T Cell Regulation of Cutaneous Malignancy

描述(由申请人提供)：人们对肿瘤免疫监测和癌症免疫治疗的前景越来越感兴趣。这主要是基于这样一个概念，即发展中的肿瘤可以被系统T细胞识别，系统T细胞将直接或通过TH1介导的细胞因子效应杀死它。然而，这种观点在很大程度上忽略了驻留在许多肿瘤发生部位的局部T细胞的潜在参与，并且它不能适应对细胞介导的免疫反应的复杂性的日益增长的认识，这种细胞介导的免疫反应可以涉及各种调节性和效应性T细胞。因此，我们已经开始了解免疫系统的特定组成部分对调节皮肤恶性肿瘤的个别和独特的贡献。这项工作建立在最近发表的使用小鼠致癌模型的实验基础上，这些实验共同揭示了免疫反应的复杂性，并指出了我们在理解免疫监测和设计免疫治疗策略时需要考虑的各种问题。 提出的假设是，不同亚群的α-β和伽马-德尔塔T细胞在调节皮肤恶性肿瘤方面起着不同的作用。这项研究的主要目标是确定这些特定的T细胞亚群，开始阐明它们的作用机制(S)，并展示免疫系统在肿瘤发生中的关键作用，这些作用以前是通过不同免疫活性宿主中肿瘤发生的基因表达谱的变化来揭示的。为了实现这些目标，提出了以下四(4)个具体目标：目标1-确定VGamma5-DETC本身是否足以介导对皮肤恶性肿瘤的保护，以及全身循环伽马-德尔塔T细胞增加或减少肿瘤保护的程度。目的2-确定特定的α-βT细胞亚群在肿瘤发生(即乳头状瘤形成)和癌变过程中的相对抗肿瘤和促肿瘤特性。目的3-评价几种关键免疫效应分子(IFNGamma、IL-10、FasL和穿孔素)在选择性地用免疫效应分子缺陷小鼠不同亚群的T细胞再繁殖后，皮肤T细胞缺陷小鼠的γ-β和α-βT细胞调节中的作用。目的在体内分析PDV肿瘤细胞在免疫成分存在和不存在的情况下，通过RNAi抑制塌陷蛋白、骨桥蛋白和Syndecan-1表达的生物学效应。

DESCRIPTION (provided by applicant): There is intensifying interest in tumor immunosurveillance and the prospect of cancer immunotherapy. This is principally founded on the concept that a developing tumor can be recognized by systemic T cells that will kill it either directly or via TH1-mediated cytokine effects. However, this view largely ignores the potential involvement of local T cells that are resident at many sites of carcinoma development, and it fails to accommodate the increasing appreciation of the complexity of the cell-mediated immune response that can involve a variety of regulatory as well as effector T cells. Therefore, we have set out to understand the individual and distinct contributions of defined components of the immune system to the regulation of cutaneous malignancy. The work builds on recently published experiments using murine models of carcinogenesis that collectively have exposed the complexity of the immune response and indicate a variety of issues that need to be considered in our understanding of immunosurveillance and the design of immunotherapy strategies. The hypothesis proposed is that various subsets of alpha-beta and gamma-delta T cells act differentially to regulate cutaneous malignancy. The major goals of the proposed studies are to identify those specific T cell subsets, begin to elucidate their mechanism(s) of action, and demonstrate critical effects of the immune system on tumor development previously revealed by altered gene expression profiles of tumors developing in hosts of different immunocompetence. To achieve these goals, the following four (4) specific aims are proposed: Aim 1 -Determine whether Vgamma5+ DETC alone are sufficient to mediate protection against cutaneous malignancy, and the degree to which systemic recirculating gamma-delta+ T cells add or subtract from tumor protection. Aim 2 -Determine the relative anti- and pro-tumor properties of specific subsets of alpha-beta T cells as determined by their effects on tumor development (i.e. papilloma formation) and progression to carcinoma. Aim 3 - Assess the role of several key immune effector molecules (IFNgamma, IL-10, FasL, and perforin) in gamma-delta and alpha-beta T cell regulation of cutaneous T cell deficient mice following selective repopulation of T cell deficient mice with various subsets of T cells from mice genetically deficient in immune effector molecules. Aim 4 - Analyze in vivo the biological effects of plasmid driven over-expression vs. inhibition of expression (using RNAi) of collapsin, osteopontin and syndecan-1 by PDV tumor cells in the presence and absence of immune components.