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 Krppel-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 this aggressive and currently incurable disease.
Tumor-associated macrophages (TAMs) control the immune response to cancer, but the mechanisms that regulate TAMs are not completely understood. We found that the transcription factor aryl hydrocarbon receptor (AHR) in TAMs suppresses tumor-specific immunity in glioblastoma multiforme, the most common primary brain tumor in adults with a median survival of around 15 months despite aggressive treatment. In this project, we propose to study the role of AHR in TAMs on GBM pathogenesis and its potential as a therapeutic target for GBM and other tumors.
