Advancing Immunotherapy for Pancreatic Cancer Through Hidden Antigen Discovery

Pancreatic cancer remains one of the most difficult cancers to treat. Most patients are diagnosed with advanced disease, responses to current therapies are limited, and immunotherapies that have transformed the treatment of other cancers have so far shown only modest benefit. A major reason is that pancreatic tumours are immunologically complex and often lack obvious therapeutic targets. This PhD project will use advanced immunopeptidomics and mass spectrometry to uncover hidden antigenic vulnerabilities in pancreatic cancer, with a particular focus on the dark and cryptic immunopeptidome and non-classical HLA molecules such as HLA-E and HLA-G. HLA molecules display short peptides on the surface of cells, allowing the immune system to monitor what is happening inside them. These peptides can provide highly specific targets for cancer vaccines, T-cell receptor therapies and other immune-based treatments. However, conventional approaches focus mainly on peptides derived from well-characterised proteins and classical HLA molecules. This may overlook an important layer of tumour biology. Emerging evidence suggests that cancers can present peptides derived from non-canonical open reading frames, alternative translation events, aberrant transcripts and other regions of the “dark proteome”. At the same time, non-classical HLA molecules may present distinct peptide repertoires and are often less polymorphic than classical HLA molecules, potentially creating opportunities to identify shared therapeutic targets that could be used across many patients. The student will analyse pancreatic cancer tissues, cell models and clinically relevant experimental systems to define these previously underexplored antigen landscapes. Using high-sensitivity mass spectrometry, immunopeptidomics and integrated multi-omics analysis, the project will identify tumour-associated peptides, determine their origin, assess their tumour specificity and prioritise candidates for therapeutic development. A central objective will be to identify antigens that are consistently presented across multiple pancreatic tumours but absent, or present at very low levels, in healthy tissues. Particular attention will be given to peptides presented by HLA-E and HLA-G, because their limited polymorphism could enable the development of off-the-shelf immunotherapies that are applicable to broader groups of patients rather than being restricted to individual HLA types. The project may also investigate how tumour biology, treatment or environmental conditions alter antigen presentation and whether these changes can be exploited therapeutically. Candidate antigens emerging from the discovery phase can then be prioritised for downstream functional validation and development towards cancer vaccines, T-cell-based therapies or other peptide-targeted approaches. What will the student learn? The successful candidate will gain multidisciplinary training spanning cancer immunology, immunopeptidomics, mass spectrometry, molecular biology and translational therapeutics. They will learn how to isolate and analyse HLA-bound peptides, work with advanced mass spectrometry datasets, identify canonical and non-canonical antigens, integrate proteomic and genomic information, and distinguish tumour-specific targets from the normal immunopeptidome. The student will also develop expertise in non-classical HLA biology, including HLA-E and HLA-G, antigen processing and presentation, tumour immune escape, bioinformatics and quantitative data analysis. Depending on the direction of the project, they may also gain experience in cell culture, perturbation experiments, functional immunology and validation of therapeutic targets. A major strength of the project is its translational focus. The student will work with clinically relevant samples and collaborate with researchers in tumour biology, immunology, proteomics and therapeutic development. This provides an opportunity to follow discoveries from patient material through to potential therapeutic targets. The bigger vision is to move beyond the conventional cancer proteome and reveal previously invisible targets in pancreatic cancer. By combining the dark immunopeptidome with non-classical HLA biology, this project aims to identify shared antigenic vulnerabilities that could support the development of next-generation cancer vaccines and broadly applicable off-the-shelf immunotherapies.