Antigen Frontiers in Childhood Brain Cancer

Childhood brain cancers are among the most devastating paediatric malignancies. For several aggressive tumour types, including diffuse midline glioma, treatment options remain extremely limited and survival has changed little for decades. One of the major challenges is that these tumours are often poorly recognised by the immune system and lack obvious targets for immunotherapy. This PhD project asks a fundamental question: what if some of the best immune targets in childhood brain cancer are hidden in parts of the proteome that conventional approaches fail to see? The project will use advanced immunopeptidomics and high-resolution mass spectrometry to decode the repertoire of peptides displayed on the surface of childhood brain tumour cells. Rather than focusing only on conventional tumour antigens, the student will explore the dark and cryptic immunopeptidome, including peptides generated from non-canonical open reading frames, alternative translation events, aberrant transcripts and other poorly characterised regions of the genome and proteome. A second major focus will be non-classical HLA molecules, particularly HLA-E and HLA-G. Unlike highly polymorphic classical HLA molecules, these molecules are relatively conserved across the population and may provide opportunities to identify shared tumour targets that could support the development of off-the-shelf immunotherapies applicable to larger groups of patients. The student will work with clinically relevant childhood brain tumour models and patient-derived samples and integrate immunopeptidomics with genomics, transcriptomics, proteomics and ribosome profiling. The aim will be to determine where tumour-associated peptides originate, how consistently they are presented across different tumours, and which candidates are absent or strongly depleted in healthy tissues. The project will also investigate how the antigenic landscape changes in response to treatment. Radiation, epigenetic therapies and other targeted interventions can alter HLA expression, antigen processing and peptide presentation. By mapping these changes, the student will test whether existing therapies can be used to expose previously hidden antigens and create rational combinations with immunotherapy. The most promising targets will be prioritised according to tumour specificity, abundance, recurrence across patients and therapeutic potential. Selected candidates may then progress to targeted mass spectrometry and functional validation, with the longer-term goal of supporting the development of cancer vaccines, T-cell receptor therapies and other peptide-directed immunotherapies. What will the student learn? The successful candidate will receive multidisciplinary training across cancer immunology, immunopeptidomics, mass spectrometry and translational oncology. They will learn how to isolate HLA-bound peptides, generate and interpret high-resolution mass spectrometry data, analyse complex immunopeptidomics datasets and integrate these data with genomic, transcriptomic and proteomic information. The student will also develop expertise in antigen processing and presentation, dark-proteome biology, non-canonical translation, HLA-E and HLA-G biology, tumour antigen prioritisation and experimental models of childhood brain cancer. Depending on the direction of the project, training may also include targeted mass spectrometry, treatment perturbation experiments and functional immune assays. A unique aspect of this project is its close connection with the childhood brain cancer community. Our research is conducted in partnership with clinicians, patient advocates and families, including families who have lost children to these devastating cancers. Their experiences and perspectives help shape our research priorities and keep the project focused on questions with the greatest potential to make a meaningful difference for future patients. The student will therefore work in an environment where fundamental discovery, technology development and clinical translation are closely connected to the people affected by the disease. The bigger vision is to build a new map of the antigenic vulnerabilities of childhood brain cancer. By identifying targets that are invisible to conventional approaches, understanding how they can be exposed therapeutically, and translating these discoveries towards vaccines and T-cell therapies, this project aims to open new treatment opportunities for children with currently incurable brain tumours.