The Aryl Hydrocarbon Receptor and Tumor Immunity

Abstract

The aryl hydrocarbon receptor (AhR) is an important cytosolic, ligand-dependent transcription factor. Emerging evidence suggests the promoting role of the AhR in the initiation, promotion, progression, invasion, and metastasis of cancer cells. Studies on various tumor types and tumor cell lines have shown high AhR expression, suggesting that AhR is activated constitutively in tumors and facilitates their growth. Interestingly, immune evasion has been recognized as an emerging hallmark feature of cancer. A connection between the AhR and immune system has been recognized, which has been suggested as an immunosuppressive effector on different types of immune cells. Certain cancers can escape immune recognition via AhR signaling pathways. This review discusses the role of the AhR in tumor immunity and its potential mechanism of action in the tumor microenvironment.

Keywords: aryl hydrocarbon receptor; cancer immunotherapy; immune surveillance; tumor development; tumor immunity.

Figure 1

Functional structure of the aryl hydrocarbon receptor (AhR). The functional structure of the AhR protein consists of three parts: the basic helix–loop–helix (bHLH) motifs, the Per-ARNT-Sim (PAS) domains, and a Q-rich domain. bHLH motifs are involved in the activity of aryl hydrocarbon response elements (AHREs) binding and AhR nuclear translocator (ARNT) binding. PAS domains are required for ARNT binding and ligand binding. Transcriptional activation can be observed in Q-rich domain.

Figure 2

Mechanism of activation of the aryl hydrocarbon receptor (AhR). The AhR is abundantly expressed in lung, liver, and brain. It can be activated in many cell types, including epithelial cell, microglia, macrophage, B cell, T cell, etc. Without a ligand, AhR is inactivated in the cytoplasm as a part of a complex with heat shock protein (HSP)90, AhR-interacting protein (AIP), and p23. After binding with an exo/endogenous ligand, the AhR will be activated and translocates to the nucleus to interact with AhR nuclear translocator (ARNT) and simultaneously detaches from the complex. The AhR/ARNT heterodimer finally binds to the dioxin-response elements (DREs), which is called the promoter region of target genes [classical target genes include cytochrome P450 (Cyp)1a1, Cyp1a2, Cyp1b1, and AHRR], to promote transcriptional activation.

Figure 3

Aryl hydrocarbon receptor (AhR) in tumor environment. Abnormal expression of AhR in tumor environment affects both the immune cells and tumor cells in tumor environment. The AhR plays an important role in various stages of tumorigenesis, including cell proliferation, tissue invasion, angiogenesis, tumor-associated inflammation, metastasis etc., suggesting AhR as a promoter for tumor initiation. It can also suppress proliferation and function of immune cells thus suppressing tumor immune responses.