Mechanism of dendritic cell differentiation in cancer

描述（由申请方提供）：宿主免疫系统无法产生和维持抗肿瘤免疫应答是肿瘤进展的机制之一。我们以前描述了一种新的机制，免疫缺陷的癌症与缺陷分化的树突状细胞（DC）。这些发现在许多实验室得到了证实。缺陷性DC分化由肿瘤源性因子介导，并且表现为成熟DC的产生减少和能够抑制抗原特异性免疫应答的未成熟骨髓细胞（ImC）的积累。功能活性DC的减少实质上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。已知在健康个体中，髓样细胞的分化发生在骨髓中，在骨髓中，其受到细胞因子的复杂网络和与骨髓基质的直接接触的严格控制。HPC中的转录调节因子Notch及其基质细胞上的配体Jagged和Delta在骨髓细胞分化过程中的细胞-细胞直接接触中起主要作用。在我们的初步实验中，我们发现肿瘤源性因子诱导造血祖细胞（HPC）中JAK/STAT通路的组成性激活。具体而言，它表现为JAK 2磷酸化增加和STAT 3 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。该提案的总体目标是确定癌症中有缺陷的髓样细胞分化的机制。为了实现这一目标，我们提出了三个具体目标：具体目标1。研究JAK/STAT 3在肿瘤相关的DC分化缺陷中的作用。具体目标2。研究选择性Jak 2/STAT 3抑制剂JSI-124对荷瘤小鼠抗肿瘤免疫应答的影响。具体目标3。研究转录调节因子Notch-1在DC分化中的作用。具体目标4。Notch-1在癌症中缺陷DC分化中的作用的研究。在所提出的实验的结果中，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。

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.