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Autochthonous liver tumors induce systemic T cell tolerance associated with T cell receptor down‐modulation
Author(s) -
Ney Jasmin T.,
Schmidt Thomas,
Kurts Christian,
Zhou Qi,
Eckert Dawid,
Felsher Dean W.,
Schorle Hubert,
Knolle Percy,
Tüting Thomas,
Barchet Winfried,
Büttner Reinhard,
Limmer Andreas,
Gütgemann Ines
Publication year - 2009
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.22652
Subject(s) - biology , immunology , antigen , cancer research , immunosurveillance , immune system
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. (H EPATOLOGY 2009.)