Department of Medical Oncology & Immunology, Nagoya City University Graduate School of Medical Sciences, Japan.
Cancer Sci. 2012 Oct;103(10):1764-73. doi: 10.1111/j.1349-7006.2012.02371.x. Epub 2012 Aug 13.
We expanded CTL specific for Tax (a human T-lymphotropic virus type-1-encoded gene product) in vitro from PBMC of several adult T-cell leukemia/lymphoma (ATL) patients, and document its potential significance as a target for ATL immunotherapy. Tax-specific CTL responses against tumor cells were restricted by Tax-expression and the appropriate human leukocyte antigen (HLA) type. Tax-specific CTL recognized HLA/Tax-peptide complexes on autologous ATL cells, even when their Tax expression was so low that it could only be detected by RT-PCR but not by flow cytometry. Recognition resulted in interferon gamma (IFN-γ) production and target cell lysis. This would be the first report that Tax-specific CTL from ATL patients specifically recognized and killed autologous tumor cells that expressed Tax. The Tax-specific CTL responded to as little as 0.01 pM of the corresponding peptide, indicating that their T-cell receptor avidity was much higher than that of any other CTL recognizing viral or other tumor antigens. This is presumably the reason why the Tax-specific CTL recognized and killed autologous ATL cells despite their very low Tax expression. In addition, cell cycle analyses and experiments with primary ATL cell-bearing mice demonstrated that ATL cells present at the site of active cell proliferation, such as in the tumor masses, expressed substantial amounts of Tax, but it was minimally expressed by the tumor cells in a quiescent state, such as in the blood. The present study not only provides a strong rationale for exploiting Tax as a possible target for ATL immunotherapy but also contributes to our understanding of the immunopathogenesis of ATL.
我们从几位成人 T 细胞白血病/淋巴瘤（ATL）患者的外周血单个核细胞中体外扩增了针对 Tax（一种人类 T 淋巴细胞白血病病毒 1 编码的基因产物）的 CTL，并证明其作为 ATL 免疫治疗靶标的潜在意义。Tax 特异性 CTL 对肿瘤细胞的反应受到 Tax 表达和适当的人类白细胞抗原（HLA）类型的限制。Tax 特异性 CTL 识别自体 ATL 细胞上的 HLA/Tax 肽复合物，即使其 Tax 表达低至只能通过 RT-PCR 检测而不能通过流式细胞术检测。识别导致干扰素 γ（IFN-γ）产生和靶细胞裂解。这将是第一个报道来自 ATL 患者的 Tax 特异性 CTL 特异性识别和杀伤表达 Tax 的自体肿瘤细胞的报告。Tax 特异性 CTL 对低至 0.01 pM 的相应肽的反应表明，其 T 细胞受体亲和力远高于任何其他识别病毒或其他肿瘤抗原的 CTL。这大概就是 Tax 特异性 CTL 尽管其 Tax 表达非常低，但仍能识别和杀伤自体 ATL 细胞的原因。此外，细胞周期分析和带有原发性 ATL 细胞的小鼠实验表明，在活跃增殖的细胞部位（如肿瘤块）存在的 ATL 细胞表达大量的 Tax，但在静止状态（如血液中）的肿瘤细胞中则很少表达。本研究不仅为利用 Tax 作为 ATL 免疫治疗的可能靶标提供了强有力的理论依据，也有助于我们理解 ATL 的免疫发病机制。
