Profile of Tumor Antigen-Specific CD8 T Cells in Patients With Hepatitis B Virus-Related Hepatocellular Carcinoma
Profile of Tumor Antigen-Specific CD8 T Cells in Patients With Hepatitis B Virus-Related Hepatocellular Carcinoma
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DOI：
10.1053/j.gastro.2009.04.045
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发表时间：
2009-08-01
期刊：
影响因子：
29.4
通讯作者：
Bertoletti, Antonio
中科院分区：
文献类型：
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作者：
Gehring, Adam J.;Ho, Zi Zong;Bertoletti, Antonio
背景与目的：慢性B型肝炎患者肝细胞癌（HCC）表达肿瘤和病毒抗原，但对这些患者肿瘤和病毒特异性CD 8 + T细胞的免疫优势和功能知之甚少。方法：使用49个先前描述的表位测试HLA-A2限制性T细胞对16种肿瘤抗原和B肝炎病毒（HBV）蛋白的应答。在扩增后，通过酶联免疫吸附斑点（ELISPOT）分析来自30名HLA-A2+ HBV感染患者（10名患有HCC，10名患有HBV肝硬化，和10名HBV但无肝硬化）的细胞。评价了干扰素（IFN）-γ、肿瘤坏死因子（TNF）-α和白细胞介素（IL）-2的产生，以及肿瘤特异性CD 8 + T细胞上脱粒标志物CD 107 a的表达。结果：所有组的细胞均具有肿瘤特异性反应。肿瘤抗原NY-ESO-1和SSX-2是最常靶向的，并且在亚洲种族特有的HLA-A2亚型中具有免疫原性。肿瘤特异性T细胞具有低亲和力;来自非HCC患者的T细胞是多功能的（IFN-γ +、TNF-α +、CD 107 a+），而来自HCC患者的T细胞显示耗尽的表型（IFN-γ +、CD 107 a+）。程序性死亡1（PD-1）在肝癌患者肿瘤和肝脏的T细胞上的表达水平高于外周血，可能有助于T细胞耗竭。阻断PD-1/PD-L1增加了HCC患者中肿瘤特异性T细胞的频率，但没有恢复T细胞功能。结论：无论是否患有HCC，患者的肿瘤特异性T细胞在数量和功能上都有一定的层次。来自HCC患者的HLA-A2限制性T细胞靶向NY-ESO-1，但处于耗尽状态，可能需要额外的激活来恢复功能。
BACKGROUND & AIMS: Tumor and viral antigens are expressed by hepatocellular carcinoma (HCC) in patients with chronic hepatitis B, but little is known about the immunodominance and function of tumor- and virus-specific CD8+ T cells in these patients. METHODS: HLA-A2-restricted T-cell responses to 16 tumor antigens and hepatitis B virus (HBV) proteins were tested using 49 previously described epitopes. Cells from 30 HLA-A2+, HBV-infected patients (10 with HCC, 10 with HBV cirrhosis, and 10 HBV but no cirrhosis) were analyzed, after expansion, by enzyme-linked immunosorbent spot (ELISPOT). Interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-2 production, as well as expression of the degranulation marker CD107a on tumor-specific CD8+ T cells, were evaluated. RESULTS: Cells from all groups had tumor-specific responses. The tumor antigens NY-ESO-1 and SSX-2 were most frequently targeted and were immunogenic in the HLA-A2 subtypes that are characteristic of Asian ethnicity. Tumor-specific T cells had low affinities; T cells from non-HCC patients were polyfunctional (IFN-gamma+, TNF-alpha+, CD107a+) and those from HCC patients displayed an exhausted phenotype (IFN-gamma+, CD107a+). Programmed Death 1 (PD-1) was expressed at higher levels on T cells from tumor and liver than peripheral blood from HCC patients and might contribute to T-cell exhaustion. Blocking PD-1/PD-L1 increased the frequency of tumor-specific T cells in HCC patients but did not restore T cell function. CONCLUSIONS: Patients with or without HCC have a quantitative and functional hierarchy of tumor-specific T cells. HLA-A2-restricted T cells from HCC patients target NY-ESO-1, but exist in an exhausted state that might require additional activation to restore function.