AB042. Combined anti-PD-L1 and anti-VEGFR2 therapy promotes the antitumor immune response in glioblastoma multiforme by reprogramming tumor microenvironment
Year: 2024
Type: conference-abstract
Abstract: BACKGROUND: Inhibitors of programmed cell death ligand 1 (PD-L1) and vascular endothelial growth factor receptor 2 (VEGFR2) are commonly used in the clinic, but they are beneficial for only a minority of glioblastoma multiforme (GBM) patients. GBM has significant immunosuppressive properties, and there are many immunosuppressive cells and dysfunctional effector T-cell in the tumor microenvironment (TME), which is one of the important reasons for the failure of clinical treatment of GBM. P21-activated kinase 4 (PAK4) is a threonine protein kinase, and as a pivotal immune suppressor in the TME. PAK4 knockdown attenuates vascular abnormalities and promotes T-cell infiltration. METHODS: Using RNA sequencing (RNA-seq) technology, western blotting, and immunofluorescence, we identified changes in genes expression following VEGFR2 knockdown. The impact of anti-PD-L1 and anti-VEGFR2 on GBM cells apoptosis was assessed using coculture assays, western blotting, and flow cytometry. Additionally, the therapeutic efficacy of anti-PD-L1 and anti-VEGFR2 therapy was evaluated through in vivo experiments, immunohistochemistry, and immunofluorescence. RESULTS: Our studies revealed that VEGFR2 binds and phosphorylates signal transducer and activator of transcription 3 (p-STAT3), thereby regulating the expression of PAK4. Anti-PD-L1 and anti-VEGFR2 therapy can increase the secretion of interferon-gamma (IFN-γ), granzyme B, and perforin by immune cells and promoting the cytotoxic effects of cytotoxic cluster of differentiation 8 (CD8)+ T cells, and overexpression of PAK4 could reverse this effect. We also demonstrated that combination therapy with anti-PD-L1 and anti-VEGFR2 agents prevents tumor growth in an intracranial tumor model. CONCLUSIONS: Our results support that anti-VEGFR2 therapy can downregulate PAK4, reprogram the TME by increasing CD8+ T cells infiltration and activation, and enhance the therapeutic effect of anti-PD-L1 therapy on GBM cells.
Source: Chinese Clinical Oncology
Authors: Yao Lin, Hao Wang, Youxin Zhou
Institution: First Affiliated Hospital of Soochow University
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W4401614355