Vascular Leukocytes Influence the Tumor Microenvironment

描述（由申请人提供）：我们的长期研究旨在了解免疫抑制/促血管生成白细胞的免疫生物学，这些白细胞表型类似于树突状细胞，并在人类和小鼠卵巢癌中明显蓄积，我们将其称为血管白细胞（VLC）。该提议集中于理解最终驱动肿瘤位置处的VLC（和一般的调节性DC）的致耐受性活性和选择性积累的分子因子。正在进行的资助的关键发现是：在小鼠和人类的肿瘤VLC细胞核中，特殊的富含AT的序列结合蛋白1（Satb 1），控制全基因组转录程序的主程序员的过表达; β-连环蛋白与Satb 1的共定位;以及通过体内Satb 1沉默消除VLC的免疫抑制表型。基于这些和其他研究结果，我们的中心假设是Satb 1是卵巢癌中免疫抑制活性和调节性DC/VLCs优先积累的主程序员。 由于几乎没有什么是已知的Satb 1在髓系白细胞亚群中的作用，我们已经为这些研究产生了一种新的条件性敲除小鼠模型，开发了一种更好的卵巢癌遗传模型，并优化了沉默工具，用于体内使用。有了这些独特的资源，我们建议把申请集中于以下三个具体目标： 在具体目标1中，我们将定义Satb 1如何成为卵巢癌相关VLC免疫抑制特性的主要驱动因素。 在具体目标2中，我们将确定Satb 1在卵巢癌中调节性DC/VLC积累中的作用。 在具体目标3中，我们将建立调节卵巢癌中调节性DC/VLCs中Satb 1过表达的分子因素。 我们的工作将在该领域产生深远的影响，通过定义Satb 1-一个全球性的组织者， 全基因组转录程序-作为最终驱动免疫抑制活性和VLC在卵巢癌中优先积累的主调节因子，这将适用于其他致命肿瘤中的调节性DC，并对改进的免疫疗法的开发具有明显的意义。

DESCRIPTION (provided by applicant): The long term of our studies is to understand the immunobiology of the immunosuppressive/proangiogenic leukocytes that phenotypically resemble dendritic cells and distinctively accumulate in human and mouse ovarian cancer, termed by us Vascular Leukocytes (VLCs). This proposal focuses on comprehending the molecular factors that ultimately drive the tolerogenic activity and selective accumulation of VLCs (and regulatory DCs in general) at tumor locations. Key findings for the ongoing grant have been: The overexpression of special AT-rich sequence binding protein 1 (Satb1), a master programmer controlling genome-wide transcriptional programs, in the nuclei of tumor VLCs, in both mice and humans; the co-localization of ß-catenin with Satb1; and the abrogation of the immunosuppressive phenotype of VLCs by in vivo Satb1 silencing. Based on these and other findings, our central hypothesis is that Satb1 is the master programmer of the immunosuppressive activity and preferential accumulation of regulatory DCs/VLCs in ovarian cancer. Because virtually nothing is known about the role of Satb1 in myeloid leukocyte subsets, we have generated for these studies a novel conditional knockout mouse model, developed a better genetic model of ovarian cancer, and optimized silencing tools for in vivo use. With these unique resources in hand, we propose to focus the application on the following three specific aims: In Specific Aim 1, we will define how Satb1 is the primary driver of the immunosuppressive properties of ovarian cancer-associated VLCs. In Specific Aim 2, we will define the role of Satb1 in the accumulation of regulatory DCs/VLCs within ovarian cancer. In Specific Aim 3, we will establish the molecular factors modulating the overexpression of Satb1 in regulatory DCs/VLCs in ovarian cancer. Our work will exert a profound effect in the field by defining Satb1 - a global organizer of genome-wide transcriptional programs - as the master regulator ultimately driving the immunosuppressive activity and preferential accumulation of VLCs in ovarian cancer, which will be applicable to regulatory DCs in other lethal tumors and has obvious implications for development of improved immunotherapies.