Immune cells regulate VEGF signaling via release of VEGF and antagonistic soluble VEGF receptor-1

Abstract

Vascular endothelial growth factor (VEGF) is an important regulator of physiological and pathological angiogenesis. Beside malignant and stromal cells, local immune cells shape VEGF signaling in the tumor microenvironment. Aminobisphosphonates like zoledronic acid (Zol) are drugs known to inhibit osteoclast activity and bone resorption, but also have immunomodulatory and anti-tumor effects. These properties have previously been linked to the downregulation of VEGF and interference with tumor neo-angiogenesis. It was therefore surprising to find that treatment with Zol in combination with low dose interleukin (IL)-2 increased serum VEGF levels in cancer patients.

In this study we aimed to characterize the effect of Zol and IL-2 on VEGF signaling of blood derived immune cells in vitro.

Upon stimulation with IL-2, T-cells and NK-cells increase production of VEGF consecutively to the release of pro-inflammatory interferon-γ, and Zol accelerates this response specifically in γδ T-cells. VEGF can in turn be antagonized by soluble VEGF- receptor (sVEGFR)-1, which is released depending on stimulatory conditions and the presence of monocytes. Additionally, malignant cells represented by leukemia and lymphoma cell lines produce VEGF and some release sVEGFR-1 simultaneously.

Our findings indicate a mechanism by which the VEGF and the sVEGFR-1 production by immune cells regulates local VEGF signaling. Therefore, immunotherapeutic interventions may enable both pro-tumor as well as anti-tumor effects via immune cell mediated alterations of VEGF homeostasis. This article is protected by copyright. All rights reserved.