# Proj 4: Triggers for the Induction of T Cell Dysfunction on T cells in Glioblastoma

> **NIH NIH P01** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $445,712

## Abstract

PROJECT SUMMARY
Therapies that block co-inhibitory or checkpoint receptors (eg. CTLA-4, PD-1) have realized the potential of the
immune system to successfully fight multiple cancers, including melanoma, lung, and renal cancer.
Unfortunately, patients with glioblastoma (GBM) have not benefitted from these checkpoint blockade therapies.
This likely reflects the fact that the brain is a site of immune privilege; it has set up a state of inherent immune
suppression in order to prevent inflammation that would be detrimental to the host. This immune suppressed
state likely underlies the failure of current immunotherapies in GBM. The lack of response to anti-CTLA-4 and
anti-PD-1 in GBM raises the issue of whether alternative checkpoints are active in the GBM tumor
microenvironment (TME), which need to be identified and exploited to achieve the promise of immunotherapy
for GBM. Moreover, GBM patients routinely undergo treatment with high dose glucocorticoid (GC, eg. Decadron),
a potent immune suppressive agent, prior to surgical resection and during treatment. This raises the important
issue of whether glucocorticoid therapy plays an important role in enhancing the immune suppressed state
present in GBM, which in turn further antagonizes the potential of checkpoint blockade therapy.
We have identified that the immunoregulatory cytokine IL-27 is a key driver of a “co-inhibitory module” of genes
that contains several novel receptors that function as checkpoint receptors. Further, we have identified that both
exogenous as well as endogenous GC can promote the expression of multiple checkpoint receptors and that
GC cooperates with IL-27 to promote expression of the “co-inhibitory module” and expression of gene programs
associated with T cell dysfunction. Based on our preliminary data, we hypothesize that IL-27 and glucocorticoid
signaling act in the GBM TME to promote the expression of checkpoint receptors and set the stage for a dominant
immune suppression. Indeed, interrogation of the single-cell RNA profiles of the immune infiltrate in human GBM
shows significant expression of the IL-27-induced co-inhibitory gene module and signatures indicating active GC
signaling. Achieving a thorough understanding of the IL-27 and glucocorticoid signaling circuits within the GBM
TME will not only provide a means to understand how GBM tumors set a state of immune suppression but also
provide a set of novel targets for improving the immune response to GBM. We propose the following specific
aims: 1) Determine the impact of the IL-27 signaling circuit in the GBM tumor microenvironment and 2) Determine
how glucocorticoid (GC) signaling contributes to checkpoint receptor expression and induction of a state of
immune suppression in GBM.

## Key facts

- **NIH application ID:** 10210223
- **Project number:** 5P01CA236749-02
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** VIJAY K. KUCHROO
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $445,712
- **Award type:** 5
- **Project period:** 2020-07-03 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10210223

## Citation

> US National Institutes of Health, RePORTER application 10210223, Proj 4: Triggers for the Induction of T Cell Dysfunction on T cells in Glioblastoma (5P01CA236749-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10210223. Licensed CC0.

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