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Volume 32, No 6, Jun 2022

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 32 Issue 6, June 2022: 543-554   |  Open Access

ORIGINAL ARTICLES

Meningeal lymphatics regulate radiotherapy efficacy through modulating anti-tumor immunity

Changping Zhou1,† , Lu Ma1,† , Han Xu1,† , Yingqing Huo1 , Jincai Luo1,*

1Laboratory of Vascular Biology, Institute of Molecular Medicine, College of Future Technology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, China
These authors contributed equally: Changping Zhou, Lu Ma and Han Xu
Correspondence: Jincai Luo(jincailuo@pku.edu.cn)

As a first-line treatment, radiotherapy (RT) is known to modulate the immune microenvironment of glioma, but it is unknown whether the meningeal lymphatic vessel (MLV)-cervical lymph node (CLN) network regulates the process or influences RT efficacy. Here, we show that the MLV-CLN network contributes to RT efficacy in brain tumors and mediates the RT-modulated anti-tumor immunity that is enhanced by vascular endothelial growth factor C (VEGF-C). Meningeal lymphatic dysfunction impaired tumor-derived dendritic cell (DC) trafficking and CD8+ T cell activation after RT, whereas tumors overexpressing VEGF-C with meningeal lymphatic expansion were highly sensitive to RT. Mechanistically, VEGF-C-driven modulation of RT-triggered anti-tumor immunity was attributed to C-C Motif Chemokine Ligand 21 (CCL21)-dependent DC trafficking and CD8+ T cell activation. Notably, delivery of VEGF-C mRNA significantly enhanced RT efficacy and anti-tumor immunity in brain tumors. These findings suggest an essential role of the MLV-CLN network in RT-triggered anti-tumor immunity, and highlight the potential of VEGF-C mRNA for brain tumor therapy.


https://doi.org/10.1038/s41422-022-00639-5

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