Deparment of Immunotherapeutics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
Cancer Cell Biology Laboratory, Department of Cancer Biology, Clinical Research Institute, National Hospital Organization, Kyushu Cancer Center, Fukuoka, Japan.
PLoS Pathog. 2023 Feb 2;19(2):e1011104. doi: 10.1371/journal.ppat.1011104. eCollection 2023 Feb.
A small proportion of human T-cell leukemia virus type-1 (HTLV-1)-infected individuals develop adult T-cell leukemia/lymphoma, a chemotherapy-resistant lymphoproliferative disease with a poor prognosis. HTLV-1-specific cytotoxic T lymphocytes (CTLs), potential anti-tumor/virus effectors, are impaired in adult T-cell leukemia/lymphoma patients. Here, using Japanese monkeys naturally infected with simian T-cell leukemia/T-lymphotropic virus type-1 (STLV-1) as a model, we demonstrate that short-term-cultured autologous peripheral blood mononuclear cells (PBMCs) can serve as a therapeutic vaccine to activate such CTLs. In a screening test, STLV-1-specific CTL activity was detectable in 8/10 naturally STLV-1-infected monkeys. We conducted a vaccine study in the remaining two monkeys with impaired CTL responses. The short-term-cultured PBMCs of these monkeys spontaneously expressed viral antigens, in a similar way to PBMCs from human HTLV-1 carriers. The first monkey was subcutaneously inoculated with three-day-cultured and mitomycin C (MMC)-treated autologous PBMCs, and then boosted with MMC-treated autologous STLV-1-infected cell line cells. The second monkey was inoculated with autologous PBMC-vaccine alone twice. In addition, a third monkey that originally showed a weak STLV-1-specific CTL response was inoculated with similar autologous PBMC-vaccines. In all three vaccinated monkeys, marked activation of STLV-1-specific CTLs and a mild reduction in the STLV-1 proviral load were observed. Follow-up analyses on the two monkeys vaccinated with PBMCs alone indicated that STLV-1-specific CTL responses peaked at 3-4 months after vaccination, and then diminished but remained detectable for more than one year. The significant reduction in the proviral load and the control of viral expression were associated with CTL activation but also diminished 6 and 12 months after vaccination, respectively, suggesting the requirement for a booster. The vaccine-induced CTLs in these monkeys recognized epitopes in the STLV-1 Tax and/or Envelope proteins, and efficiently killed autologous STLV-1-infected cells in vitro. These findings indicated that the autologous PBMC-based vaccine could induce functional STLV-1-specific CTLs in vivo.
一小部分人类 T 细胞白血病病毒 1 型（HTLV-1）感染者会发展为成人 T 细胞白血病/淋巴瘤，这是一种化疗耐药的淋巴增生性疾病，预后不良。HTLV-1 特异性细胞毒性 T 淋巴细胞（CTL）是潜在的抗肿瘤/抗病毒效应物，在成人 T 细胞白血病/淋巴瘤患者中受损。在这里，我们使用自然感染猴 T 细胞白血病/T 淋巴细胞病毒 1（STLV-1）的日本猕猴作为模型，证明短期培养的自体外周血单个核细胞（PBMC）可作为一种治疗性疫苗来激活这种 CTL。在筛选试验中，在 10 只自然 STLV-1 感染的猕猴中有 8 只可检测到 STLV-1 特异性 CTL 活性。我们对剩余的 2 只 CTL 反应受损的猕猴进行了疫苗研究。这些猕猴的短期培养 PBMC 自发表达病毒抗原，与人类 HTLV-1 携带者的 PBMC 相似。第一只猕猴接受了为期三天培养并用丝裂霉素 C（MMC）处理的自体 PBMC 接种，并随后用 MMC 处理的自体 STLV-1 感染细胞系细胞进行了加强接种。第二只猕猴仅接受了两次自体 PBMC 疫苗接种。此外，一只最初表现出较弱的 STLV-1 特异性 CTL 反应的第三只猕猴也接种了类似的自体 PBMC 疫苗。在所有接受疫苗接种的 3 只猕猴中，均观察到 STLV-1 特异性 CTL 的显著激活和 STLV-1 前病毒载量的轻度降低。对仅接受 PBMC 疫苗接种的两只猕猴的后续分析表明，STLV-1 特异性 CTL 反应在接种后 3-4 个月达到峰值，然后减弱但仍可检测超过一年。前病毒载量的显著降低和病毒表达的控制与 CTL 激活相关，但分别在接种后 6 和 12 个月也减弱，表明需要加强接种。这些猕猴中的疫苗诱导的 CTL 识别 STLV-1 Tax 和/或 Envelope 蛋白中的表位，并在体外有效杀伤自体 STLV-1 感染细胞。这些发现表明，自体 PBMC 为基础的疫苗可以在体内诱导功能性 STLV-1 特异性 CTL。
