Sten Cell Gene Therapy of Breast Cancer

描述(申请人提供)：虽然在IV期乳腺癌患者中发现了肿瘤特异性免疫细胞，但它们无法控制肿瘤的生长。这在一定程度上是由于肿瘤间质紧紧围绕着肿瘤巢造成的。肿瘤间质至少在两个关键方面有助于乳腺癌的免疫逃逸：通过创建物理屏障，防止肿瘤浸润性免疫细胞与恶性肿瘤细胞直接接触，以及通过产生免疫抑制细胞因子，直接阻止免疫细胞的激活和/或吸引/激活免疫抑制细胞，如调节性T细胞。在这项提案中，我们将测试一种新的干细胞基因治疗方法，该方法针对肿瘤间质细胞，目的是使现有的免疫细胞能够控制肿瘤的生长。特定的肿瘤微环境以及肿瘤细胞产生的细胞因子/生长因子促使肿瘤浸润性造血肿瘤细胞分化为独特类型的巨噬细胞(所谓的肿瘤相关巨噬细胞-TAMS)，其基因表达特征与组织巨噬细胞和髓系细胞不同。TAMs是常见的间质细胞类型，TAMs的数量与乳腺癌的恶性程度直接相关。我们的中心假设是：一)骨髓来源的前体细胞可用于将治疗性转基因导入肿瘤间质；二)TAMS独特的基因和微RNA表达谱可用于构建特异的转基因表达系统；以及三)药物控制的、转基因介导的对间质细胞的杀伤和/或间质蛋白的降解使癌症能够长期控制。我们提供了一系列支持我们战略可行性的初步数据。我们将在涉及大鼠neu转基因小鼠(neu-TG)和同基因乳腺癌细胞(MMC)的乳腺癌小鼠模型中测试我们的假设。关键发现将在涉及4T1细胞和BALB/c小鼠的第二个乳腺癌模型中得到验证。

DESCRIPTION (provided by applicant): Although tumor-specific immune cells are found in stage IV breast cancer patients, they are not able to control tumor growth. This is in part due to tumor stroma that tightly surrounds tumor nests. Tumor stroma contributes to immune evasion of breast cancer in at least two critical ways; by creating a physical barrier that prevents direct contact between tumor infiltrating immune cells and malignant cells, and by producing immunosuppressive cytokines that directly block activation of immune cells and/or attract/activate immuno-suppressive cells such as regulatory T-cells. In this proposal, we will test a new stem cell gene therapy approach that targets tumor stroma cells with the goal to enable existing immune cells to control tumor growth. The specific tumor microenvironment as well as cytokines/growth factors produced by tumor cells trigger differentiation of tumor-infiltrating hematopoietic tumor cells into a unique type of macrophages (so called tumor-associated macrophages -"TAMs"), with a gene expression signature that is distinct from that of tissue macrophages and myeloid cells. TAMs are the prevalent stroma cell type and the number of TAMs directly correlates with breast cancer malignancy. Our central hypotheses are that i) bone marrow derived TAM progenitors can be used to deliver therapeutic transgenes to the tumor stroma, ii) the unique mRNA and microRNA expression profile of TAMs can be used to construct TAM-specific transgene expression systems, and iii) that drug controlled, transgene mediated killing of stroma cells and/or degradation of stroma protein enable long-term control of cancer. We provide a series of preliminary data that support the feasibility of our strategy. We will test our hypotheses in a mouse model of breast cancer involving rat neu-transgenic mice (neu-tg) and syngeneic mammary carcinoma cells (MMC). Key findings will be validated in a second breast cancer model that involves 4T1 cells and BALB/c mice.