Head and neck squamous cell carcinoma (HNSCC) consists of heterogeneous tumours originating from the head and neck region. Although advances in the treatment of HNSCC have been made during the last decade, cancer recurrence and treatment resistance remain challenges in HNSCC. Currently, human papilloma virus (HPV), and its surrogate marker p16 for oropharyngeal cancer and Epstein–Barr virus (EBV) for nasopharyngeal cancer are the only biomarkers widely used in clinics. Thus, there is an urgent need for biomarkers to predict the prognosis and treatment response of HNSCC.

Translocator protein (TSPO) is a small protein located on the outer mitochondrial membrane. It has been suggested that it participates in several cellular functions, but its exact role remains unclear. Studies have shown an association between high TSPO expression and worse prognosis in several types of cancer.

The aim of this thesis was to evaluate the prognostic and predictive potential of TSPO in HNSCC. TSPO expression was determined in a large population-based tissue microarray (TMA) and The Cancer Genome Atlas (TCGA) patient cohorts, and possible associations with clinicopathological information were analysed. In addition, the role of TSPO in oxidative metabolism and DNA damage response was studied in HNSCC cells. Finally, the specificity of the TSPO-PET tracer [18F]F-DPA was evaluated in HNSCC xenografts and cell lines.

Lower TSPO tumour expression was associated with worse survival in HNSCC, particularly in patients with p16-positive oropharyngeal cancer. Furthermore, lower TSPO expression was associated with worse survival in patients receiving radiotherapy. Low TSPO expression was associated with reduced mitochondrial respiration and DNA damage response in FaDu cells. The [18F]F-DPA uptake was specific in HNSCC xenografts and cells and increased after radiotherapy.

The results of this thesis indicate that TSPO can be used as a prognostic biomarker of HNSCC and, mechanistically, may participate in the radiotherapy-induced DNA damage response via the regulation of oxidative phosphorylation. Further investigation in the usability of TSPO-PET imaging for predicting radiotherapy response and clinical value of the association between low TSPO expression and worse outcomes in p16-positive oropharyngeal cancer are warranted.