Autochthonous liver tumors induce systemic T cell tolerance associated with T cell receptor down-modulation.
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.
Ney
Jasmin T
JT
Department of Pathology, University of Bonn, Bonn, Germany.
Schmidt
Thomas
T
Kurts
Christian
C
Zhou
Qi
Q
Eckert
Dawid
D
Felsher
Dean W
DW
Schorle
Hubert
H
Knolle
Percy
P
Tüting
Thomas
T
Barchet
Winfried
W
Büttner
Reinhard
R
Limmer
Andreas
A
Gütgemann
Ines
I
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
D017931:DNA Primers; D011948:Receptors, Antigen, T-Cell; D010047:Ovalbumin