CD8型
免疫优势
细胞毒性T细胞
癌症研究
抗原
免疫学
免疫疗法
生物
T细胞
表位
免疫系统
体外
生物化学
作者
Tobias Flecken,Nathalie M. Schmidt,Sandra Hild,Emma Gostick,Oliver Drognitz,Robert Zeiser,Peter Schemmer,Helge Bruns,Thomas Eiermann,David A. Price,Hubert E. Blum,Christoph Neumann‐Haefelin,Robert Thimme
出处
期刊:Hepatology
[Wiley]
日期:2014-02-20
卷期号:59 (4): 1415-1426
被引量:283
摘要
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. (Hepatology 2014;59:1415-1426)
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