Immune cells regulate VEGF signalling via release of VEGF and antagonistic soluble VEGF receptor‐1

Summary Vascular endothelial growth factor (VEGF) is an important regulator of physiological and pathological angiogenesis. Besides malignant and stromal cells, local immune cells shape VEGF signalling in the tumour microenvironment. Aminobisphosphonates such as zoledronic acid (Zol) are drugs known to inhibit osteoclast activity and bone resorption, but also have immunomodulatory and anti‐tumour effects. These properties have been linked previously to the down‐regulation of VEGF and interference with tumour 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 signalling of blood‐derived immune cells in vitro. Upon stimulation with IL‐2, T cells and natural killer (NK) cells increase production of VEGF consecutively to the release of proinflammatory interferon (IFN)‐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 leukaemia 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 signalling. Therefore, immunotherapeutic interventions may enable both pro‐ as well as anti‐tumour effects via immune cell‐mediated alterations of VEGF homeostasis. Stimulation induces VEGF production but also the release of sVEGFR‐1 by immune cells, which sequesters free VEGF and inhibit angiogenesis. Depending on the process of lymphocyte ‐ monocyte interaction, VEGF signaling is predominantly influenced in either way. Immune cells regulate VEGF homeostasis locally in a time dependent manner, influenced by the type and strength of primary stimuli and co‐stimulation.