Arming the Immune System Against Childhood Sarcoma

Childhood sarcomas are aggressive cancers of bone and soft tissue. While many children initially respond to surgery and chemotherapy, tumour cells can survive treatment, remain clinically undetectable and later re-emerge as recurrent or metastatic disease. Once sarcoma has relapsed or spread to distant organs, treatment becomes substantially more difficult. This PhD project is built around an ambitious idea: can we teach the immune system to recognise childhood sarcoma so that it continues to protect a child after their initial treatment has finished? The goal is not simply to develop another treatment for established tumours. We aim to discover tumour antigens that could be used to generate durable immune surveillance—allowing the immune system to recognise and eliminate residual cancer cells before they can establish a relapse or metastatic tumour. Using advanced immunopeptidomics and high-resolution mass spectrometry, the student will map the peptides displayed on childhood sarcoma cells and search for antigenic vulnerabilities that distinguish tumour cells from healthy tissues. A major focus will be the dark and cryptic immunopeptidome. Childhood sarcomas frequently have relatively few conventional mutations, but their unusual biology—including oncogenic fusion proteins, abnormal transcription and alternative translation—may generate an entirely different class of tumour-specific antigens. These can include peptides derived from fusion-associated sequences, non-canonical open reading frames, alternative translation products and other poorly characterised regions of the proteome. The project will also explore non-classical HLA molecules, including HLA-E and HLA-G. Their relatively limited genetic diversity creates an exciting opportunity to identify antigens shared across many patients and potentially develop broadly applicable, off-the-shelf immunotherapies. The student will investigate clinically relevant models and patient-derived samples from sarcomas including Ewing sarcoma and osteosarcoma. Wherever possible, the antigen landscape of primary tumours will be compared with treatment-resistant, relapsed and metastatic disease. This will allow us to identify targets that remain present in the tumour cells most likely to survive therapy and seed future disease. Immunopeptidomics will be integrated with genomics, transcriptomics, proteomics and other multi-omics technologies to understand where these antigens originate and why they are presented. Candidate targets will be prioritised according to tumour specificity, abundance, recurrence across patients, persistence during disease progression and therapeutic potential. The strongest candidates could ultimately be developed into cancer vaccines, T-cell receptor therapies or other peptide-directed immunotherapies. A particularly exciting possibility is vaccination following initial treatment, when tumour burden is minimal, to establish long-lasting T-cell memory capable of detecting residual or re-emerging cancer cells. What will the student learn? The successful candidate will train at the intersection of cancer immunology, immunopeptidomics, mass spectrometry and translational therapy development. They will learn how to isolate HLA-bound peptides, generate and analyse high-resolution mass spectrometry data, integrate immunopeptidomics with multi-omics datasets and identify tumour-specific antigens. The student will develop expertise in sarcoma biology, immune memory, antigen processing and presentation, fusion-driven cancers, non-canonical translation, dark-proteome biology, HLA-E and HLA-G, and therapeutic antigen prioritisation. Training may also extend to targeted mass spectrometry, tumour models and functional immune assays. A defining feature of this research program is its partnership with the childhood sarcoma community. We work closely with clinicians, patient advocates and families, including families who have lost children to these cancers. Their experiences help shape the research questions we pursue and constantly remind us why preventing recurrence is so important. The broader vision is to shift childhood sarcoma treatment from eliminating the tumour we can see to protecting against the tumour we cannot see. By discovering antigens shared by residual, recurrent and metastatic cancer cells, we aim to develop immunotherapies that establish long-term immune surveillance—so that after treatment, the immune system itself can help prevent the cancer from ever returning.