Hames-Fathi, Shadi; (2023) The Immunogenomic Landscape of Soft Tissue Sarcoma. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Cancer is a multifaceted disease influenced by various factors, including genomic alterations and methylation changes, and cancer progression is heavily impacted by the tumour microenvironment (TME). In this study, these metrics were analysed to gain a deeper understanding of their dynamic interplay in soft tissue sarcomas (STS). By examining the selective forces exerted by the immune system, this work aimed to uncover associations with different immune responses, and establish potential biomarkers for treatment stratification. This line of research holds promise in unmasking key factors influencing immune recognition and evasion. A comprehensive approach was used, integrating genomic, transcriptomic, methylation, and immunohistochemistry data. Firstly, to gain further insights into the TME, RNA-seq data was used to quantify immune infiltration. This allowed for a TME stratification system to be established, enabling these samples to be grouped based on whether the TME phenotype was immunologically “hot” or “cold”. GSEA analyses of these groups showed a number of different pathways enriched in both categories. Next, genomic mechanisms of immune evasion were considered. This included an exploration of HLA loss-of-heterozygosity (LOH), which has previously been implicated in other cancer types. HLA LOH was frequent in the STS cohorts but was not found to be specific to a TME group. Finally, the impact of methylation changes on the immune response was evaluated. A regression model identified numerous CpG probes in the promoter region of genes of interest which were frequently methylated. This included probes in the promoter region of genes important to the immune response, such as B2M, highlighting the importance of methylation as a possible immune evasion mechanism. Overall, this thesis sheds light on the intricate relationship between tumours and the immune system, providing insights into immune recognition, evasion mechanisms, and how this may aid in the development of effective immunotherapy stratification strategies.

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