IRS-1 Regulates Inflammatory Cell Recruitment in Lung Cancer

 描述（由申请人提供）：肺癌是全球癌症死亡的主要原因，仅在美国每年就有约160，000人死亡。更糟糕的是，五年生存率仍然只有15%，这突出了对新的有效疗法的需求。治疗肺癌的一种方法是优化宿主免疫系统的功能以对抗肿瘤。在许多情况下，癌细胞能够操纵宿主免疫细胞功能以使肿瘤受益。调节癌细胞用来扭曲免疫细胞功能的信号通路的关键蛋白质仍然不清楚。为了恢复癌症的免疫功能，我们必须首先确定癌细胞用来招募和操纵免疫细胞的确切机制。我们已经确定了信号衔接蛋白，胰岛素受体底物-1（IRS-1）作为限制癌细胞操纵宿主免疫反应能力的关键实体。IRS-1的功能是稳态调节癌细胞中的IL-22信号通路。在其缺乏的情况下，JAK/STAT活性增强，导致免疫细胞募集分子（细胞因子）的产生增加，从而促进肿瘤相关炎症。使用多种机制，这种肿瘤相关炎症促进肺肿瘤生长和侵袭性。这项研究的目的是确定IRS-1如何抑制癌细胞产生细胞因子的能力，并确定这些途径中代表新治疗靶点的关键步骤。

 DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer deaths worldwide, accounting for ~160,000 lives each year in the US alone. Making matters worse, five-year survival rates remains a dismal ~15%, highlighting the need for new and effective therapies. One approach to treat lung cancers is to optimize the function of the host immune system to fight tumors. In many cases, cancer cells are able to manipulate host immune cell function to the benefit of the tumor. The key proteins that regulate the signaling pathways cancer cells use to skew immune cell function remain poorly defined. In order to restore immune function in cancer, we must first identify the exact mechanisms that cancer cells use to recruit and manipulate immune cells. We have identified the signaling adaptor protein, insulin receptor substrate-1 (IRS-1) as a key entity that limits the ability of cancer cells to manipulate host immune responses. IRS-1 functions to homeostatically regulate the IL-22 signaling pathway in cancer cells. In its absence, enhanced JAK/STAT activity results, causing increased production of immune cell recruiting molecules (cytokines), which promotes tumor-associated inflammation. Using a variety of mechanisms, this tumor-associated inflammation promotes lung tumor growth and invasiveness. The purpose of this study will be to determine exactly how IRS-1 suppresses the ability of cancer cells to produce cytokines, and to identify key steps in these pathways that would represent novel therapeutic targets.