Abstract
Cutaneous melanoma represents the most aggressive and deadly form of skin cancer. Until just over a decade ago, advanced melanoma carried a dismal prognosis. While immune checkpoint inhibition (ICI) has revolutionised treatment, a majority of patients do not enjoy a sustained response, and toxicity is unpredictable and problematic. It is clear that an unmet need for biomarkers of response and toxicity to ICI exists. The gut microbiome (GM) has been shown to be an important factor in relation to response to ICI for melanoma and a number of other malignancies.This is primarily a microbiome PhD which aims to validate previous studies suggesting that the GM serves as a biomarker of therapeutic response, along with examining the impact of habitual diet and the proteomic and glycomic environments during treatment with ICI. Through metagenomic sequencing and a machine learning approach, this work explores the GM, and its associations with ICI responses and toxicity in a large, international, multi-centre cohort (n=165) and integrates this dataset with 147 metagenomic samples from published publicly-available datasets. Next, it examine both a-priori and a-posteriori high resolution dietary data, individual foods and nutrients in relation to ICI outcomes for 91 patients who prospectively provided dietary data. Additionally, serum samples from these patients are leveraged to investigate the relationship between pre- and on-treatment circulating inflammatory proteins and clinical endpoints of response to ICI in 87 patients with advanced melanoma. Also included is an analysis of pre-treatment and longitudinally collected total serum N-glycomics profiles derived from these serum samples.
Within the metagenomic analysis, a panel of species, including Bifidobacterium pseudocatenulatum, Roseburia spp. and Akkermansia muciniphila was associated with responders, but no single species could be regarded as a fully consistent biomarker across cohorts. Habitual diet affects response to ICI in a number of ways, most notably in that consumption of a Mediterranean style diet was associated with improved response parameters within this cohort; however, when integrated into the metagenomic analyses (for a limited proportion of patients) diet was not seen to have an effect. Proteomic analyses demonstrated that pre-treatment circulating IL-6, HGF, and MCP-2 levels were negatively associated with response. The glycomic analyses suggest that an increased relative abundance of highly branched trisialylated N-glycans is observed in non-responders.
The findings within this thesis confirm that the role of the GM in ICI response is more complex than previously considered and extends beyond differing microbial species simply present or absent in responders and non-responders, potentially requiring a multi-omic approach to identify more powerful markers of response. Given the intrinsic link between the GM and diet, the association found to exist between the Mediterranean diet, a diet universally felt to be amongst the healthiest in the world, and response, is hypothesis-generating and potentially clinically important. The proteomic and glycomic analyses contained within this thesis demonstrate associations between pre-treatment circulating serums markers and response and require further replication and validation in larger and more diverse cohorts, as well as integration into multi-omic GM studies.
| Date of Award | 1 Nov 2023 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Veronique Bataille (Supervisor), Paul Nathan (Supervisor) & Tim Spector (Supervisor) |