Immune Cells Regulate VEGF Signalling Via Release of VEGF and Antagonistic Soluble VEGF Receptor-1

Overview

Journal Clin Exp Immunol

Publisher Oxford University Press

Specialty Allergy & Immunology

Date 2017 Dec 14

PMID 29235095

Citations 10

Authors

T Hoeres

M Wilhelm

M Smetak

E Holzmann

G Schulze-Tanzil

J Birkmann

Affiliations

Soon will be listed here.

Abstract

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.

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References

Shin J, Yoon I, Kim J, Kim B, Park C . Vascular endothelial growth factor-induced chemotaxis and IL-10 from T cells. Cell Immunol. 2009; 256(1-2):72-8. DOI: 10.1016/j.cellimm.2009.01.006. View

Pavlakovic H, Becker J, Albuquerque R, Wilting J, Ambati J . Soluble VEGFR-2: an antilymphangiogenic variant of VEGF receptors. Ann N Y Acad Sci. 2010; 1207 Suppl 1:E7-15. PMC: 3062194. DOI: 10.1111/j.1749-6632.2010.05714.x. View

Santini D, Vincenzi B, Avvisati G, Dicuonzo G, Battistoni F, Gavasci M . Pamidronate induces modifications of circulating angiogenetic factors in cancer patients. Clin Cancer Res. 2002; 8(5):1080-4. View

Santini D, Vincenzi B, Galluzzo S, Battistoni F, Rocci L, Venditti O . Repeated intermittent low-dose therapy with zoledronic acid induces an early, sustained, and long-lasting decrease of peripheral vascular endothelial growth factor levels in cancer patients. Clin Cancer Res. 2007; 13(15 Pt 1):4482-6. DOI: 10.1158/1078-0432.CCR-07-0551. View

Clauss M, Weich H, Breier G, Knies U, ROCKL W, Waltenberger J . The vascular endothelial growth factor receptor Flt-1 mediates biological activities. Implications for a functional role of placenta growth factor in monocyte activation and chemotaxis. J Biol Chem. 1996; 271(30):17629-34. DOI: 10.1074/jbc.271.30.17629. View

Edelbauer M, Datta D, Vos I, Basu A, Stack M, Reinders M . Effect of vascular endothelial growth factor and its receptor KDR on the transendothelial migration and local trafficking of human T cells in vitro and in vivo. Blood. 2010; 116(11):1980-9. PMC: 3173992. DOI: 10.1182/blood-2009-11-252460. View

Matsuyama W, Kubota R, Hashiguchi T, Momi H, Kawabata M, Nakagawa M . Purified protein derivative of tuberculin upregulates the expression of vascular endothelial growth factor in T lymphocytes in vitro. Immunology. 2002; 106(1):96-101. PMC: 1782692. DOI: 10.1046/j.1365-2567.2002.01395.x. View

Santini D, Vincenzi B, Dicuonzo G, Avvisati G, Massacesi C, Battistoni F . Zoledronic acid induces significant and long-lasting modifications of circulating angiogenic factors in cancer patients. Clin Cancer Res. 2003; 9(8):2893-7. View

Wakita D, Sumida K, Iwakura Y, Nishikawa H, Ohkuri T, Chamoto K . Tumor-infiltrating IL-17-producing gammadelta T cells support the progression of tumor by promoting angiogenesis. Eur J Immunol. 2010; 40(7):1927-37. DOI: 10.1002/eji.200940157. View

10.

Grivennikov S, Greten F, Karin M . Immunity, inflammation, and cancer. Cell. 2010; 140(6):883-99. PMC: 2866629. DOI: 10.1016/j.cell.2010.01.025. View

11.

Voron T, Colussi O, Marcheteau E, Pernot S, Nizard M, Pointet A . VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J Exp Med. 2015; 212(2):139-48. PMC: 4322048. DOI: 10.1084/jem.20140559. View

12.

Lee S, Chen T, Barber C, Jordan M, Murdock J, Desai S . Autocrine VEGF signaling is required for vascular homeostasis. Cell. 2007; 130(4):691-703. PMC: 3010851. DOI: 10.1016/j.cell.2007.06.054. View

13.

Fava R, Olsen N, Spencer-Green G, Yeo K, Yeo T, Berse B . Vascular permeability factor/endothelial growth factor (VPF/VEGF): accumulation and expression in human synovial fluids and rheumatoid synovial tissue. J Exp Med. 1994; 180(1):341-6. PMC: 2191547. DOI: 10.1084/jem.180.1.341. View

14.

Zhang J, Silva T, Yarovinsky T, Manes T, Tavakoli S, Nie L . VEGF blockade inhibits lymphocyte recruitment and ameliorates immune-mediated vascular remodeling. Circ Res. 2010; 107(3):408-17. PMC: 2929975. DOI: 10.1161/CIRCRESAHA.109.210963. View

15.

Gunsilius E, Petzer A, Stockhammer G, Nussbaumer W, Schumacher P, Clausen J . Thrombocytes are the major source for soluble vascular endothelial growth factor in peripheral blood. Oncology. 2000; 58(2):169-74. DOI: 10.1159/000012095. View

16.

Levitt L, Nagler A, Lee F, Abrams J, Shatsky M, Thompson D . Production of granulocyte/macrophage-colony-stimulating factor by human natural killer cells. Modulation by the p75 subunit of the interleukin 2 receptor and by the CD2 receptor. J Clin Invest. 1991; 88(1):67-75. PMC: 296004. DOI: 10.1172/JCI115306. View

17.

Santos S, Dias S . Internal and external autocrine VEGF/KDR loops regulate survival of subsets of acute leukemia through distinct signaling pathways. Blood. 2004; 103(10):3883-9. DOI: 10.1182/blood-2003-05-1634. View

18.

Van Acker H, Anguille S, Willemen Y, Smits E, Van Tendeloo V . Bisphosphonates for cancer treatment: Mechanisms of action and lessons from clinical trials. Pharmacol Ther. 2015; 158:24-40. DOI: 10.1016/j.pharmthera.2015.11.008. View

19.

Wu F, Stefanini M, Mac Gabhann F, Popel A . A compartment model of VEGF distribution in humans in the presence of soluble VEGF receptor-1 acting as a ligand trap. PLoS One. 2009; 4(4):e5108. PMC: 2663039. DOI: 10.1371/journal.pone.0005108. View

20.

Kunzmann V, Smetak M, Kimmel B, Weigang-Koehler K, Goebeler M, Birkmann J . Tumor-promoting versus tumor-antagonizing roles of γδ T cells in cancer immunotherapy: results from a prospective phase I/II trial. J Immunother. 2012; 35(2):205-13. DOI: 10.1097/CJI.0b013e318245bb1e. View