A Window into Disease: Soluble HLA Immunopeptidomics for Biomarker Discovery

Blood contains a remarkable amount of information about what is happening throughout the body. Yet most current liquid-biopsy approaches focus on DNA, RNA or circulating proteins and miss one of the most direct readouts of immune recognition: the peptides carried by soluble Human Leukocyte Antigen (HLA) molecules. This PhD project will develop and apply soluble HLA immunopeptidomics as a new way to read disease-associated antigen presentation directly from blood. HLA molecules normally display short peptides on the surface of cells, allowing the immune system to monitor intracellular biology. A proportion of HLA molecules and HLA-associated peptides can also be detected in circulation. These circulating complexes may provide a dynamic snapshot of antigen presentation occurring across tissues and tumours, creating an opportunity to discover disease-associated antigens without requiring an invasive biopsy. The project will combine advanced immunopeptidomics, high-resolution mass spectrometry and bioinformatics to characterise soluble HLA peptide repertoires in blood and other body fluids. The student will investigate how these repertoires change in cancer and immune-mediated disease, and whether specific peptides can be used as biomarkers of disease presence, treatment response or biological activity. A major goal will be to move beyond conventional plasma proteomics. Rather than simply measuring which proteins are abundant in blood, soluble HLA immunopeptidomics asks a different question: which peptides are being actively selected and presented to the immune system? This may reveal biological signals that are invisible to standard proteomic or genomic approaches. The student will investigate both classical and, where feasible, non-classical HLA molecules and explore disease-associated peptides arising from canonical proteins, cryptic translation products and other components of the dark proteome. These datasets may also reveal antigens with potential relevance to immunotherapy. The project will involve optimisation of sample preparation, HLA isolation, mass spectrometry acquisition and computational analysis for low-abundance circulating HLA peptides. The student will work with clinical cohorts and integrate soluble HLA data with proteomics, genomics, transcriptomics and clinical information to identify reproducible disease-associated signatures. An important direction will be determining whether soluble HLA immunopeptidomics can be used longitudinally. If changes in circulating peptide presentation track disease progression or treatment response, the approach could ultimately become a powerful tool for minimally invasive patient monitoring. What will the student learn? The successful candidate will receive training across immunopeptidomics, mass spectrometry, proteomics, bioinformatics and translational biomarker research. They will learn how to isolate HLA-associated peptides from complex biological fluids, optimise low-input workflows, acquire and interpret high-resolution mass spectrometry data, and analyse large immunopeptidomic datasets. The student will also develop expertise in antigen processing and presentation, liquid biopsy technologies, biomarker discovery, quantitative proteomics, data integration and experimental design using clinical samples. Depending on the direction of the project, they may also gain experience in targeted mass spectrometry, longitudinal clinical studies, non-classical HLA biology and machine-learning approaches for biomarker classification. A major strength of this project is its translational potential. Blood sampling is minimally invasive and can be repeated over time, creating opportunities that tissue biopsy cannot easily provide. The bigger vision is to establish soluble HLA immunopeptidomics as a new generation of liquid biopsy—one that does not simply detect disease-associated molecules, but directly measures the antigens being presented to the immune system. By learning to read this hidden layer of information in blood, the project aims to open new possibilities for disease detection, patient monitoring, biomarker discovery and precision immunotherapy.