# Glioblastoma-secreted GABA contributes to the immunosuppressive environment

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $432,250

## Abstract

Title: Glioblastoma-secreted GABA contributes to the immunosuppressive environment
Abstract:
 Glioblastoma (GBM) is one of the most common and lethal human brain tumors and there are no
effective treatments. We have shown that immune cells have GABA-receptors (GABA-Rs) and that their
activation limits inflammatory immune responses. Indeed, three recent studies of several different types of
peripheral solid tumors have demonstrated that tumor cells, or B cells within tumors, can secrete GABA which
dramatically shifts the phenotype of human and murine tumor-infiltrating macrophages and dendritic cells
towards anti-inflammatory phenotypes and inhibits the activity of infiltrating CD8+ effector T cells, consistent
with our findings of GABA’s action in autoimmune diseases. GABA-R antagonists, or inactivation of the GABA-
synthesizing enzyme glutamic acid decarboxylase (GAD67), significantly decreases tumor burden in these
models. Thus, GABA is an important intra-tumor immunosuppressive factor in these peripheral tumors.
 There are multiple lines of evidence indicating that glioblastoma cells secrete high levels of GABA. Our
central hypothesis is that GBM-secreted GABA contributes to the immunosuppressive tumor environment. Our
proposed studies with GAD67-deficient GBM cell lines will determine 1) whether GBM-secreted GABA
modulates the frequency, phenotype, and localization of tumor infiltrating immune cells, 2) how GABA
deficiency modulates GBM gene expression, and 3) whether rendering GBMs GABA-deficient confers a
survival advantage.
 These investigations will collectively provide the first understanding of how GBM-secreted GABA
transforms the tumor microenvironment and affects survival. If our central hypothesis is supported, future
studies can examine whether making anti-tumor responses resistant to GABA inhibition could improve their
effector functions. For example, we may be able to enhance the effectiveness of NK, DC, or T cell-based
therapies by making them GABA-R deficient. Alternatively, new therapies may be designed to specifically
target immune cell GABA-Rs or their signaling pathways.

## Key facts

- **NIH application ID:** 10809148
- **Project number:** 1R21NS131767-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** DANIEL KAUFMAN
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $432,250
- **Award type:** 1
- **Project period:** 2024-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10809148

## Citation

> US National Institutes of Health, RePORTER application 10809148, Glioblastoma-secreted GABA contributes to the immunosuppressive environment (1R21NS131767-01A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10809148. Licensed CC0.

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