{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T09:24:51Z","timestamp":1790760291148,"version":"4.1.0"},"reference-count":27,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2014,2,20]],"date-time":"2014-02-20T00:00:00Z","timestamp":1392854400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0\/"},{"start":{"date-parts":[[2014,4,1]],"date-time":"2014-04-01T00:00:00Z","timestamp":1396310400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2014,4]]},"abstract":"<jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      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\n                      <jats:sup>+<\/jats:sup>\n                      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\n                      <jats:sup>+<\/jats:sup>\n                      T-cell responses in a large cohort of HCC patients. After nonspecific expansion\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      , we detected interferon-\u03b3 (IFN-\u03b3)-producing CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells specific for all four TAA in the periphery as well as in liver and tumor tissue. These CD8\n                      <jats:sup>+<\/jats:sup>\n                      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\n                      <jats:sup>+<\/jats:sup>\n                      T cells were detectable by tetramer staining but impaired in their ability to produce IFN-\u03b3. Furthermore, regulatory T cells (T\n                      <jats:sub>reg<\/jats:sub>\n                      ) were increased in HCC lesions. Depletion of T\n                      <jats:sub>reg<\/jats:sub>\n                      from cultures improved TAA-specific CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cell proliferation but did not restore IFN-\u03b3-production.\n                      <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>\n                      : Naturally occurring TAA-specific CD8\n                      <jats:sup>+<\/jats:sup>\n                      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-\u03b3 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\n                      <jats:sup>+<\/jats:sup>\n                      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\n                      <jats:sup>+<\/jats:sup>\n                      T-cell responses. (HEPATOLOGY 2014;59:1415-1426)\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.26731","type":"journal-article","created":{"date-parts":[[2013,9,3]],"date-time":"2013-09-03T13:06:43Z","timestamp":1378213603000},"page":"1415-1426","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":325,"title":["Immunodominance and functional alterations of tumor-associated antigen-specific CD8+ T-cell responses in hepatocellular 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