma model described here can be used for the design of therapeutic strategies against hepatocellular carcinoma.
Stahl
Simone
S
DKFZ, German Cancer Research Center, Division of Molecular Immunology, D-69120 Heidelberg, Germany.
Sacher
Torsten
T
Bechtold
Astrid
A
Protzer
Ulrike
U
Ganss
Ruth
R
Hämmerling
Günter J
GJ
Arnold
Bernd
B
Garbi
Natalio
N
D000418:Albumins / Q000276:immunology; D000595:Amino Acid Sequence; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology; D006528:Carcinoma, Hepatocellular / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005822:Genetic Vectors; D007108:Immune Tolerance; D008113:Liver Neoplasms / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010455:Peptides / Q000276:immunology*; D011995:Recombination, Genetic; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D000418:Albumins; D000952:Antigens, Polyomavirus Transforming; D019496:Cancer Vaccines; D010455:Peptides