The Role of SHIP-1 in the Modulation of Immunoregulatory Cells in Pancreatic Canc

描述(申请人提供)：胰腺癌是人类最致命的癌症之一。虽然免疫治疗在这种疾病中显然是有希望的，但它在大多数患者中无效，部分原因是与调节性髓系来源抑制细胞(MDSC)和调节性T细胞(Tregs)相关的免疫抑制。肿瘤诱导的MDSC和Tregs被认为可以抑制抗肿瘤免疫反应。然而，控制这一过程的分子事件并不完全清楚。SRC同源肌醇磷酸酶(SHIP-1)缺陷小鼠表现出MDSC和Tregs的扩张，对抗肿瘤免疫产生负面影响。SHIP-1的表达受细胞因子的调节。此外，Ship-1在T细胞中的表达受发育调节。活化的T细胞可诱导MDSC的增殖和功能，但其机制尚不清楚。我们在胰腺结核模型中的初步数据显示，SHIP-1蛋白表达的抑制与体内MDSC和Tregs的扩张有关。然而，我们发现Ship-1的表达仅限于T细胞，这表明其对MDSC聚集的影响可能是间接的。这项建议的长期目标是阐明SHIP-1在胰腺肿瘤微环境中MDSC和Tregs分子相互作用中的作用。我们假设胰腺肿瘤衍生因子(TDF)抑制Tregs中SHIP-1的表达，从而使这些Tregs能够诱导MDSC的激活和扩张，从而改变其在胰腺肿瘤微环境中的功能。因此，为了验证我们的假说，我们提出了以下目标：1.体外研究胰腺肿瘤衍生因子(TDF)对T细胞分化为Tregs的影响及其SHIP-1的表达和活性。特定目的2.阐明分子 TB Treg诱导胰腺癌原位动物模型和自发转基因胰腺癌模型中骨髓间充质干细胞的机制(S)。

DESCRIPTION (provided by applicant): Pancreatic cancer is one of the most lethal cancers in humans. While immunotherapy clearly holds promise in this disease, it has been ineffective in most patients partly due to immunosuppression associated with regulatory Myeloid Derived Suppressor Cells (MDSC) and regulatory T cells (Tregs). Tumor-induced MDSC and Tregs are known to suppress anti-tumor immune responses. However, the molecular events controlling this process are not fully known. Src Homology Inositol Phosphatase (SHIP-1) deficient mice showed an expansion of MDSC and Tregs that negatively affect anti-tumor immunity. SHIP-1 expression is regulated by cytokines. In addition, SHIP-1 expression is developmentally regulated in T cells. Activated T cells induce MDSC expansion and function, however the mechanisms are yet unknown. Our preliminary data in a pancreatic TB model revealed that suppression of SHIP-1 protein expression is associated with the expansion of MDSC and Tregs, in vivo. However, we discovered that SHIP-1 expression was restricted to T-cells suggesting that the effects on MDSC accumulation may be indirect. The long-term goal of this proposal is to elucidate the role of SHIP-1 regarding the molecular interaction of MDSC and Tregs in a pancreatic tumor microenvironment. We hypothesize that pancreatic tumor-derived factors (TDF) suppress SHIP-1 expression in Tregs, which enable these Tregs to induce the activation and expansion of MDSC thus altering their function in pancreatic tumor microenvironments. Therefore in order to test our hypothesis, the following aims are proposed: Specific Aim 1. To evaluate the effect of pancreatic tumor derived factors (TDF) on na¿ve T cell polarization into Tregs and their expression/activity of SHIP-1, in vitro. Specific Aim 2. To elucidate the molecular mechanism(s) by which TB Tregs induce MDSC in an orthotopic animal model of pancreatic cancer and in a spontaneous transgenic model of pancreatic cancer.