Jak/STAT and dendritic cell differentiation 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。肿瘤生长导致成熟树突状细胞减少和未成熟骨髓细胞的积累，直接抑制抗原特异性免疫反应。然而，癌症中DC分化缺陷的分子机制尚不清楚。这项研究试图澄清这些问题。我们的初步数据表明，造血祖细胞中Jak/STAT通路的过度激活可能对癌症DC分化缺陷有重要意义。该建议的总体假设是，肿瘤衍生因子在造血祖细胞或髓系分化的早期阶段过度激活Jak/STAT通路。这种本构激活导致DC分化缺陷。为了验证这一假设，我们将研究Jak/STAT通路在体外和体内DC分化中肿瘤相关缺陷中的作用。我们还将验证阻断STAT3活性是否会改善荷瘤小鼠DC分化和免疫应答，以及癌症疫苗的抗肿瘤作用。了解DC分化缺陷的机制可能会导致新的治疗方法的发展，旨在改善癌症的免疫功能。

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.