Neuropilin-1 as mediator for Vascular Endothelial Growth Factor (VEGF)-dependent T cell migration

最近，我们已经确定了神经纤毛蛋白-1（Nrp-1）的作用，这是高度表达的CD 4 + CD 25+调节性T细胞（T细胞），作为一个介导的Treg肿瘤浸润，在响应肿瘤衍生的血管内皮生长因子（VEGF）。与野生型（WT）小鼠相比，具有Nrp-1表达的T细胞特异性消融的转基因小鼠表现出极大降低的肿瘤生长和进展。这种表型与抗肿瘤免疫应答的强烈增加和肿瘤组织内Foxp 3 + T细胞数量的显著减少有关。此外，肿瘤产生的VEGF的消融同样导致肿瘤内Foxp 3 + T细胞的数量减少，免疫应答增加和肿瘤生长受损。从这些结果中，我们得出结论，Nrp-1引导TcB进入肿瘤组织，朝向VEGF，因此代表了用于治疗癌症的治疗性干预的有希望的靶点。在本提案中，我们的目标是了解Nrp-1/ VEGF依赖性T细胞迁移是否是肿瘤特异性机制，或者也参与其他炎症免疫反应，特别是自身免疫性疾病。此外，我们的目标是剖析这种机制是否可以翻译为T效应细胞，以引导它们直接进入产生VEGF的肿瘤组织，以提高抗肿瘤免疫应答。我们的初步数据表明，异位表达Nrp-1的T效应细胞有助于有效的抗肿瘤免疫应答，因为在转基因小鼠系（CD 4-Nrp-1）中Nrp-1的T细胞特异性过表达损害肿瘤生长。为了详细研究这一点，更重要的是开发一种新的免疫策略（引导T效应细胞到肿瘤），我们的目标是在幼稚的CD 4+和CD 8 + T细胞以及体外分化的CD 8+细胞毒性淋巴细胞（CTL），CD 4 + Th 1细胞和CD 4 + Th 17细胞中过表达Nrp-1，并分析其对小鼠肿瘤生长的预防和治疗作用。在概念证明后，我们希望在未来的项目中将我们的发现转化为人类系统，从而开发一种新的免疫学方法（将T效应细胞引导到肿瘤组织中），以改善抗肿瘤免疫反应。

Most recently, we have identified the role of Neuropilin-1 (Nrp-1), that is highly expressed by CD4+CD25+ regulatory T cells (Tregs), as a mediator for Treg tumor infiltration in response to tumor-derived Vascular Endothelial Growth Factor (VEGF). Transgenic mice with T cell-specific ablation in Nrp-1 expression exhibit a tremendously reduced tumor growth and progression in contrast to wildtype (WT) mice. This phenotype is associated with a strong increase in the anti-tumor immune response and strikingly significant reduced numbers of Foxp3+ Tregs within the tumor tissue. In addition, ablation of tumor-produced VEGF likewise leads to decreased numbers of Foxp3+ Tregs within the tumor, an increased immune response and impaired tumor growth. From these results we conclude that Nrp-1 guides Tregs into the tumor tissue towards VEGF, and therefore represents a promising target for therapeutic interventions for the treatment of cancer. In the present proposal we aim to understand whether the Nrp-1/ VEGF dependent T cell migration is a tumor-specific mechanism or also involved in other inflammatory immune responses in particular autoimmune diseases. Moreover, we aim to dissect whether this mechanism can be translated to T effector cells for guiding them directly into VEGF producing tumor tissues to improve anti-tumor immune responses. Our preliminary data suggest that T effector cells that ectopically express Nrp-1 contribute to an effective anti-tumor immune response as T cell-specific over-expression of Nrp-1 in a transgenic mouse line (CD4-Nrp-1) impairs tumor growth. To study this in detail and more importantly to develop a new immunotherapeutic strategy (guiding T effector cells to tumors), we aim to over-express Nrp-1 in naïve CD4+ and CD8+ T cells as well as in in vitro differentiated CD8+ cytotoxic lymphocytes (CTLs), CD4+ Th1 cells and CD4+ Th17 cells and analyze their prophylactic and also therapeutic effect on tumor growth in mice. Upon proof of concept we would like to translate our findings to the human system in future projects and thereby develop a new immunotherapeutic approach (directing T effector cells into tumor tissues) for improving anti-tumor immune responses.