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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 ORCID:, Blum, Hubert E., Neumann-Haefelin, Christoph and Thimme, Robert 2014. Immunodominance and functional alterations of tumor-associated antigen-specific CD8+T-cell responses in hepatocellular carcinoma. Hepatology 59 (4) , pp. 1415-1426. 10.1002/hep.26731

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > R Medicine (General)
Publisher: Wiley
ISSN: 0270-9139
Funders: Wellcome Trust
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 29 August 2013
Last Modified: 25 Oct 2022 10:07

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