# Reorienting the Glioblastoma Microenvironment to Respond to Immunotherapy

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $599,837

## Abstract

Abstract
 Nowhere is the potential for immune system activation to control and potentially eliminate cancer more
acutely needed than in glioblastoma (GBM) patients; successful use of immuno-oncology (IO) drugs to
eliminate GBM would be transformative. Understanding how to influence anti-tumor immunity in GBM as a
function of its unique microenvironment, which includes the uniquely constituted brain extracellular matrix
(ECM) and the blood-brain barrier protection of parenchyma, is critical to success. Equally important is that
patients most often present with critical symptoms that require rapid treatment, usually surgery followed by
radiation therapy, thus presenting a challenge in terms of how addition of IO drugs will intersect with the effects
of prior treatment. Here we hypothesize that transforming growth factor β (TGFβ) is at the root of the
profoundly immunosuppressive tumor microenvironment (TME) of primary GBM. Furthermore, this
immunosuppressive TME is perpetuated by standard of care, radiation therapy. We postulate that high levels
of TGFβ activity affect the cellular composition and biomechanical properties by respectively, increasing the
presence of myeloid derived suppressor cells (MDSC) and inducing a stiff, hyaluronan and tenascin rich ECM
that activates integrins and focal adhesion kinase (FAK). This mechanopathology feeds forward to greater
TGFβ activation, increased stiffness and activated FAK, all of which foster immunosuppressive myeloid cells
that cordon off GBM to prevent T-cell infiltration. Moreover, the response to surgery and RT reinforce this
biology because both induce TGFβ activation that further ‘stiffens’ the recurrent TME. This vicious cycle must
be interrupted to achieve T-cell infiltration and effective immune response in GBM. We propose to use
immune competent murine models that recapitulate key GBM features to investigate how TGFβ mediates
mechanopathology and immune response, provide detailed analysis of TME remodeling as a function of TGFβ
after radiation, and translate these mechanisms into therapeutic strategies to re-orient the immune landscape
for greater response to IO. Our specific aims are to: 1. Test whether blocking TGFβ can disrupt the cycle that
perpetuates immunosuppressive mechanopathology of primary and recurrent GBM and promote response to
radiation and subsequent immunotherapy in intracranial syngeneic mouse models. 2. Evaluate the
correlations among biomechanics, MDSC, T cell activity and ECM composition as a function of treatment and
TGFβ inhibition. 3. Determine the specific mechanisms by which mechanopathology promote GBM
immunosuppression. By applying the discoveries generated from mechanistic preclinical studies, our
translational objective is to reorient the TME from one that is a barrier to effective immunotherapy to one that
aids successful anti-tumor immunity in humans.

## Key facts

- **NIH application ID:** 10093157
- **Project number:** 5R01NS109911-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Mary Helen Barcellos-Hoff
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $599,837
- **Award type:** 5
- **Project period:** 2019-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10093157

## Citation

> US National Institutes of Health, RePORTER application 10093157, Reorienting the Glioblastoma Microenvironment to Respond to Immunotherapy (5R01NS109911-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10093157. Licensed CC0.

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