# Aberrant activation of epidermal growth factor receptor signaling drives programming of an immunosuppressive brain tumor microenvironment in glioblastoma

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $44,670

## Abstract

PROJECT SUMMARY/ABSTRACT
Glioblastoma (GBM) is the most common primary malignant brain tumor with a dismal prognosis that lacks
effective therapeutic strategies. While the advent of immunotherapy has significantly improved patient outcomes
in a variety of extracranial cancers, these novel approaches have achieved limited success in GBM. The goal of
this study is to investigate mechanisms underlying brain microenvironment-specific suppression of effective anti-
tumor immunity mediated by aberrant epidermal growth factor receptor (EGFR) signaling, and furthermore
whether targeting this oncogene creates novel vulnerabilities to enhance immune response in this deadly
disease. Extensive preliminary data, which leverages a highly innovative EGFR activated immunocompetent
murine glioma model (MADR-mEGFRvIII), indicate tumor-intrinsic EGFR signaling impairs intratumoral T cell
infiltration and promotes the development of a tumor microenvironment (TME) enriched in microglia, a myeloid
cell type unique to the brain. Moreover, preliminary data demonstrate an association between EGFR activation
and an immunosuppressive wound healing signature linked with poor prognosis in the myeloid compartment of
immune cells isolated from newly diagnosed GBM patient tumors. Specific Aim 1 utilizes a transgenic T cell
system engineered to be antigen-specific in conjunction with multiple modalities of in vivo EGFR ablation to
determine the precise impact of aberrant EGFR signaling and tumor-programmed myeloid cells on T cell
cytotoxic function, clonal proliferation, and exhaustion. Through the incorporation of functional and phenotypic
assays designed to isolate the contributions of each factor in the complex brain immune TME, this approach is
expected to provide novel insight into the role of EGFR activation in dysregulating effector T cell responses.
Specific Aim 2 endeavors to elucidate the axis by which aberrant EGFR signaling promotes a distinct
immunosuppressive microglia phenotype characterized by VEGF and IL-1β in the brain TME with an emphasis
on EGFR-mediated tumor-microglia crosstalk. Using in vitro co-culture approaches and in vivo knockdown
strategies, the precise impact of EGFR activation in coordination with microglia IL-1β signaling on tumor-
associated microglia phenotype and overall anti-tumor immune response will be assessed. Specific Aim 3
focuses on assessing rational combinatorial strategies targeting EGFR using ERAS-801, a novel clinical stage
small molecule inhibitor, to drive enhanced T cell infiltration followed by immune checkpoint blockade to support
prolonged T cell function within the TME. Overall, this project will provide the first comprehensive assessment of
the mechanistic underpinnings and functional consequences of aberrant EGFR activation on the myeloid-
dominant tumor immune microenvironment and the resultant impact on anti-tumor immune response in GBM.
By identifying the dynamics of interplay between oncogenic EGFR signaling and immune...

## Key facts

- **NIH application ID:** 10998458
- **Project number:** 1F31CA294887-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Marissa S Pioso
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $44,670
- **Award type:** 1
- **Project period:** 2024-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10998458

## Citation

> US National Institutes of Health, RePORTER application 10998458, Aberrant activation of epidermal growth factor receptor signaling drives programming of an immunosuppressive brain tumor microenvironment in glioblastoma (1F31CA294887-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10998458. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*