T Cell Regulation of Cutaneous Malignancy

描述（由申请人提供）：对肿瘤免疫监测和癌症免疫治疗的前景的兴趣日益浓厚。这主要是建立在这样的概念上，即发展中的肿瘤可以被系统性T细胞识别，系统性T细胞将直接或通过TH 1介导的细胞因子效应杀死肿瘤。然而，这种观点在很大程度上忽略了驻留在癌症发展的许多位点的局部T细胞的潜在参与，并且它未能适应对细胞介导的免疫应答的复杂性的日益增长的理解，所述细胞介导的免疫应答可以涉及各种调节性T细胞以及效应T细胞。因此，我们已经着手了解的个人和独特的贡献，确定的免疫系统的组成部分，以调节皮肤恶性肿瘤。这项工作建立在最近发表的使用致癌小鼠模型的实验基础上，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视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，α-β和γ-δ T细胞的各种亚群的行为差异，以调节皮肤恶性肿瘤。拟议研究的主要目标是鉴定这些特异性T细胞亚群，开始阐明它们的作用机制，并证明免疫系统对肿瘤发展的关键作用，这些作用先前通过在不同免疫活性宿主中发展的肿瘤的改变的基因表达谱揭示。为了实现这些目标，提出了以下四（4）个具体目标：目标1 -确定单独的V γ 5 + DETC是否足以介导对皮肤恶性肿瘤的保护，以及全身再循环γ-δ + T细胞增加或减少肿瘤保护的程度。目的2 -确定α-β T细胞特定亚群的相对抗肿瘤和促肿瘤特性，如通过其对肿瘤发展（即乳头状瘤形成）和癌进展的影响所确定的。目的3 -评估几种关键的免疫效应分子（IFN γ，IL-10，FasL和穿孔素）在皮肤T细胞缺陷小鼠的γ-δ和α-β T细胞调节中的作用，这些T细胞缺陷小鼠用来自免疫效应分子遗传缺陷小鼠的各种T细胞亚群进行选择性再增殖。目的4 -在存在和不存在免疫组分的情况下，分析PDV肿瘤细胞的质粒驱动的过表达与抑制（使用RNAi）的骨桥蛋白、骨桥蛋白和多配体蛋白聚糖-1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.