These authors contributed equally to this study.
Immunodominance and functional alterations of tumor-associated antigen-specific CD8+ T-cell responses in hepatocellular carcinoma
Article first published online: 20 FEB 2014
© 2014 The Authors. Hepatology published by Wiley on behalf of the American Association for the Study of Liver Diseases
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Volume 59, Issue 4, pages 1415–1426, April 2014
How to Cite
Flecken, T., Schmidt, N., Hild, S., Gostick, E., Drognitz, O., Zeiser, R., Schemmer, P., Bruns, H., Eiermann, T., Price, D. A., Blum, H. E., Neumann-Haefelin, C. and Thimme, R. (2014), Immunodominance and functional alterations of tumor-associated antigen-specific CD8+ T-cell responses in hepatocellular carcinoma. Hepatology, 59: 1415–1426. doi: 10.1002/hep.26731
See Editorial on Page 1232
Supported by the Deutsche Forschungsgemeinschaft (RT: Heisenberg Professorship TH-719/3-1), the European Union (EFRE, INTERREG IV Oberrhein), the Wellcome Trust (DAP), and the Excellence Initiative of the German Federal and State Governments (GSC-4, Spemann Graduate School).
Potential conflict of interest: Nothing to report.
- Issue published online: 24 MAR 2014
- Article first published online: 20 FEB 2014
- Accepted manuscript online: 3 SEP 2013 11:49AM EST
- Manuscript Accepted: 29 AUG 2013
- Manuscript Revised: 10 JUL 2013
- Manuscript Received: 7 MAR 2013
Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide with a poor prognosis and limited therapeutic options. To aid the development of novel immunological interventions, we studied the breadth, frequency, and tumor-infiltration of naturally occurring CD8+ T-cell responses targeting several tumor-associated antigens (TAA). We used overlapping peptides spanning the entire alpha-fetoprotein (AFP), glypican-3 (GPC-3), melanoma-associated gene-A1 (MAGE-A1) and New York-esophageal squamous cell carcinoma-1 (NY-ESO-1) proteins and major-histocompatibility-complex-class-I-tetramers specific for epitopes of MAGE-A1 and NY-ESO-1 to analyze TAA-specific CD8+ T-cell responses in a large cohort of HCC patients. After nonspecific expansion in vitro, we detected interferon-γ (IFN-γ)-producing CD8+ T cells specific for all four TAA in the periphery as well as in liver and tumor tissue. These CD8+ T-cell responses displayed clear immunodominance patterns within each TAA, but no consistent hierarchy was observed between different TAA. Importantly, the response breadth was highest in early-stage HCC and associated with patient survival. After antigen-specific expansion, TAA-specific CD8+ T cells were detectable by tetramer staining but impaired in their ability to produce IFN-γ. Furthermore, regulatory T cells (Treg) were increased in HCC lesions. Depletion of Treg from cultures improved TAA-specific CD8+ T-cell proliferation but did not restore IFN-γ-production. Conclusion: Naturally occurring TAA-specific CD8+ T-cell responses are present in patients with HCC and therefore constitute part of the normal T-cell repertoire. Moreover, the presence of these responses correlates with patient survival. However, the observation of impaired IFN-γ production suggests that the efficacy of such responses is functionally limited. These findings support the development of strategies that aim to enhance the total TAA-specific CD8+ T-cell response by therapeutic boosting and/or specificity diversification. However, further research will be required to help unlock the full potential of TAA-specific CD8+ T-cell responses. (Hepatology 2014;59:1415-1426)