Lentiviral-Vector-Based Dendritic Cell Vaccine Synergizes with Checkpoint Blockade to Clear Chronic Viral Infection.
Lentiviral-Vector-Based Dendritic Cell Vaccine Synergizes with Checkpoint Blockade to Clear Chronic Viral Infection.
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基于慢病毒载体的树突状细胞疫苗与检查点封锁协同作用以清除慢性病毒感染。
DOI：
10.1016/j.ymthe.2020.05.018
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
Landau,NathanielR
中科院分区：
文献类型：
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作者：
Norton,ThomasD;Tada,Takuya;Leibowitz,Rebecca;vanderHeide,Verena;Homann,Dirk;Landau,NathanielR
树突状细胞疫苗是治疗癌症和感染性疾病的一种有前途的策略，但取得的成功参差不齐。我们报告了一种基于慢病毒载体的树突状细胞疫苗策略，该策略产生的分化簇8（CD 8）T细胞反应比标准肽脉冲方法所实现的反应强得多。该策略在小鼠淋巴细胞性脉络丛脑膜炎病毒（LCMV）模型中进行了测试。用表达GP 33主要组织相容性复合物（MHC）I类限制性肽表位和CD 40配体（CD 40 L）的慢病毒载体转导来自SAMHD 1敲除小鼠的骨髓来源的树突状细胞，并注射到野生型小鼠中。这些小鼠对急性和慢性变异CL-13 LCMV具有高度保护作用，导致比肽表位脉冲树突状细胞所实现的减少大100倍。在慢病毒载体中包含MHC-II类限制性表位进一步增加了CD 8 T细胞应答，并导致抗原特异性CD 8 T细胞表现出与功能性细胞毒性T细胞相关的表型。疫苗接种与检查点阻断协同作用，将慢性感染CL-13的小鼠的病毒载量降低至不可检测的水平。该策略改进了目前的树突状细胞疫苗策略;适用于治疗疾病，包括艾滋病和癌症;并支持含Vpx载体的效用。
Dendritic cell vaccines are a promising strategy for the treatment of cancer and infectious diseases but have met with mixed success. We report on a lentiviral vector-based dendritic cell vaccine strategy that generates a cluster of differentiation 8 (CD8) T cell response that is much stronger than that achieved by standard peptide-pulsing approaches. The strategy was tested in the mouse lymphocytic choriomeningitis virus (LCMV) model. Bone marrow-derived dendritic cells from SAMHD1 knockout mice were transduced with a lentiviral vector expressing the GP33 major-histocompatibility-complex (MHC)-class-I-restricted peptide epitope and CD40 ligand (CD40L) and injected into wild-type mice. The mice were highly protected against acute and chronic variant CL-13 LCMVs, resulting in a 100-fold greater decrease than that achieved with peptide epitope-pulsed dendritic cells. Inclusion of an MHC-class-II-restricted epitope in the lentiviral vector further increased the CD8 T cell response and resulted in antigen-specific CD8 T cells that exhibited a phenotype associated with functional cytotoxic T cells. The vaccination synergized with checkpoint blockade to reduce the viral load of mice chronically infected with CL-13 to an undetectable level. The strategy improves upon current dendritic cell vaccine strategies; is applicable to the treatment of disease, including AIDS and cancer; and supports the utility of Vpx-containing vectors.