| dc.description.abstract | Actinic Keratosis (AK) is a highly prevalent skin condition, caused by UV-induced DNA damage to keratinocytes. In <1% of cases, it may progress to cutaneous squamous cell carcinoma (cuSCC) which is liable to metastasis. At present, there is no way to predict which AK lesions will become cancerous, thus treatment is widely given, at a significant cost. Both AK and cuSCC exhibit high mutational burdens and dysregulated epigenomes, hallmarks of cancer. However, immune suppressed individuals are 60-200 times more likely to develop AK and cuSCC, and immune-modulating therapies have efficacy in treating both AK and cuSCC, implying that the immune system plays an important role in protecting against cuSCC. Existing data suggests that anti-tumour immune cells are present in cuSCC lesions, but are rendered ineffective by exhaustion, while cytotoxicity is repressed by regulatory immune cells, and potentially pro-tumorigenic immune responses are activated. However, very little is known about the state of the immune system in AK. To investigate this, samples of AK, cuSCC, a second pre-cancerous skin condition Bowen’s disease (BD), and lesion-adjacent skin underwent single cell transcriptomic sequencing. This revealed the expansion of exhausted cytotoxic cells in cuSCC compared to AK and BD, which correlated with an expansion of regulatory T cells and dendritic cells with an immunoregulatory phenotype. This was confirmed in flow cytometry analysis using a specifically developed 30-colour immunophenotyping panel. A large bulk transcriptomic dataset has been generated to further test these findings. Additionally, a novel immune-competent 3D human skin equivalent model was developed by incorporating primary human monocytes and monocyte-derived cells into the dermis of a well-established human skin model. This work forms the foundation for a more comprehensive skin immunology model containing a diverse community of immune cells with wide ranging applications, including the study of the immune microenvironment in AK and cuSCC. | en_US |
