Mechanism of dendritic cell differentiation in cancer

树突状细胞在癌症中的分化机制

• 批准号: 7078534
• 负责人: Dmitry I Gabrilovich
• 金额: $ 25.07万
• 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: 2004-07-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7078534
• 关键词: JAK kinase; acute phase protein; biological models; biological signal transduction; cell differentiation; cellular oncology; cellular pathology; dendritic cells; genetic transcription; hematopoietic stem cells; immune response; inhibitor /antagonist; laboratory mouse; molecular oncology; myeloid stem cell; neoplasm /cancer genetics; neoplasm /cancer immunology; protein structure function; transcription factor; tumor antigens

DESCRIPTION (provided by applicant): Inability of host immune system to develop and maintain antitumor immune response is one of the mechanisms of tumor progression. We have previously described a new mechanism of immune deficiency in cancer associated with defective differentiation of dendritic cells (DC). These findings were confirmed in many laboratories. Defective DC differentiation is mediated by tumor-derived factors and manifests in decreased production of the mature DCs and accumulation of immature myeloid cells (ImC) able to suppress antigen-specific immune responses. Decreased presence of functionally competent DCs substantially altered the ability of immune system to react to tumor-associated antigens. The mechanisms of the defective DC differentiation in cancer remain unknown. It is known that in healthy individuals differentiation of myeloid cells is taking place in bone marrow, where it is tightly controls by a complex network of cytokines and by direct contact with bone marrow stroma. Transcriptional regulator Notch in HPC and its ligands Jagged and Delta on stromal cells play major role in direct cell-cell contact during cell differentiation in bone marrow. In our preliminary experiments we have discovered that tumor-derived factors induce constitutive activation of JAK/STAT pathway in hematopoietic progenitor cells (HPC). Specifically, it manifested in increased phosphorylation of JAK2 and increased DNA binding of STAT3. In addition, tumor-derived factors downregulate expression of Notch-1 transcriptional regulator. The overall goal of this proposal is to identify mechanisms of the defective myeloid cell differentiation in cancer. To achieve this goal we propose three specific aims: Specific Aim 1. Investigate the role of JAK/STAT3 in tumor associated defects in DC differentiation. Specific Aim 2. Investigate the effect of selective Jak2/STAT3 inhibitor JSI-124 on the development of antitumor immune response in tumor-bearing mice. Specific Aim 3. Investigate the role of transcriptional regulator Notch-1 in DC differentiation. Specific Aim 4. Study of Notch-1 role in the defective DC differentiation in cancer. In the result of the proposed experiments we hope to be able to establish new molecular mechanisms of the defective myeloid cell differentiation in cancer and to propose new approaches to correct DC defects based on those new mechanisms.

描述（由申请人提供）：宿主免疫系统无法开发和维持抗肿瘤免疫反应是肿瘤进展的机制之一。我们先前已经描述了一种与树突状细胞有缺陷（DC）有缺陷的癌症免疫缺陷的新机制。这些发现在许多实验室中得到了证实。 DC分化有缺陷是由肿瘤衍生的因子和成熟DC的产生减少以及能够抑制抗原特异性免疫反应的未成熟髓样细胞（IMC）的积累的表现。功能合理的DC的存在下降大大改变了免疫系统对肿瘤相关抗原反应的能力。癌症中DC分化有缺陷的机制仍然未知。众所周知，在健康个体中，骨髓细胞的分化发生在骨髓中，在骨髓中，它通过复杂的细胞因子网络紧密控制，并通过直接接触骨髓基质。 HPC中的转录调节器缺口及其配体在骨髓中细胞分化期间在直接细胞接触中锯齿状和三角洲的配体发挥了主要作用。在我们的初步实验中，我们发现肿瘤衍生的因素诱导造血祖细胞（HPC）中JAK/STAT途径的组成型激活。具体而言，它体现在JAK2的磷酸化增加和STAT3的DNA结合增加。此外，肿瘤衍生的因子下调了Notch-1转录调节剂的表达。该提案的总体目标是确定癌症中缺陷的髓样细胞分化的机制。为了实现这一目标，我们提出了三个特定目标：特定目标1。研究JAK/STAT3在与DC分化相关的缺陷中的作用。具体目标2。研究选择性JAK2/STAT3抑制剂JSI-124对肿瘤抗肿瘤免疫反应发展的影响。具体目标3。研究转录调节器Notch-1在DC分化中的作用。特定目的4。研究Notch-1在癌症中DC分化有缺陷中的作用。在提出的实验的结果下，我们希望能够建立癌症中有缺陷的髓样细胞分化的新分子机制，并提出基于这些新机制纠正DC缺陷的新方法。