# Dissecting the tumor cell-immune TME axis to identify therapeutically actionable vulnerabilities that potentiate immunotherapy in GBM

> **NIH NIH F99** · JOHNS HOPKINS UNIVERSITY · 2024 · $48,974

## Abstract

Glioblastoma multiforme (GBM) is a common and highly aggressive form of brain cancer in adults with a dismal
prognosis and limited therapeutic options. A critical component of GBM malignancy derives from the distinct
population of glioma stem cells (GSCs) that function to promote and maintain malignancy through their capacity
for self-renewal, cellular adaptation and multipotency. These stem-like cells engage in a synergistic relationship
with the surrounding microenvironment to promote tumor progression and are key drivers of intratumoral
heterogeneity, immune-suppression, and therapy resistance. Targeting GSCs and mechanisms that drive the
stem-like phenotype presents a promising avenue for targeted therapeutics.
 The broad goal of this proposal is to understand the cell-intrinsic mechanisms driving maintenance of a
unique, immunosuppressive GSC subset, identify cellular vulnerabilities associated with immunosuppressive
GBM cells, and develop preclinical therapeutics to target these cells. We will achieve this goal by utilizing our
validated GSC cell models, state-of-the art single-cell sequencing technology, and cutting-edge spatially
resolved omics platforms applied to clinical GBM specimens, and advanced molecular in vitro techniques to
define immunosuppressive tumor cell populations and determine the transcriptomic and metabolic changes
associated with these cell populations that are amenable to therapeutic targeting.
 Our preliminary findings demonstrate that TGF-beta type II receptor (TGFBR2) signaling induces a
TGFBR2high subset of GSCs that co-opt certain immunosuppressive mechanisms associated with and utilized by
regulatory T cells (Tregs) to exert immunosuppressive behavior. In the F99 phase, we will investigate the
potential for boosting the anti-tumor immune response by targeting this specific subset of TGFBR2-induced
immunosuppressive GSCs endowed with Treg-like capabilities. To do so, we will utilize inducible shRNA
constructs and a clinically translatable small-molecule drug to inhibit TGFBR2 in orthotopic tumor allografts in
immune-competent mice and analyze the effects on tumor growth, immune cell infiltration and function, and
cooperativity with check point inhibitor therapy. In the K00 phase, we will conduct spatially resolved
transcriptomics and metabolomics on patient GBM tissue specimens to identify potential metabolic vulnerabilities
in immunosuppressive GBM cells. Metabolic inhibitors will be utilized to exploit candidate vulnerabilities in an
attempt to attenuate the transcriptomic and functional immune-suppressive characteristics of these cells.
Subsequently, validated metabolic vulnerabilities will be targeted in vivo to assess the effects on tumor growth
and the anti-tumor immune response. Our proposed methods of pharmacological TGFBR2 inhibition and
metabolic exploitation will inform the development of novel strategies to reprogram the GBM microenvironment
and enhance anti-tumor immune responses when combined with ...

## Key facts

- **NIH application ID:** 10909340
- **Project number:** 5F99CA284254-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Amanda Johnson
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 5
- **Project period:** 2023-09-01 → 2025-02-06

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10909340

## Citation

> US National Institutes of Health, RePORTER application 10909340, Dissecting the tumor cell-immune TME axis to identify therapeutically actionable vulnerabilities that potentiate immunotherapy in GBM (5F99CA284254-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10909340. Licensed CC0.

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