Effect of Tumor Derived TGF B on Dendritic Cell Vaccines

描述（由申请人提供）：树突状细胞的独特能力， 有效刺激幼稚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，用抗原脉冲的疫苗接种， 树突状细胞提供针对随后的肿瘤的保护。无法 基于DC的疫苗导致现有肿瘤的显著消退， 部分归因于肿瘤的负面免疫调节作用， 微环境已经提出了许多肿瘤衍生产品， 通过干扰DC功能促进肿瘤的建立和发展 所需的诱导有效的抗肿瘤反应。一个最好的 转化生长因子-β是这些肿瘤衍生因子的特征 （TGF-β），一种多功能细胞因子， 免疫系统的细胞。在黑色素瘤、乳腺和肺的肿瘤活检中， 在癌症患者中，TGF-β免疫染色与 转移、疾病复发和死亡率。TGF-β特异性干扰 与DC成熟、趋化性、抗原识别和T细胞活化有关。 这些研究结果强烈表明，增加耐药性的策略， DCs对TGF-β介导的免疫抑制的作用应增强 DC疫苗有待检验的假设是， 树突状细胞中TGF-β介导的信号传导将消除肿瘤来源的， TGF-β介导的免疫抑制导致更有效的DC疫苗的 本研究的具体目的是：1）确定肿瘤源性 TGF-β对DC体内迁移和免疫刺激活性的影响 评估肿瘤来源的TGF-β对DC疫苗的影响。3)块 TGF-β介导的DC信号转导，以增强 DC疫苗的有效性。4)制定补充办法， TGF-β抗性DC对已建立的肿瘤的有效性。 TGF-β介导的信号转导将被基因转移所废除 编码有缺陷的TGF-β II型受体或TGF-β抑制剂 蛋白、Smad 7转染DC。这些研究有望改善我们的 了解肿瘤源性TGF-β对DC功能的作用， 开发用于治疗产生TFG-β的癌症的改进方法。

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.