Evolutionary dynamics of radiotherapy resistance in head and neck cancer

Head and neck squamous cell carcinoma (HNSCC) is a debilitating disease responsible for 450,000 deaths a year, disproportionately affecting socially disadvantaged groups globally. Radiotherapy is given with curative intent, but cancer recurs in over 50% of patients. Recurrence is often within the irradiated area, after which most patients will die within a year. The mechanisms driving this intrinsic radiotherapy resistance are not understood. HNSCC demonstrates substantial genomic instability, with widespread aneuploidy and somatic copy number aberrations. Paradoxically, despite the established link between acute genome damage and the inflammatory response, the most aneuploid HNSCCs demonstrate immune deplete microenvironments, suggesting co-evolution of tumour genomic instability and immune escape. With recent data supporting an important role for the immune system in tumour response to radiotherapy, I hypothesise that the co-evolution of genomic instability and immune escape in HNSCC results in an impaired immune response to radiotherapy, ultimately leading to radiotherapy treatment failure. I will perform an evolutionary analysis incorporating genomics, immunogenomics and the tumour microenvironment using a large, unique, disease-defining cohort of longitudinal patient HNSCC samples from before radiotherapy and after local recurrence within the irradiated area. I aim to identify the mechanisms of radiotherapy resistance in HNSCC to ultimately improve radiotherapy treatment.