Immunodominance and functional alterations of tumor-associated antigen-specific CD8+ T-cell responses in hepatocellular carcinoma.
Immunodominance and functional alterations of tumor-associated antigen-specific CD8+ T-cell responses in hepatocellular carcinoma.
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DOI：
10.1002/hep.26731
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发表时间：
2014-04
期刊：
影响因子：
13.5
通讯作者：
Thimme, Robert
中科院分区：
文献类型：
--
作者：
Flecken, Tobias;Schmidt, Nathalie;Hild, Sandra;Gostick, Emma;Drognitz, Oliver;Zeiser, Robert;Schemmer, Peter;Bruns, Helge;Eiermann, Thomas;Price, David A.;Blum, Hubert E.;Neumann-Haefelin, Christoph;Thimme, Robert
肝细胞癌（HCC）是全球第五大常见恶性肿瘤，预后差，治疗选择有限。为了帮助开发新的免疫干预措施，我们研究了针对几种肿瘤相关抗原（TAA）的天然CD 8 + T细胞应答的广度、频率和肿瘤浸润。我们使用覆盖整个甲胎蛋白（AFP）、磷脂酰肌醇蛋白聚糖-3（GPC-3）、黑色素瘤相关基因-A1（法师-A1）和纽约食管鳞状细胞癌-1（NY-ESO-1）蛋白的重叠肽以及对法师-A1和NY-ESO-1表位特异的主要组织相容性复合物I类四聚体，分析了一个大型HCC患者队列中的TAA特异性CD 8 + T细胞应答。在体外非特异性扩增后，我们在外周以及肝脏和肿瘤组织中检测到对所有四种TAA特异性的产生干扰素-γ（IFN-γ）的CD 8 + T细胞。这些CD 8 + T细胞应答在每个TAA内显示出明确的免疫优势模式，但在不同TAA之间未观察到一致的层次结构。重要的是，反应宽度在早期HCC中最高，并与患者生存相关。抗原特异性扩增后，TAA特异性CD 8 + T细胞可通过四聚体染色检测到，但其产生IFN-γ的能力受损。此外，调节性T细胞（Treg）在HCC病变中增加。从培养物中耗尽Treg改善了TAA特异性CD 8 + T细胞增殖，但没有恢复IFN-γ-产生。结论：自然发生的TAA特异性CD 8 + T细胞应答存在于HCC患者中，因此构成正常T细胞库的一部分。此外，这些反应的存在与患者生存相关。然而，IFN-γ产生受损的观察结果表明，这种反应的功效在功能上是有限的。这些发现支持旨在通过治疗性加强和/或特异性多样化来增强总TAA特异性CD 8 + T细胞应答的策略的开发。然而，需要进一步的研究来帮助释放TAA特异性CD 8 + T细胞应答的全部潜力。（肝病学2014;59：1415 - 1426）
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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