NDLI: Immunodominance and functional alterations of tumor-associated antigen-specific CD8+ T-cell responses in hepatocellular carcinoma.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Flecken, Tobias Schmidt, Nathalie Hild, Sandra Gostick, Emma Drognitz, Oliver Zeiser, Robert Schemmer, Peter Bruns, Helge Eiermann, Thomas Price, David A. Blum, Hubert E. Neumann-Haefelin, Christoph Thimme, Robert
Description	Country affiliation: Germany Author Affiliation: Flecken T ( Department of Internal Medicine II, University Hospital Freiburg, Freiburg, Germany)
Abstract	UNLABELLED: 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-Î³ (IFN-Î³)-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-Î³. 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-Î³-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-Î³ 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.
File Format	HTM / HTML
ISSN	02709139
e-ISSN	15273350
DOI	10.1002/hep.26731
Journal	Hepatology
Issue Number	4
Volume Number	59
Language	English
Publisher	Wiley
Publisher Date	2014-04-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Hepatology Antigens, Neoplasm Metabolism Cd8-positive T-lymphocytes Pathology Carcinoma, Hepatocellular Immunodominant Epitopes Liver Neoplasms Biopsy Immunology Mortality Case-control Studies Cell Proliferation Interferon-gamma Liver Survival Rate T-lymphocytes, Regulatory Research Support, Non-u.s. Gov't
Content Type	Text
Resource Type	Article
Subject	Hepatology

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Immunodominance and functional alterations of tumor‐associated antigen‐specific CD8+ T‐cell responses in hepatocellular carcinoma

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