Immunodominance and Functional Alterations of Tumor-Associated Antigen-Specific CD8(+) T-Cell Responses in Hepatocellular Carcinoma

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 -