A Mouse Model of TGFB1 and Tumor Immunosurveillance in Squamous Cell Cancer

描述（由申请人提供）：TGFbeta1在人类癌症发展中具有抑瘤和致癌作用，但这种功能变化的机制尚不清楚。确定TGFbeta1这些不同功能的机制以及这种变化是如何发生的，将为癌症治疗提供重要的新靶点。我们最近建立了TGFbeta1条件表皮表达小鼠模型，以确定TGFbeta1表达的肿瘤分期特异性作用和靶点。初步研究表明，TGFbeta1在正常表皮、良性和恶性皮肤肿瘤中的表达引起宿主免疫系统截然不同的反应，这些反应与肿瘤的消退或进展有关。本研究建议的中心假设是，TGFbeta1在癌症进展过程中的作用变化与免疫系统对肿瘤细胞衍生的TGFbeta1的不同反应有关。特异性目标1验证了对表皮来源的TGFbeta1的适应性免疫反应是阶段特异性的假设，使用遗传和免疫学手段消耗和恢复特异性免疫细胞亚群。第二个特定目的是验证这样一个假设，即TGFbeta1在正常表皮中的过度表达和由此产生的炎症是表皮角质形成细胞中含有化学或基因激活的ras癌基因的肿瘤促进刺激。特异性Aim 3通过体外和体内生化和分子分析，以及阻断NF-kappaB信号传导的遗传方法，验证了NF-kappaB信号传导对于正常表皮和鳞状肿瘤中免疫系统对TGFbeta1的阶段特异性反应至关重要的假设。普通人群中非黑色素瘤皮肤癌发病率的增加，以及免疫功能低下的器官移植患者皮肤侵袭性鳞状细胞癌的日益严重的问题代表了一个重大的公共卫生问题。本研究项目的目标是利用该条件表达小鼠模型了解肿瘤细胞发育产生的TGFbeta1如何差异调节抗肿瘤免疫反应，从而最终确定治疗靶点和策略，阻断肿瘤源性TGFbeta1的免疫抑制作用，增强其抗肿瘤炎症作用。

DESCRIPTION (provided by applicant): TGFbeta1 has both tumor suppressor and oncogenic roles in human cancer development, but the mechanisms underlying this change in function remain elusive. Identifying the mechanisms underlying these distinct functions of TGFbeta1 and how this change occurs will provide important new targets for cancer therapy. We have recently developed a TGFbeta1 conditional epidermal expression mouse model to identify tumor stage specific effects and targets of TGFbeta1 expression. Preliminary studies reveal that TGFbeta1 expression in the normal epidermis, benign and malignant skin tumors provokes profoundly distinct responses from the host immune system that are associated with tumor regression or progression. The central hypothesis of this research proposal is that the changing roles of TGFbeta1 during cancer progression are linked to distinct responses of the immune system to tumor cell derived TGFbeta1. Specific Aim 1 tests the hypothesis that the adaptive immune response to epidermally derived TGFbeta1 is stage specific using genetic and immunological means to deplete and restore specific immune cell subsets. The second specific aim is to test the hypothesis that overexpression of TGFbeta1 in the normal epidermis and the resulting inflammation is a tumor-promoting stimulus for epidermal keratinocytes harboring a chemically or genetically activated ras oncogene. Specific Aim 3 tests the hypothesis that NF-kappaB signaling is essential for the stage specific response of the immune system to TGFbeta1 in the normal epidermis and in squamous tumors using in vitro and in vivo biochemical and molecular analysis, and genetic methods to block NF-kappaB signaling. The increased incidence of non-melanoma skin cancer in the general population, and the increasing problem of aggressive SCC of the skin in immunocompromised organ transplant patients represent a significant public health problem. The goal of this research project are to use this conditional expression mouse model to understand how TGFbeta1 produced by developing tumor cells differentially regulates the anti-tumor immune response, so that ultimately therapeutic targets and strategies can be identified that will block the immunosuppressive effects and enhance the anti-tumor inflammatory effects of tumor derived TGFbeta1.