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Characterization of dendritic cells transduced with Venezuelan equine encephalitis virus replicon particles as therapeutic cancer vaccines .

机译：表征的树突状细胞转委内瑞拉马脑炎病毒复制颗粒作为治疗癌症疫苗。

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摘要

Cancer vaccines seek to harness the specificity of T and B lymphocytes for reduction of tumor burden, as well as prevention of recurrent disease by establishing immunological memory. Because of their ability to initiate adaptive immune responses, dendritic cells (DCs) presenting tumor antigens have frequently been used as cancer vaccines. Unfortunately, induction of therapeutic responses in cancer patients has been sporadic, suggesting that current DC vaccines are unable to surmount tolerance against tumor antigens. The transduction of DCs with recombinant viral vectors may be a viable strategy for augmenting the ability of DC vaccines to break tolerance, as this approach can be used to efficiently deliver tumor antigens to DCs in the context of an immunostimulatory viral infection. Therefore, we have investigated the potential of DCs transduced with Venezuelan equine encephalitis virus replicon particles (VRPs) as cancer vaccines. VRPs could efficiently transduce human and murine immature DCs ex vivo, leading to high-level transgene expression, DC maturation, secretion of proinflammatory cytokines and efficient presentation of VRP-encoded antigens to T cells. VRP-transduced DCs (VRP-DCs) expressing a truncated neu oncoprotein stimulated neu-specific T cell and antibody responses and induced regression of established tumors in nontolerant mice. In contrast, VRP-DCs failed to induce robust antitumor responses in mice tolerant to neu, and were likewise unable to inhibit tumor growth. Depletion of CD4+CD25+ regulatory T cells (Treg) improved the effectiveness of VRP-DC vaccines in tolerant mice, demonstrating that VRP-DCs alone were unable to overcome Treg activity. Furthermore, provision of tolerant mice with neu-specific T cells from nontolerant mice did not augment vaccine efficacy, indicating that tolerogenic mechanisms are dominant over effector T cell activity. These results demonstrate that while highly immunogenic, virally-activated DCs cannot break tolerance against self/tumor antigens. Moreover, these findings imply that potent DC vaccines alone are unlikely to induce therapeutic antitumor immunity unless additional measures are undertaken to inhibit immunoregulatory mechanisms.
机译：癌症疫苗试图利用T和B淋巴细胞的特异性来减轻肿瘤负担，并通过建立免疫记忆来预防复发性疾病。由于具有启动适应性免疫反应的能力，呈递肿瘤抗原的树突状细胞（DC）经常被用作癌症疫苗。不幸的是，在癌症患者中诱导治疗反应是零星的，这表明当前的DC疫苗无法克服对肿瘤抗原的耐受性。用重组病毒载体转导DC可能是增强DC疫苗破坏耐受性的可行策略，因为这种方法可用于在免疫刺激性病毒感染的情况下将肿瘤抗原有效地递送至DC。因此，我们研究了委内瑞拉马脑炎病毒复制子颗粒（VRPs）转导的DCs作为癌症疫苗的潜力。 VRP可以离体有效地转导人和鼠的未成熟DC，从而导致高水平的转基因表达，DC成熟，促炎细胞因子的分泌以及VRP编码的抗原向T细胞的有效呈递。 VRP转导的DC（VRP-DC）表达截短的神经癌蛋白刺激的neu特异性T细胞和抗体反应，并诱导了非耐受小鼠中已建立的肿瘤的消退。相比之下，VRP-DCs不能在耐受neu的小鼠中诱导强大的抗肿瘤反应，并且同样不能抑制肿瘤的生长。 CD4 + CD25 +调节性T细胞（Treg）的耗竭提高了VRP-DC疫苗在耐受小鼠中的有效性，表明仅VRP-DC不能克服Treg活性。此外，向耐受性小鼠提供来自非耐受性小鼠的neu-特异性T细胞并不能提高疫苗效力，这表明耐受性机制在效应T细胞活性上占主导地位。这些结果表明，尽管具有高度免疫原性，但病毒激活的DC不能破坏对自身/肿瘤抗原的耐受性。此外，这些发现暗示，除非采取其他措施抑制免疫调节机制，否则单独的强力DC疫苗不太可能诱导治疗性抗肿瘤免疫。

著录项

  • 作者

    Moran, Timothy P.;

  • 作者单位

    The University of North Carolina at Chapel Hill.;

  • 授予单位 The University of North Carolina at Chapel Hill.;
  • 学科 Health Sciences Immunology.
  • 学位 Ph.D.
  • 年度 2006
  • 页码 222 p.
  • 总页数 222
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 预防医学、卫生学;
  • 关键词

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