Immunodominance and Functional Alterations of Tumor-Associated Antigen-Specific CD8(+) T-Cell Responses in Hepatocellular Carcinoma
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Immunodominance and Functional Alterations of Tumor-Associated Antigen-Specific CD8(+) T-Cell Responses in Hepatocellular Carcinoma. / 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.
in: HEPATOLOGY, Jahrgang 59, Nr. 4, 01.04.2014, S. 1415-26.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Immunodominance and Functional Alterations of Tumor-Associated Antigen-Specific CD8(+) T-Cell Responses in Hepatocellular Carcinoma
AU - Flecken, Tobias
AU - Schmidt, Nathalie
AU - Hild, Sandra
AU - Gostick, Emma
AU - Drognitz, Oliver
AU - Zeiser, Robert
AU - Schemmer, Peter
AU - Bruns, Helge
AU - Eiermann, Thomas
AU - Price, David A
AU - Blum, Hubert E
AU - Neumann-Haefelin, Christoph
AU - Thimme, Robert
N1 - © 2014 The Authors. Hepatology published by Wiley on behalf of the American Association for the Study of Liver Diseases.
PY - 2014/4/1
Y1 - 2014/4/1
N2 - 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.
AB - 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.
KW - Adult
KW - Aged
KW - Aged, 80 and over
KW - Antigens, Neoplasm
KW - Biopsy
KW - CD8-Positive T-Lymphocytes
KW - Carcinoma, Hepatocellular
KW - Case-Control Studies
KW - Cell Proliferation
KW - Female
KW - Humans
KW - Immunodominant Epitopes
KW - Interferon-gamma
KW - Liver
KW - Liver Neoplasms
KW - Male
KW - Middle Aged
KW - Survival Rate
KW - T-Lymphocytes, Regulatory
U2 - 10.1002/hep.26731
DO - 10.1002/hep.26731
M3 - SCORING: Journal article
C2 - 24002931
VL - 59
SP - 1415
EP - 1426
JO - HEPATOLOGY
JF - HEPATOLOGY
SN - 0270-9139
IS - 4
ER -