title: Autochthonous liver tumors induce systemic T cell tolerance associated with T cell receptor down-modulation.
abstract: The reason the adaptive immune system fails in advanced liver tumors is largely unclear. To address this question, we have developed a novel murine model that combines c-myc-induced autochthonous tumorigenesis with expression of a cognate antigen, ovalbumin (OVA). When c-myc/OVA transgenic mice were crossed with liver-specific inducer mice, multifocal hepatocellular carcinomas co-expressing OVA developed in a tetracycline-dependent manner with a short latency and 100% penetrance. Transferred OVA-specific T cells, although infiltrating the tumor at high numbers, were hyporesponsive, as evidenced by a lack of in vivo cytotoxicity and interferon gamma production. This allowed the tumor to progress even in the presence of large numbers of antigen-specific T cells and even after vaccination (OVA+CpG-DNA). Interestingly, T cell receptor down-modulation was observed, which may explain antigen-specific hyporesponsiveness. This model is helpful in understanding liver cancer-specific mechanisms of T cell tolerance and dissection of antigen-specific and nonspecific mechanisms of immunotherapies in the preclinical phase.
authors.affiliation: Department of Pathology, University of Bonn, Bonn, Germany.
authors.forename: Jasmin T
authors.initials: JT
authors.lastname: Ney
authors.forename: Thomas
authors.initials: T
authors.lastname: Schmidt
authors.forename: Christian
authors.initials: C
authors.lastname: Kurts
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhou
authors.forename: Dawid
authors.initials: D
authors.lastname: Eckert
authors.forename: Dean W
authors.initials: DW
authors.lastname: Felsher
authors.forename: Hubert
authors.initials: H
authors.lastname: Schorle
authors.forename: Percy
authors.initials: P
authors.lastname: Knolle
authors.forename: Thomas
authors.initials: T
authors.lastname: Tüting
authors.forename: Winfried
authors.initials: W
authors.lastname: Barchet
authors.forename: Reinhard
authors.initials: R
authors.lastname: Büttner
authors.forename: Andreas
authors.initials: A
authors.lastname: Limmer
authors.forename: Ines
authors.initials: I
authors.lastname: Gütgemann
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D003433:Crosses, Genetic; D017931:DNA Primers; D004195:Disease Models, Animal; D005434:Flow Cytometry; D016259:Genes, myc; D005838:Genotype; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis
chemical_list: D017931:DNA Primers; D011948:Receptors, Antigen, T-Cell; D010047:Ovalbumin