title: Immunodominance and functional alterations of tumor-associated antigen-specific CD8+ T-cell responses in hepatocellular carcinoma.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Internal Medicine II, University Hospital Freiburg, Freiburg, Germany; Spemann Graduate School of Biology and Medicine (SGBM), Albert-Ludwigs-University, Freiburg, Germany; Faculty of Biology, Albert-Ludwigs-University, Freiburg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Flecken
authors.forename: Nathalie
authors.initials: N
authors.lastname: Schmidt
authors.forename: Sandra
authors.initials: S
authors.lastname: Hild
authors.forename: Emma
authors.initials: E
authors.lastname: Gostick
authors.forename: Oliver
authors.initials: O
authors.lastname: Drognitz
authors.forename: Robert
authors.initials: R
authors.lastname: Zeiser
authors.forename: Peter
authors.initials: P
authors.lastname: Schemmer
authors.forename: Helge
authors.initials: H
authors.lastname: Bruns
authors.forename: Thomas
authors.initials: T
authors.lastname: Eiermann
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Hubert E
authors.initials: HE
authors.lastname: Blum
authors.forename: Christoph
authors.initials: C
authors.lastname: Neumann-Haefelin
authors.forename: Robert
authors.initials: R
authors.lastname: Thimme
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000378:metabolism*; D001706:Biopsy; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology*; D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000401:mortality / Q000473:pathology*; D016022:Case-Control Studies; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D016056:Immunodominant Epitopes / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000276:immunology / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D015996:Survival Rate; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology
chemical_list: D000951:Antigens, Neoplasm; D016056:Immunodominant Epitopes; D007371:Interferon-gamma