Singapore Institute for Clinical Sciences, Agency for Science Technology and Research, Singapore.
J Hepatol. 2011 Jul;55(1):103-10. doi: 10.1016/j.jhep.2010.10.025. Epub 2010 Nov 23.
BACKGROUND & AIMS: Virus-specific T cells capable of controlling HBV and eliminating hepatocellular carcinoma (HCC) expressing HBV antigens are deleted or dysfunctional in patients with chronic HBV or HBV-related HCC. The goal of this study was to determine if T cell receptor (TCR) gene transfer can reconstitute HBV-specific T cell immunity in lymphocytes of chronic HBV patients and investigate whether HCC cells with natural HBV-DNA integration can be recognized by genetically modified T cells.
We used vector-mediated gene transfer to introduce HLA-A2-restricted, HBV-specific TCRs into T cells of chronic HBV as well as HBV-related HCC patients.
The introduced TCRs were expressed on the cell surface, evidenced by Vβ and pentamer staining. TCR transduced T cells produced IFN-γ, TNF-α, IL-2, and lysed HBV infected hepatocyte-like cell lines. Furthermore, HCC cell lines with natural HBV-DNA integration could be recognized by HBV-specific TCR-re-directed T cells.
TCR re-directed HBV-specific T cells generated from PBMC of chronic HBV and HBV-related HCC patients were multifunctional and capable of recognizing HBV-infected cells and HCC tumor cells expressing viral antigens from naturally integrated HBV DNA. These genetically modified T cells could be used to reconstitute virus-specific T cell immunity in chronic HBV patients and target tumors in HBV-related HCC.
能够控制 HBV 并清除表达 HBV 抗原的肝细胞癌（HCC）的病毒特异性 T 细胞在慢性 HBV 或 HBV 相关 HCC 患者中被删除或功能失调。本研究的目的是确定 T 细胞受体（TCR）基因转移是否可以在慢性 HBV 患者的淋巴细胞中重建 HBV 特异性 T 细胞免疫，并研究是否可以识别具有天然 HBV-DNA 整合的 HCC 细胞的遗传修饰 T 细胞。
我们使用载体介导的基因转移将 HLA-A2 限制性、HBV 特异性 TCR 引入慢性 HBV 以及 HBV 相关 HCC 患者的 T 细胞中。
通过 Vβ 和五聚体染色证明，引入的 TCR 表达在细胞表面上。转导 TCR 的 T 细胞产生 IFN-γ、TNF-α、IL-2，并裂解 HBV 感染的肝细胞样细胞系。此外，具有天然 HBV-DNA 整合的 HCC 细胞系可以被 HBV 特异性 TCR 导向的 T 细胞识别。
从慢性 HBV 和 HBV 相关 HCC 患者的 PBMC 中产生的 TCR 重定向的 HBV 特异性 T 细胞是多功能的，能够识别感染 HBV 的细胞和表达来自天然整合 HBV DNA 的病毒抗原的 HCC 肿瘤细胞。这些遗传修饰的 T 细胞可用于重建慢性 HBV 患者的病毒特异性 T 细胞免疫，并靶向 HBV 相关 HCC 中的肿瘤。
