The role of the AhR in melanoma

Thesis

For a malignant tumour to develop, progress, and metastasise, cancerous cells, generally, must dedifferentiate to acquire more phenotypic plasticity. Cancer cells must also evade detection by the immune system, which recognises mutated proteins from within and on the surface of oncogenically transforming cells, to not be eliminated. Understanding the mechanisms through which a developing tumour can lose phenotypic identity whilst suppressing recognition and elimination by the immune system is essential to developing more effective cancer therapies. Melanoma is a highly immunogenic cancer type, with a high mutational burden that enhances the antigenicity of the tumour, meaning that it must develop robust immunosuppressive mechanisms to survive. The Aryl Hydrocarbon Receptor (AhR) is a ligand-activated transcription factor that acts as a sensor of endogenous and exogenous molecules known to have a pro-oncogenic role in melanoma in establishing an immunosuppressive tumour microenvironment (TME). The AhR is an unambiguous modulator of immunosuppression in the TME in some cancers, although the mechanism through which it acts is unclear, as current in vivo and in vitro studies do not align. I demonstrate the unliganded AhR mediates immunosuppression in melanoma through suppression of pro-tumorigenic interferon gamma signalling. Melanomas are tumours derived from melanocytes: neural-crest cell derivatives whose cell lineage is defined through the expression and activity of the microphthalmia-associated transcription factor (MITF). Loss of MITF expression is a known driver of dedifferentiation, invasion, and metastasis in melanoma. The mechanisms underlying loss of MITF expression are both essential to tumour progression and poorly characterised. Herein, I describe the role of the AhR as antagonistic of MITF-mediated transcription and a facilitator of dedifferentiation and metastasis of melanoma cells. My work demonstrates the AhR potentially mediates immunosuppression in melanoma via oncogenic STAT1 signalling and contributing to phenotypic plasticity through antagonism of MITF activity, together highlighting mechanisms whereby the AhR could be central to tumour survival and growth.

Authors: Featherstone, OPL

• DOI: 10.5287/ora-5zgx1eg4k
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: AhR; IFNg; melanoma; IDO1; cancer; interferon gamma; phenotype switching; Aryl Hydrocarbon Receptor; tryptophan metabolism; MITF; immunosuppression; FICZ; kynurenine
• Subjects: Clinical biochemistry; Melanoma; Biochemistry; Oncology