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Cancer immunoediting and dioxin-activating aryl hydrocarbon receptor: a missing link in the shift toward tumor immunoescape?

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Author(s): Ruggero Ridolfi | Massimo Guidoboni | Laura Ridolfi

Journal: Journal of Nucleic Acids Investigation
ISSN 2036-7996

Volume: 1;
Issue: 1;
Start page: e6;
Date: 2010;
Original page

Keywords: Dioxin | Cancer immunoediting | Tumor immunoescape | Aryl hydrocarbon receptor (AhR) | T reg lymphocytes

ABSTRACT
The aryl hydrocarbon receptor (AhR), a member of the PAS protein family, is found in organisms as diverse as Drosophila melano­gaster, nematodes, and mammals. While several reviews have reported that AhR, once activated by agonist ligands, causes long-term effects such as modification of cell growth through cell cycle control, there is also recent evidence of its decisive role in immunosuppression. The most widely studied AhR agonist is 2,3,7,8-tetrachlorodibenzo-p-dioxin, which binds AhR with the highest known affinity, leading to profound suppression of both humoral and cellular immune responses, with praecox thymus involution, consequent thymocyte loss, and induction of T-cell apoptosis. Dioxin-AhR binding causes a decline in the number of dendritic cells and enhances apoptosis following their inappropriate activation. Dioxin-mediated activation of AhR also has a direct influence on the expansion of regula­tory T-cells CD4+CD25+ FoxP3+ (T-regs) and an adverse affect on CD8+ T-cell responses. Dioxin released from industrial and waste incinerators over the last few decades has caused widespread contamination of food, leading to its accumulation in fatty tissue in animals and humans. The elimination half-life of dioxin in humans (7-10 years) may favor the potentially continuous and long-lasting activation of AhR, leading to perpetual immune suppression and facilitating the onset, growth, and diffusion of tumors, especially in young people. In the cancer immunoediting hypoth­esis, which subdivides the relationship between tumor and immune system into three phases: elimination, equilibrium, and escape, it is thought that dioxin accumulation may cause an inevitable shift toward tumor escape.
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