Jak/STAT and dendritic cell differentiation in cancer

Jak/STAT 和癌症中的树突状细胞分化

• 批准号: 6905614
• 负责人: Yulia Nefedova
• 金额: $ 5.75万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-15 至 2007-05-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6905614
• 关键词: JAK kinase; biological signal transduction; cell differentiation; cell growth regulation; cellular oncology; dendritic cells; enzyme activity; enzyme inhibitors; enzyme mechanism; genetically modified animals; hematopoietic stem cells; immune response; laboratory mouse; myeloid stem cell; neoplasm /cancer; neoplasm /cancer vaccine; postdoctoral investigator; posttranslational modifications; protein structure function; tissue /cell culture; transcription factor

DESCRIPTION (provided by applicant): One of the reasons for the defects of immune system in cancer is abnormal dendritic cell (DC) differentiation. Tumor growth results in decrease of mature DCs and accumulation of immature myeloid cells, which directly suppress antigen-specific immune responses. However, the molecular mechanisms of the defective DC differentiation in cancer are still unknown. This study is an attempt to clarify them. Our preliminary data have demonstrated possible importance for the defective DC differentiation in cancer of hyper-activation of Jak/STAT pathway in hematopoietic progenitor cells. The overall hypothesis of this proposal is that tumor-derived factors hyper-activate Jak/STAT pathway in hematopoietic progenitor cells or on early stages of myeloid differentiation. This constitutive activation results in defective DC differentiation. To test this hypothesis we will investigate the role of Jak/STAT pathway in tumor-associated defects in DC differentiation in vitro and in vivo. We will also test the hypothesis that block of STAT3 activity will improve DC differentiation and immune response in tumor-bearing mice and antitumor effect of cancer vaccines. Understanding the mechanisms of the defective DC differentiation may lead to the development of new therapeutic approaches aimed on the improvement of immune function in cancer.

描述（申请人提供）：肿瘤免疫系统缺陷的原因之一是树突状细胞（DC）分化异常。肿瘤生长导致成熟DC减少和未成熟髓样细胞积聚，这直接抑制抗原特异性免疫应答。然而，肿瘤中DC分化缺陷的分子机制仍不清楚。本研究试图澄清它们。我们的初步数据已经证明了造血祖细胞中Jak/STAT通路的过度激活对于癌症中缺陷DC分化的可能重要性。该提议的总体假设是，肿瘤衍生因子在造血祖细胞中或在骨髓分化的早期阶段过度激活Jak/STAT途径。这种组成性激活导致缺陷性DC分化。为了验证这一假设，我们将在体外和体内研究Jak/STAT通路在DC分化中的肿瘤相关缺陷中的作用。我们还将检验阻断STAT 3活性将改善荷瘤小鼠中DC分化和免疫应答以及癌症疫苗的抗肿瘤作用的假设。了解缺陷DC分化的机制可能导致旨在改善癌症免疫功能的新治疗方法的发展。