Autocrine VEGF signalling on M2 macrophages regulates PD-L1 expression for immunomodulation of T cells.
M2-polarized macrophages, on one hand, can promote tumour vascularization by producing proangiogenic factors, such as vascular endothelial growth factor (VEGF). On the other hand, the expression of VEGF receptors (VEGFR) in this cell lineage was also reported. Although the function of VEGF/VEGFR axis plays a pivotal role in macrophages infiltration and angiogenesis, however, there is still lack of the direct evidence to show the role of VEGF as an autocrine operating in M2 macrophages, particularly for immunomodulation. In our study, we surprisingly discovered that M2 macrophages polarized by baicalin can simultaneously express VEGF and its receptors. Taking advantage of this unique culture system, we were able to investigate the biological activity of M2 macrophages in response to the autocrine VEGF milieu. Our results showed that the expression of programmed death-ligand 1 (PD-L1) on M2 macrophages was significantly up-regulated in autocrine VEGF milieu. Through the blockade of autocrine VEGF signalling, PD-L1 expression on M2 macrophages was dramatically down-regulated. Furthermore, transplantation of PD-L1+ M2 macrophage stimulated by autocrine VEGF into allogeneic mice significantly suppressed host CD4+ /CD8+ T cells in the peripheral blood and increased CD4+ CD25+ regulatory T cells in the bone marrow. In conclusion, our findings provide a novel biological basis to support the current successful strategy using combined VEGF/PD-1 signalling blockade in cancer therapy.
['Lai|Yin-Siew|YS|', 'Wahyuningtyas|Rika|R|', 'Aui|Shin-Peir|SP|', 'Chang|Ko-Tung|KT|0000-0001-9383-831X']
D000818:Animals D019898:Autocrine Communication D000077784:Axitinib D060890:B7-H1 Antigen D018414:CD8-Positive T-Lymphocytes D002454:Cell Differentiation D005260:Female D005419:Flavonoids D005786:Gene Expression Regulation D008070:Lipopolysaccharides D008264:Macrophages D051379:Mice D008810:Mice, Inbred C57BL D061251:Primary Cell Culture D047428:Protein Kinase Inhibitors D000067996:RAW 264.7 Cells D015398:Signal Transduction D050378:T-Lymphocytes, Regulatory D014184:Transplantation, Homologous D042461:Vascular Endothelial Growth Factor A D040281:Vascular Endothelial Growth Factor Receptor-1
autocrine macrophage immunomodulation vascular endothelial growth factor programmed death-ligand 1