Cancer Institute A national cancer institute
designated cancer center

Dean W. Felsher

Publication Details

  • Autochthonous Liver Tumors Induce Systemic T Cell Tolerance Associated with T Cell Receptor Down-Modulation HEPATOLOGY Ney, J. T., Schmidt, T., Kurts, C., Zhou, Q., Eckert, D., Felsher, D. W., Schorle, H., Knolle, P., Tueting, T., Barchet, W., Buettner, R., Limnier, A., Guetgemann, I. 2009; 49 (2): 471-481


    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.

    View details for DOI 10.1002/hep.22652

    View details for Web of Science ID 000262923300019

    View details for PubMedID 19105207

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