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SHR Neuro Cancer Cardio Lipid Metab Microb

Flecken, T; Schmidt, N; Hild, S; Gostick, E; Drognitz, O; Zeiser, R; Schemmer, P; Bruns, H; Eiermann, T; Price, DA; Blum, HE; Neumann-Haefelin, C; Thimme, R.
Immunodominance and functional alterations of tumor-associated antigen-specific CD8+ T-cell responses in hepatocellular carcinoma.
Hepatology. 2014; 59(4):1415-1426 Doi: 10.1002/hep.26731 [OPEN ACCESS]
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Co-authors Med Uni Graz: Schemmer Peter
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Abstract:: 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. 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. © 2014 The Authors. Hepatology published by Wiley on behalf of the American Association for the Study of Liver Diseases.
Find related publications in this database (using NLM MeSH Indexing): Adult -; Aged -; Aged, 80 and over -; Antigens, Neoplasm - metabolism; Biopsy -; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - pathology; Carcinoma, Hepatocellular - immunology; Carcinoma, Hepatocellular - mortality; Carcinoma, Hepatocellular - pathology; Case-Control Studies -; Cell Proliferation -; Female -; Humans -; Immunodominant Epitopes - metabolism; Interferon-gamma - metabolism; Liver - pathology; Liver Neoplasms - immunology; Liver Neoplasms - mortality; Liver Neoplasms - pathology; Male -; Middle Aged -; Survival Rate -; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - pathology