# Meningeal lymphangiogenesis effect on malignancy ofglioblastoma.

> **NIH NIH F30** · YALE UNIVERSITY · 2020 · $30,300

## Abstract

Project Summary
Glioblastomas are the most common form of primary malignant brain tumors and affect over 15,000 new
individuals in the United States annually. With surgical resection, chemotherapy and radiotherapy the
prognosis for patients is only at 15 months; and while checkpoint inhibitor therapy has provided unprecedented
clinical benefit for other cancers, its effect on brain tumors is unclear. This is attributed to the unique immune
environment in the central nervous system, with the draining lymphatic vasculature only being (re)identified few
years ago. Before this discovery, the brain was often thought to be immune-privileged, not having traditional
efferent and afferent immune cell trafficking and unable to evoke similar immune responses as peripheral
organs. But even with the characterization of this CNS lymphatic network, little is known about what makes the
meningeal lymphatics unique from other lymphatic networks in the body, especially during chronic
inflammatory states such as the presence of a tumor. We hypothesize that at homeostasis, the CNS
immunosurveillance may not be sufficient to evoke an immune response; but by increasing the lymphatic
drainage to allow for more T cell priming, we can generate an adequate inflammatory response against tumors.
In Aim 1, we will identify which cells are required for immunosurveillance and rejection of brain tumors.
By introducing VEGFC-AAV into the cisterna magna of mice, the meningeal lymphatic network proliferates,
prompting a strong immune response against orthotopic brain tumor models. With depletion antibodies and
various ko mice, we will identify which cell types are required for tumor rejection in these mice through survival
studies, flow cytometry and immunofluorescent staining. In Aim 2, we will investigate whether upregulation
of VEGF-C can be used either as a monotherapy, or to potentiate current immunotherapy strategies. To
accomplish this, we will use mRNA gene therapy to transiently increase VEGF-C in mice after brain tumor
implantation. mRNA has several advantages to other gene therapy strategies-including its cost, efficiency and
controlled protein expression kinetics in mammalian systems. We designed the mRNA enhancement strategy
to mitigate any potential long-term harm of VEGF-C expression, while allowing VEGF-C to synergistically work
with checkpoint inhibitor therapies such as, PDL-1, CTLA-4 and 4-1BB in treating GBM. Finally, in Aim 3
dural lymphatic vessels from postmortem GBM patients or from unrelated diseases will be evaluated.
The dural lymphatics have only recently been identified in mice, and there are still many questions regarding its
role in patients. We will evaluate what effects the chronic inflammatory state of a brain tumor has on the
meningeal lymphatics by staining GBM patient’s dura (postmortem) and compared to those who died of
unrelated causes. These three aims will help support our hypotheses of how immunosurveillance occurs in the
CNS and help us de...

## Key facts

- **NIH application ID:** 10048633
- **Project number:** 5F30CA239444-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Hoyeon Eric Song
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $30,300
- **Award type:** 5
- **Project period:** 2019-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10048633

## Citation

> US National Institutes of Health, RePORTER application 10048633, Meningeal lymphangiogenesis effect on malignancy ofglioblastoma. (5F30CA239444-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10048633. Licensed CC0.

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