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Published on: November 28, 2019
Aryl Hydrocarbon Receptor Signaling Controls CD155 Expression on Macrophages and Mediates Tumor Immunosuppression
Zachary P McKay1, Michael C Brown1, Matthias Gromeier2
1Department of Neurosurgery, Duke University Medical School, Durham, NC 27710.
Abstract:
Crosstalk between costimulatory and coinhibitory ligands are a prominent node of immune cell regulation. Mounting evidence points toward a critical role for CD155, the poliovirus receptor, in suppressing T cell function, particularly in cancer. However, relative to other known costimulatory/coinhibitory ligands (e.g., CD86, CD80, PD-L1), the physiological functions of CD155 and the mechanisms controlling its expression remain unclear. We discovered that CD155 expression is coregulated with PD-L1 on tumor-associated macrophages, is transcriptionally regulated by persistently active aryl hydrocarbon receptor (AhR), and can be targeted for suppression via AhR inhibition in vivo. Therapeutic inhibition of AhR reversed tumor immunosuppression in an immune competent murine tumor model, and markers of AhR activity were highly correlated with tumor-associated macrophage markers in human glioblastomas. Thus, CD155 functions within a broader, AhR-controlled macrophage activation phenotype that can be targeted to reverse tumor immunosuppression.
Insights
CD155, a T cell suppressor, is regulated by the aryl hydrocarbon receptor (AhR) on macrophages. Inhibiting AhR reversed tumor immunosuppression in mice, suggesting a new therapeutic target for cancer.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Biology
Background:
- Immune cell regulation involves costimulatory and coinhibitory ligands.
- CD155 (poliovirus receptor) is implicated in T cell suppression, especially in cancer.
- Mechanisms controlling CD155 expression and its precise functions are not fully understood.
Purpose of the Study:
- To elucidate the regulatory mechanisms of CD155 expression.
- To investigate the role of CD155 in tumor immunosuppression.
- To explore therapeutic strategies targeting CD155 regulation.
Main Methods:
- Analysis of CD155 and PD-L1 coregulation on tumor-associated macrophages.
- Investigating transcriptional regulation of CD155 by the aryl hydrocarbon receptor (AhR).
- In vivo studies using AhR inhibition in a murine tumor model.
- Correlation analysis of AhR activity and macrophage markers in human glioblastomas.
Main Results:
- CD155 expression is coregulated with PD-L1 on tumor-associated macrophages.
- CD155 expression is transcriptionally controlled by persistently active AhR.
- AhR inhibition in vivo reversed tumor immunosuppression in a murine model.
- AhR activity markers correlated with tumor-associated macrophage markers in human glioblastomas.
Conclusions:
- CD155 is part of a broader AhR-controlled macrophage activation phenotype.
- Targeting AhR can reverse tumor-induced immunosuppression.
- CD155 and AhR represent potential therapeutic targets in cancer immunotherapy.
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