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

描述（由申请人提供）：胰腺癌是人类最致命的癌症之一。虽然免疫疗法在这种疾病中具有明显的前景，但它在大多数患者中无效，部分原因是与调节性髓源性抑制细胞（MDSC）和调节性T细胞（Tregs）相关的免疫抑制。已知肿瘤诱导的MDSC和Tregs可抑制抗肿瘤免疫反应。然而，控制这一过程的分子事件尚不完全清楚。Src同源肌醇磷酸酶（SHIP-1）缺陷小鼠显示MDSC和Tregs的扩增，这对抗肿瘤免疫产生负面影响。SHIP-1的表达受细胞因子的调控。此外，SHIP-1的表达在T细胞中受发育调控。活化的T细胞诱导MDSC的扩增和功能，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，体内SHIP-1蛋白表达的抑制与MDSC和Tregs的扩增有关。然而，我们发现SHIP-1的表达仅限于t细胞，这表明对MDSC积累的影响可能是间接的。本研究的长期目标是阐明SHIP-1在胰腺肿瘤微环境中与MDSC和Tregs分子相互作用的作用。我们假设胰腺肿瘤衍生因子（TDF）抑制SHIP-1在treg中的表达，这使得这些treg能够诱导MDSC的激活和扩增，从而改变它们在胰腺肿瘤微环境中的功能。因此，为了检验我们的假设，提出以下目标：探讨胰腺肿瘤衍生因子（TDF）对na - ve T细胞分化为Tregs及SHIP-1表达/活性的影响。具体目标2。来阐明分子

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.