IRS-1 Regulates Inflammatory Cell Recruitment in Lung Cancer

IRS-1 调节肺癌中炎症细胞的募集

• 批准号: 8888840
• 负责人: A McGarry Houghton
• 金额: $ 41.55万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8888840
• 关键词: Accounting; Adaptor Signaling Protein; Address; Antibodies; Area; CXC Chemokines; CXCR4 gene; Cancer Etiology; Cell physiology; Cells; Cessation of life; Clinical; Cytokine Receptors; Data; Genetic; Goals; Growth; Human; Immune; Immune response; Immune system; Infiltration; Inflammation; Inflammatory; Interleukin-17; Interleukin-6; Investigation; KRAS2 gene; Leukocyte Elastase; Lung Adenocarcinoma; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Mus; Mutation; Nature; Non-Small-Cell Lung Carcinoma; Outcome; Pathway interactions; Patients; Phenotype; Process; Production; Proteins; Recruitment Activity; Role; Signal Pathway; Signal Transduction; Staging; Survival Rate; T-Lymphocyte; Therapeutic; Time; Tissue Microarray; Tumor Burden; base; beta-Chemokines; cancer cell; chemokine; cohort; combat; cytokine; effective therapy; fighting; immune function; insulin receptor substrate 1 protein; interleukin-22; mortality; mouse model; neutrophil; new therapeutic target; novel; novel therapeutic intervention; protein expression; public health relevance; receptor; therapeutic target; treatment effect; tumor; tumor growth

 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.

 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 人死于肺癌。更糟糕的是，五年生存率仍然很低，约为 15%，这凸显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对抗肿瘤的功能。在许多情况下，癌细胞能够操纵宿主免疫细胞功能，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明确。为了恢复癌症中的免疫功能，我们必须首先确定癌细胞用于招募和操纵免疫细胞的确切机制。我们已经确定信号转接蛋白胰岛素受体底物 1 (IRS-1) 是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。如果没有它，JAK/STAT 活性就会增强，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。这种与肿瘤相关的炎症通过多种机制促进肺肿瘤的生长和侵袭。这项研究的目的是准确确定 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。