Vascular Leukocytes influence the tumor microenvironment

描述（由申请人提供）：PI先前的工作揭示了人和小鼠卵巢癌中血管形成的新机制：β-防御素显示出大量招募CD 45 + CD 11 c + CCR 6+骨髓细胞至肿瘤微环境，在肿瘤微环境中，它们在体内被VEGF转化为内皮样细胞，称为血管白细胞（VLC）。 VLC表达内皮细胞和树突状细胞前体的标志物，并具有生理特征。 我们的中心假设是，VLC是CD 11 c+骨髓细胞的一个特定谱系，在肿瘤形成过程中显著促进血管形成;因此，这些细胞可能代表癌症治疗中重要和新颖的治疗靶点。 该假设基于以下观察：首先，从肿瘤标本中分选的小鼠和人VLC可以在血管生成条件下在体内产生可灌注的血管。 其次，我们的结果表明，用GFP标记的CD 45 + CD 11 c+细胞在肿瘤血管内积聚。 第三，在合适的ITGAX-DTR-GFP小鼠模型中CD 11 c+细胞的消耗导致肿瘤生长的显著降低。 我们研究的长期目标是确定VLC的确切起源及其参与肿瘤血管生成，以设计新的临床有效的癌症干预措施。 在具体目标1中，我们将确定具有血管生成潜能的白细胞的来源。 小鼠将耗尽VLC，然后用与标记的白细胞的不同亚群混合的肿瘤进行攻击，使我们能够精确地定义哪些白细胞亚群能够促进血管形成。 具体目标2将评估VLC促进肿瘤血管形成的肿瘤发展阶段。 我们建议产生一个转基因小鼠永久“标记”VLCs，允许随时识别这个子集随着时间的推移，即使他们失去了他们的白细胞表型过程中内皮化。 具体目标3将评估VLC耗竭作为癌症治疗干预的有效性，重点关注归巢于肿瘤微环境的抗VLC免疫毒素的功效。 这些努力将导致对肿瘤血管发生机制的新见解，并为更有效地靶向卵巢癌微环境提供基础，重点是在阻止肿瘤血管形成的同时引发有效的免疫反应。

DESCRIPTION (provided by applicant): The PI's previous work unveiled a novel mechanism of vascularization in human and mouse ovarian carcinoma: beta-defensins were shown to massively recruit CD45+CD11c+CCR6+ myeloid cells to the tumor microenvironment, where they were transformed by VEGF in vivo into endothelial-like cells, termed Vascular Leukocytes (VLCs). VLCs express markers - and have physiologic characteristics - of both endothelial cells and dendritic cell precursors. Our central hypothesis is that VLCs are a specific lineage of CD11c+ myeloid cells that significantly contributes to vascularization during tumor formation; as such, these cells may represent important and novel therapeutic targets in the treatment of cancer. This hypothesis is based on the following observations: First, mouse and human VLCs sorted from tumor specimens can create perfusable blood vessels in vivo under angiogenic conditions. Second, our results show that CD45+CD11c+ cells labelled with GFP accumulate within tumor blood vessels. Third, the depletion of CD11c+ cells in suitable ITGAX-DTR-GFP mouse model resulted in a dramatic decrease in tumor growth. The long-term objectives of our research are to determine the exact origin of VLCs and their involvement in tumor vasculogenesis, in order to design new clinically effective cancer interventions. In Specific Aim 1, we will determine the origin of leukocytes with vasculogenic potential. Mice will be depleted of VLCs, and then challenged with tumors admixed with different subsets of labelled leukocytes, enabling us to precisely define which leukocyte subset(s) are capable of contributing to vascularization. Specific Aim 2 will assess the stage in tumor development at which VLCs contribute to tumor vascularization. We propose to generate a transgenic mouse with permanently "tagged" VLCs, permitting the ready identification of this subset over time, even if they lose their leukocyte phenotype during the process of endothelialization. Specific Aim 3 will evaluate the effectiveness of VLC depletion as a therapeutic intervention in cancer, focusing on the efficacy of anti-VLC immunotoxins homed to the tumor microenvironment. These endeavours will lead to new insights into the mechanisms of tumor vasculogenesis and provide a basis for a more effective targeting of the ovarian cancer microenvironment, focused on triggering an effective immune response while impeding tumor vascularization.