# AHR-mediated immunosuppression in glioblastoma

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $482,198

## Abstract

PROJECT SUMMARY
Tumor-associated macrophages (TAMs) play an important role in the immune response to cancer, but the
mechanisms that control TAMs and T-cell immunity are not completely understood. Glioblastoma (GBM) is the
most common primary brain tumor in adults, with a median survival of ~15 months despite aggressive
treatment. TAMs constitute more than 30% of infiltrating cells in GBM. Consequently, targeting immune
checkpoints in TAMs is considered a promising immunotherapeutic approach for GBM and other tumors. Our
data indicate that kynurenine (Kyn) produced by glioma cells controls TAMs and T-cell immunity through the
ligand-activated transcription factor aryl hydrocarbon receptor (AHR). Our data demonstrate that: 1) the
expression of AHR and AHR-driven genes is upregulated in TAMs in GBM patients and experimental models,
and is significantly linked to patient survival; 2) AHR deletion in TAMs significantly decreases tumor growth in
experimental GBM; 3) AHR activation by Kyn induces the expression of the transcription factor Krüppel-like
factor 4 (KLF4) and controls TAM function; 4) AHR also drives the expression of CD39 in TAMs, an
ectonucleotidase that promotes the generation of the immunosuppressive metabolite adenosine; 5) CD39
deletion in TAMs ameliorates tumor infiltrating T-lymphocyte (TIL) dysfunction in GBM; 6) A new brain-
penetrant AHR antagonist and candidate immune checkpoint inhibitor suppresses growth of several tumors
including GBM. Based on these findings, we view AHR in TAMs as a master regulator that responds to
oncometabolites (e.g., Kyn) to suppress GBM-specific immunity. Therefore, we hypothesize that AHR in TAMs
limits tumor-specific immunity and is a potential immunotherapeutic target for GBM. Our specific aims are:!
SPECIFIC AIM 1: Define the role of AHR in the transcriptional control of TAMs. We propose to: 1)
Determine if AHR controls TAM polarization via modulation of KLF4 and NF-kB signaling, and 2) Define the
transcriptional programs controlled by AHR in TAMs using whole population and single cell approaches.
SPECIFIC AIM 2: Study the control of TILs by AHR-driven CD39 expression in TAMs.
We propose to: 1) Define the effects of AHR-induced CD39 in TAMs on GBM-specific T cells, 2) Determine if
the AHR/CD39 axis controls TILs via adenosine generation, and 2) Dissect the relative contribution of AHR
and CD39 in microglia- and peripheral macrophage-derived TAMs to GBM pathology.
SPECIFIC AIM 3: Evaluate the therapeutic value of targeting AHR in a GBM preclinical model.
We propose to: 1) Study the effects of AHR inhibition on GBM TAMs, 2) Analyze the effects of AHR inhibition
on tumor-specific regulatory and effector T cells, and 3) Evaluate the effects of an AHR inhibitor on the immune
system in the absence of a direct effect on glioma tumor cells.
IN SUMMARY, this project uses unique experimental systems to study a novel pathway that regulates TAMs
and T cells in GBM and is a potential therapeutic target for thi...

## Key facts

- **NIH application ID:** 9997937
- **Project number:** 5R01ES029136-02
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Francisco J. Quintana
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $482,198
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9997937

## Citation

> US National Institutes of Health, RePORTER application 9997937, AHR-mediated immunosuppression in glioblastoma (5R01ES029136-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9997937. Licensed CC0.

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