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

点击翻译按钮获取中文摘要

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.