Background and research hypothesis.
Sex differences in liver cancer incidence and outcomes are well recognised, yet the underlying immunogenetic mechanisms remain poorly understood. Protective effects of sex hormones (particularly estrogen) have been observed in certain liver diseases, and it is well established that immune responses differ significantly between males and females. Recent research has further highlighted the potential importance of sex genetics in shaping immunity and thus tumour development. Nevertheless, these mechanisms have never been investigated in liver cancers, despite the hypothesis of contributing roles being reasonable and supported from other disease contexts.
Project overview.
The overarching aim of the project is to investigate how sex-linked genes regulate immune cell function and anti-tumour immunity, and to clarify their role in the well-established sex disparities observed in liver cancers. Insights from this work may help to inform the development of sex-specific biomarkers and therapeutic strategies, potentially improving patient stratification and outcomes. By including predisposing liver conditions (such as fibrosis and cirrhosis) the project will also explore hypotheses concerning sex-specific early detection and surveillance.
Techniques and skills.
The student will gain expertise in cutting-edge techniques, including digital PCR, RNA sequencing, flow cytometry, multiplex assays (Luminex, MSD), gene editing tools, as well as advanced bioinformatics and statistics for data analysis. Training in immunophenotyping, cell culture, and in vitro functional assays will also be provided, alongside opportunities to work with clinical samples and collaborate with translational research teams.
PhD project objectives.
• Year 1 (including a potential 3-month rotation project): Characterise the expression patterns of sex-linked genes in immune cells from healthy/diseased liver tissue and peripheral blood, using publicly available datasets. Additionally, generate and interrogate a new RNA-seq immune cell dataset focussed on our specific sample cohorts, and conduct initial laboratory-based validations.
• Years 2-3: Investigate how these genes influence immune cell phenotypes and functions in vitro, employing optimised staining protocols, functional assays, and – where appropriate – gene editing tools. Extend immunogenetic characterisations to conditions predisposing to liver cancers (fibrosis, cirrhosis, primary sclerosing cholangitis) to gain relevant experimental controls and explore possibilities for early detection. Identify in vitro liver cancer models to study tumour-immune interactions and assess in vitro immunotherapy.
• Year 4: Explore the impact of candidate genes on liver cells and immune cell-tumour interactions in liver cancer models. Assess possible associations with in vitro and clinical outcomes of immunotherapy. Integrate findings to identify potential biomarkers or therapeutic targets, perhaps validating key results in patient cohorts.