Meningeal lymphatics regulate radiotherapy efficacy through modulating anti-tumor immunity

Area of Science:

• Neuro-oncology
• Immunology
• Radiotherapy

Background:

• Radiotherapy (RT) modulates glioma's immune microenvironment.
• The role of the meningeal lymphatic vessel (MLV)-cervical lymph node (CLN) network in RT efficacy is unclear.

Purpose of the Study:

• To investigate the MLV-CLN network's role in RT efficacy for brain tumors.
• To explore the influence of vascular endothelial growth factor C (VEGF-C) on RT-mediated anti-tumor immunity.

Main Methods:

• Assessment of MLV-CLN network function in brain tumor models.
• Analysis of dendritic cell (DC) trafficking and CD8+ T cell activation post-RT.
• Evaluation of tumors overexpressing VEGF-C and meningeal lymphatic expansion.
• Investigation of C-C Motif Chemokine Ligand 21 (CCL21) in VEGF-C-mediated immunity.
• Testing the efficacy of VEGF-C mRNA delivery in combination with RT.

Main Results:

• MLV-CLN network integrity is crucial for RT efficacy and anti-tumor immunity.
• Meningeal lymphatic dysfunction impairs DC trafficking and T cell activation after RT.
• VEGF-C overexpression enhances RT sensitivity and meningeal lymphatic expansion.
• VEGF-C promotes DC trafficking and CD8+ T cell activation via CCL21.
• VEGF-C mRNA delivery significantly improved RT efficacy and anti-tumor immunity.

Conclusions:

• The MLV-CLN network plays a vital role in RT-triggered anti-tumor immunity in brain tumors.
• VEGF-C enhances RT efficacy by modulating the MLV-CLN network and immune cell activation.
• VEGF-C mRNA represents a promising therapeutic strategy for brain tumor treatment.