Interaction between PD-L1 and soluble VEGFR1 in glioblastoma-educated macrophages.

PURPOSE: The combined application of immune checkpoint inhibitors (ICIs) and anti-angiogenesis therapy has shown synergistic effects on glioblastoma (GBM). As important resources of PD-L1 in the tumor microenvironment (TME), tumor-associated macrophages (TAMs) have significant impact of the efficiency of ICIs. However, the effects of anti-angiogenesis agents on immune checkpoints expression are not fully understood. METHOD: GBM-educated macrophages were generated from circulating monocytes of healthy controls and GBM patients under the education of GBM cell line. Surface expression of PD-L1 and VEGFR1 on GBM-educated macrophages was analyzed. VEGFR1 NAb and soluble VEGFR1 (sVEGFR1) were added and their effects on PD-L1 expression on TAMs was investigated. Serum soluble PD-L1 (sPD-L1) and sVEGFR1 levels in GBM patients were measured and their correlation was analyzed. RESULT: The expression intensity of PD-L1 on GBM-educated macrophages was higher and its up-regulation partially depends on VEGFR1 signaling pathway. GBM-educated macrophages secreted less levels of soluble VEGFR1 (sVEGFR1), and exogenous sVEGFR1 down-regulated PD-L1 expression intensity. PD-L1 blockade promoted the secretion of sVEGFR1. Finally, sVEGFR1 and sPD-L1 in serum of GBM patients were overexpressed, and a positive correlation was found. CONCLUSION: These findings reveal the interaction between PD-L1 and VEGFR1 signaling pathway in GBM-educated macrophages. VEGFR1 is involved with PD-L1 overexpression, which can be impeded by autocrine regulation of sVEGFR1. sVEGFR1 secretion by GBM-educated macrophages can be promoted by PD-L1 blockade. Taken together, these findings provide evidences for the combined application of ICIs and anti-angiogenesis therapies in the treatment of GBM.