Mechanism of dendritic cell differentiation in cancer

描述(申请人提供)：宿主免疫系统不能发展和维持抗肿瘤免疫反应是肿瘤进展的机制之一。我们之前已经描述了一种与树突状细胞(DC)分化缺陷相关的癌症免疫缺陷的新机制。这些发现在许多实验室得到了证实。DC分化缺陷是由肿瘤来源的因子介导的，表现为成熟DC的产生减少和能够抑制抗原特异性免疫反应的未成熟髓系细胞(IMC)的积累。功能正常的树突状细胞的存在减少，大大改变了免疫系统对肿瘤相关抗原的反应能力。肿瘤中DC分化缺陷的机制尚不清楚。众所周知，在健康个体中，髓系细胞的分化发生在骨髓中，在那里它受到复杂的细胞因子网络的严格控制，并通过与骨髓基质的直接接触来控制。在骨髓细胞分化过程中，HPC的转录调控因子Notch及其配体锯齿状和Delta在细胞与细胞的直接接触中发挥重要作用。在我们的初步实验中，我们发现肿瘤衍生因子诱导造血祖细胞(HPC)JAK/STAT通路的结构性激活。具体地说，它表现为JAK2的磷酸化增加和STAT3的DNA结合增加。此外，肿瘤衍生因子下调Notch-1转录调节因子的表达。这项建议的总体目标是确定癌症中髓系细胞分化缺陷的机制。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在肿瘤相关缺陷中在DC分化中的作用。具体目的2.研究选择性JAK2/STAT3抑制剂JSI-124对荷瘤小鼠抗肿瘤免疫反应的影响。具体目的3.研究转录调控因子Notch-1在DC分化中的作用。具体目的4.研究Notch-1在肿瘤DC分化缺陷中的作用。在这些实验的结果中，我们希望能够建立新的肿瘤髓系细胞分化缺陷的分子机制，并在这些新机制的基础上提出纠正DC缺陷的新方法。

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.