Using primary tumour transcriptomes to better understand immune responses to melanoma

Strong immune responses to melanoma predict improved survival and better responses to immunotherapies. However the host-tumour interactions are not yet fully elucidated, especially for early stage tumours and increasing understanding of this interaction was the aim of this thesis. The analyses were carried out using 703 primary melanoma transcriptomes generated from the Leeds Melanoma Cohort (LMC), detailed clinico-histopathological, and additional genomic data. Bioinformatics was applied to infer the immune environment within the tumours. Using a modified “Immunome Compendium” developed by Angelova et al. [1], consensus clustering was applied to identify three immune subgroups: low, intermediate and high, associated with survival. Differentially expressed genes between the immune subgroups in the LMC were identified and analysed in the context of networks and pathways using Reactome FIViz. The oncogene MYC was identified as a nodal gene for the Low and NFKB1 for the High Immune Subgroup. The expression of both genes showed significant association with protein scores from immunohistochemistry and with copy number alterations. The genes from NF-kB and IFN-g pathways were more frequently deleted and MYC was amplified in the Low Immune Subgroup. These observations were considered as immune evasion mechanisms in primary melanoma. Furthermore, it was observed that MYC expression was negatively correlated with many antigen processing and presentation genes (HLA-B , HLA-C, B2M, TAP1 and ERAP1) in the LMC and patient-derived melanoma cell lines and with HLA-B at a protein level in the LMC. My hypothesis was that MYC drives immunosuppression at least in part by reducing antigen presentation by the histocompatibility complex. Finally, it was demonstrated that smoking was detrimental for melanoma specific survival overall, with the strongest effect for patients with tumours classified in the High Immune Subgroup suggesting a specific effect on tumour progression and it is a clear demonstration of an environmental modifier of survival.