Association between PLVAP downregulation and increased lymphocyte infiltration in newly diagnosed glioblastoma treated with bevacizumab.

Glioblastoma (GBM) is a highly lethal brain tumor resistant to immunotherapy such as immune checkpoint inhibitors, partly because of an immunosuppressive tumor microenvironment and blood-brain barrier (BBB) dysfunction. Although bevacizumab can remodel the tumor vasculature, the relationship between BBB-related vascular changes and immune cell infiltration in GBM remains poorly understood. We analyzed human isocitrate dehydrogenase (IDH)-wildtype GBM tissues obtained after bevacizumab administration. Immunohistochemistry was performed for CD34 and plasmalemma vesicle-associated protein (PLVAP/PV-1), an endothelial marker associated with BBB disruption. Infiltrating T cells (CD3, CD8) and tumor-associated macrophages/microglia (TAMs; CD163) were also examined. PLVAP was broadly expressed in tumor vessels of untreated GBM and significantly reduced after bevacizumab administration, with marked downregulation in 3 of 10 treated cases. Among the 10 treated cases, significant increases in T-cell and cytotoxic T-lymphocyte infiltration were seen in PLVAP-low GBM compared with PLVAP-high GBM. TAM density did not differ significantly between groups but tended to be higher in the PLVAP-low group. These findings suggest that the bevacizumab-associated reduction of PLVAP expression is linked to increased T-cell infiltration in a subset of GBM cases. PLVAP may serve as an auxiliary histological marker for evaluating bevacizumab-related vascular/BBB remodeling in clinical specimens.