Exploring the Role of the Gut Microbiome in Toxicity and Response to Radiotherapy for Head and Neck Cancer

Abstract

Radiotherapy is a mainstay treatment modality used for the treatment of more than 80% of patients with head and neck cancer (HNC). Despite the technological advances in radiotherapy delivery, two key limitations remain a challenge for HNC radiotherapy. First, HNC radiotherapy is associated with unacceptable levels of normal tissue toxicities. One of the most frequent and troublesome toxicities is oral mucositis (OM). Radiotherapy-induced OM refers to the inflammation and/or ulceration of the oral mucosa following radiotherapy. It can affect more than 90% of patients with HNC, with varying degrees of severity. The major challenges related to OM are the lack of effective interventions to prevent or treat OM and the lack of a robust predictive marker to predict OM risk. The second limitation of HNC radiotherapy is heterogeneity in patients' response in terms of tumour control and recurrence. Currently, there are no biomarkers to identify patients with a favourable response and those at risk for primary tumour failure or tumour recurrence. Therefore, finding new targets for OM interventions and predictive biomarkers to predict radiotherapy outcomes will help address these limitations of HNC radiotherapy and improve treatment success. Recent years have witnessed a growing interest in the role of the gut microbiome in cancer treatment efficacy and toxicity, including radiotherapy. The gut microbiome, a collection of microorganisms residing in the gastrointestinal tract, plays a central role in the modulation of systemic immune and inflammatory responses. Given that OM is an inflammatory condition and radiotherapy-induced immunogenic cell death is a key pathway by which radiotherapy kills tumour cells, we hypothesised that the gut microbiome may influence both the pathogenesis of OM and radiotherapy response through modulation of immune and inflammatory signalling. As such, this thesis aimed to investigate the impact of the gut microbiome on the development of radiotherapy-induced OM and radiotherapy outcomes in preclinical and clinical settings. Firstly, I investigated this in preclinical studies described in chapters 3-5. In chapter 3, I successfully developed an antibiotic-induced gut microbiota depletion (AIMD) method that allows for studying the development of OM in the absence of major bacterial taxa. In chapter 4, I established a radiation-induced OM model in rats using a single radiation dose of 20 Gy. These two models were used to conduct the main animal study (chapter 5), which demonstrated that the gut microbiome is involved in the pathogenesis of OM, particularly the healing stage, through the modulation of inflammatory cytokines. Lastly, to translate my preclinical findings to the clinical settings, I investigated whether patient pre-treatment gut microbiome is associated with the severity of OM and radiotherapy response in patients with HNC (chapter 6). The results from this clinical study showed that certain microbes in the baseline gut microbiome are associated with OM severity and tumour recurrence. Together, the results from this thesis suggest that the gut microbiome is involved in the pathogenesis of OM and is associated with radiotherapy response offering a potential target to treat or prevent OM and predict treatment outcomes.