Effect of Tumor Derived TGF B on Dendritic Cell Vaccines

描述(申请人提供)：树突状细胞的独特能力 有效地刺激幼稚的T淋巴细胞使它们成为 癌症免疫疗法。在几种啮齿动物模型中，用抗原致敏的疫苗接种 树突状细胞对后续肿瘤具有保护作用。无能为力 以DC为基础的疫苗导致现有肿瘤显著消退 部分归因于肿瘤的负面免疫调节作用 微环境。一些肿瘤衍生产品已被建议用于 干扰DC功能促进肿瘤的发生和发展 诱导有效的抗肿瘤反应所必需的。最好的之一 这些肿瘤衍生因子的特征是转化生长因子-β 转化生长因子-β，一种发挥强大抑制作用的多功能细胞因子 在免疫系统的细胞上。在黑色素瘤、乳腺和肺的肿瘤活检中 在癌症患者中，转化生长因子-β免疫染色已经与 转移、疾病复发和死亡率。转化生长因子-β特异性干扰 与DC成熟、趋化、抗原识别和T细胞活化有关。 这些发现有力地表明，增加对艾滋病的抵抗力的策略 DC对转化生长因子-β介导的免疫抑制应增强 基于DC的疫苗。需要检验的假设是，封锁 树突状细胞中转化生长因子-β介导的信号转导将消除肿瘤来源， 转化生长因子-β介导的免疫抑制导致更有效的DC疫苗。这个 这项研究的具体目的是：1)确定肿瘤衍生的效应 转化生长因子-β对DC体内迁移和免疫刺激活性的影响 评估肿瘤来源的转化生长因子-β对DC疫苗的影响。3)区块 转化生长因子-β介导的树突状细胞信号转导 DC疫苗的有效性。4)开发互补的方法以改进 转化生长因子-β耐药树突状细胞对已建立肿瘤的疗效。 转化生长因子-β介导的信号转导将被基因转移所废除 编码有缺陷的转化生长因子-βII受体或转化生长因子-β抑制因子 蛋白质，Smad7进入DC。这些研究可望改善我们的 肿瘤来源的转化生长因子-β对树突状细胞功能的影响 治疗产生TFG-β的癌症的改进方法的发展。

DESCRIPTION (provided by applicant): The unique ability of dendritic cells to potently stimulate naive T lymphocytes has made them prime candidates for cancer immunotherapy. In several rodent models, vaccination with antigen-pulsed dendritic cells confers protection against subsequent tumors. The inability of DC-based vaccines to cause significant regression of existing tumors has been attributed, in part, to the negative immunomodulatory effects of the tumor microenvironment. A number of tumor-derived products have been suggested to promote tumor establishment and progression by interfering with DC functions required for the induction of a potent antitumor response. One of the best characterized of these tumor-derived factors is Transforming Growth Factor-beta (TGF-beta), a multifunctional cytokine that exerts potent suppressive effects on cells of the immune system. In tumor biopsies from melanoma, breast and lung cancer patients, TGF-beta immunostaining has been directly correlated with metastasis, disease recurrence and mortality. TGF-beta specifically interferes with DC maturation, chemotaxis, antigen recognition and T cell activation. These findings strongly suggest that strategies that increase the resistance of DCs to TGF-beta-mediated immunosuppression should enhance the effectiveness of DC-based vaccines. The hypothesis to be tested is that blockade of TGF-beta-mediated signaling in DCs will abrogate tumor-derived, TGF-beta-mediated immunosuppression leading to ore effective DC vaccines. The Specific Aims of this study are to: 1) determine the effect of tumor-derived TGF-beta on in vivo migratory and immune stimulatory activities of DC 2) evaluate the impact of tumor-derived TGF-beta on DC vaccines. 3) block TGF-beta-mediated signal transduction in DCs in order to enhance the effectiveness of DC vaccines. 4) develop complementary approaches to improve the effectiveness of TGF-beta-resistant DC against established tumor. TGF-beta-mediated signal transduction will be abrogated by transfer of genes encoding a defective TGF-beta type II receptor or the TGF-beta inhibitory protein, Smad7 into DCs. These studies are expected to improve our understanding of the role of tumor-derived TGF-beta on DC function and lead to the development of improved methods for treating TFG-beta producing cancers.