Tumor cell loaded type-1 polarized dendritic cells induce Th1-mediated tumor immunity
Tumor cell loaded type-1 polarized dendritic cells induce Th1-mediated tumor immunity
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DOI：
10.1158/0008-5472.can-05-1692
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发表时间：
2005-11-01
期刊：
影响因子：
11.2
通讯作者：
Falo, LD
中科院分区：
文献类型：
--
作者：
Hokey, DA;Larregina, AT;Falo, LD
树突状细胞是一种专职的抗原提呈细胞，能够诱导和调节先天免疫反应和抗原特异性免疫反应。使用体外工程或体内靶向树突状细胞的治疗性癌症疫苗正在进行临床试验评估。T辅助型1(Th1)偏斜免疫反应的特点是优先诱导抗原特异性的干扰素-γ分泌的CD4(+)T细胞，并与肿瘤和病毒免疫的重要效应机制相关。为了优先诱导Th1偏斜的免疫反应，已经开发了极化人类单核细胞来源的树突状细胞的方法，并在临床前和临床研究中对极化的树突状细胞(DC1s)进行了评估。在这里，我们表明，聚(I：C)和CPGS刺激骨髓来源的小鼠树突状细胞群体导致树突状细胞的表型成熟，并协同诱导持久的、高水平的IL-12p70分泌，这是人类1型极化树突状细胞的特征。在功能上，这些树突状细胞在体外和体内诱导抗原特异性的Th1型CD4(+)T细胞激活。活的B16黑色素瘤细胞不抑制树突状细胞的成熟和极化，携带肿瘤的DC1s在体内诱导迟发性超敏反应。携带B16黑色素瘤细胞的DC1s注射到荷瘤小鼠体内，可以诱导Th1扭曲的肿瘤特异性CD4(+)T细胞，显著减少肿瘤的生长。DC1免疫动物的肿瘤浸润物以存在CD4(+)T细胞和激活的巨噬细胞为特征。这些结果显示了DC1功能的小鼠模型，并提示CD4(+)T细胞和巨噬细胞在DO诱导的抗肿瘤免疫反应中发挥重要作用。它们对基于DC1的免疫疗法的未来发展和临床免疫监测其有效性的策略具有重要意义。
Dendritic cells are professional antigen-presenting cells capable of inducing and regulating innate and antigen-specific immune responses. Therapeutic cancer vaccines using ex vivo engineered or in vivo targeted dendritic cells are being evaluated in clinical trials. T-helper type-1 (Th1)-skewed immune responses are characterized by the preferential induction of antigen-specific IFN-gamma-secreting CD4(+) T cells and correlate with effector mechanisms important for tumor and viral immunity. Methods to "polarize" human monocyte-derived dendritic cells for the preferential induction of Th1-skewed immune responses have been developed, and polarized dendritic cells (DC1s) are being evaluated in preclinical and clinical studies. Here, we show that stimulation of bone marrow-derived murine dendritic cell populations with poly(I:C) and CpGs results in phenotypic maturation of dendritic cells and synergistic induction of durable, high-level IL-12p70 secretion characteristic of human type-1 polarized dendritic cells. Functionally, these dendritic cells induce antigen-specific Th1-type CD4(+) T-cell activation in vitro and in vivo. Dendritic cell maturation and polarization are not inhibited by the presence of live B16 melanoma tumor cells, and tumor-loaded DC1s induce delayed-type hypersensitivity responses in vivo. DC1s loaded with B16 melanoma cells and injected into tumor-bearing mice induce Th1-skewed tumor-specific CD4(+) T cells and a significant reduction in tumor growth. Tumor infiltrates in DC1-immunized animals are characterized by the presence of CD4(+) T cells and activated macrophages. These results show a murine model of DC1 function and suggest an important role for CD4(+) T cells and macrophages in DO-induced antitumor immune responses. They have implications for the future development of DC1-based immunotherapies and strategies for clinical immune monitoring of their effectiveness.