Deparment of Immunotherapeutics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
Department of Hematology, Imamura General Hospital, Kagoshima, Japan.
Cancer Sci. 2021 Mar;112(3):1161-1172. doi: 10.1111/cas.14800. Epub 2021 Feb 5.
Activation of CD8 Tax-specific CTL is a new therapeutic concept for adult T-cell leukemia (ATL) caused by HTLV-1. A recent clinical study of the dendritic cell vaccine pulsed with Tax peptides corresponding to CTL epitopes showed promising outcomes in ATL patients possessing limited human leukocyte antigen (HLA) alleles. In this study, we aimed to develop another immunotherapy to activate Tax-specific CTL without HLA limitation by using patients' own HTLV-1-infected cells as a vaccine. To examine the potential of HTLV-1-infected T-cells to activate CTL via antigen presenting cells, we established a unique co-culture system. We demonstrated that mitomycin C-treated HLA-A2-negative HTLV-1-infected T-cell lines or short-term cultured peripheral blood mononuclear cells (PBMC) derived from ATL patients induced cross-presentation of Tax antigen in co-cultured HLA-A2-positive antigen presenting cells, resulting in activation of HLA-A2-restricted CD8 Tax-specific CTL. This effect was not inhibited by a reverse transcriptase inhibitor. IL-12 production and CD86 expression were also induced in antigen presenting cells co-cultured with HTLV-1-infected cells at various levels, which were improved by pre-treatment of the infected cells with histone deacetylase inhibitors. Furthermore, monocyte-derived dendritic cells induced from PBMC of a chronic ATL patient produced IL-12 and expressed enhanced levels of CD86 when co-cultured with autologous lymphocytes that had been isolated from the same PBMC and cultured for several days. These findings suggest that short-term cultured autologous PBMC from ATL patients could potentially serve as a vaccine to evoke Tax-specific CTL responses.
CD8 特异性 CTL 的激活是由 HTLV-1 引起的成人 T 细胞白血病 (ATL) 的一种新的治疗概念。最近一项针对 Tax 肽脉冲树突状细胞疫苗的临床研究表明，对于 HLA 等位基因有限的 ATL 患者，该疫苗具有良好的效果。在这项研究中，我们旨在开发另一种免疫疗法，通过使用患者自身的 HTLV-1 感染细胞作为疫苗，在没有 HLA 限制的情况下激活 Tax 特异性 CTL。为了研究 HTLV-1 感染的 T 细胞通过抗原呈递细胞激活 CTL 的潜力，我们建立了一种独特的共培养系统。我们证明，经丝裂霉素 C 处理的 HLA-A2 阴性 HTLV-1 感染的 T 细胞系或源自 ATL 患者的短期培养外周血单核细胞 (PBMC) 在共培养的 HLA-A2 阳性抗原呈递细胞中诱导 Tax 抗原的交叉呈递，导致 HLA-A2 限制性 CD8 Tax 特异性 CTL 的激活。这种效应不受逆转录酶抑制剂的抑制。在共培养的抗原呈递细胞中也诱导产生了不同水平的 IL-12 产生和 CD86 表达，用组蛋白去乙酰化酶抑制剂预处理感染细胞可改善这种效应。此外，从慢性 ATL 患者的 PBMC 诱导产生的单核细胞衍生的树突状细胞与从同一 PBMC 分离并培养数天的自体淋巴细胞共培养时，产生了 IL-12 并表达了增强的 CD86 水平。这些发现表明，源自 ATL 患者的短期培养的自体 PBMC 有可能作为一种疫苗来引发 Tax 特异性 CTL 反应。
