Systemic biomarkers of immune response in locally-advanced human papillomavirus malignancies treated with radical chemoradiation

Abstract

Human papillomavirus (HPV)-driven malignancies exhibit viral oncogenic proteins that act as tumour-specific antigens, making them suitable candidates for monitoring the adaptive immune response during treatment. Chemoradiation is the primary treatment modality for locally-advanced HPV-related malignancies, achieving high efficacy; however, approximately 25 to 30% of patients experience relapse within five years after treatment. It is increasingly recognized that chemoradiation influences the anti-cancer immune response, but the clinical relevance of these processes in the context of treatment response remains unclear. In this research endeavour, I investigate the pre-treatment tumour microenvironment and the dynamics of the systemic adaptive immune response in locally-advanced HPV-driven malignancies undergoing radical chemoradiation. The primary objective of this study is to identify potential biomarkers that can serve as reliable determinants for predicting treatment response. To achieve this comprehensive exploration, a multifaceted approach is needed, encompassing accurate collection, processing, sequencing protocols, and statistical methodologies. Thus, first I examined and optimized various protocols for sample collection, processing, and T-cell receptor (TCR) sequencing methodologies. These protocols will later be implemented in the translational clinical trials of this research. I developed and benchmarked a bioinformatic tool to facilitate population-wide immunogenic epitope discovery, with a specific focus on HPV-derived oncogenic proteins. Next, I investigated the TCR repertoire in a cohort of HPV-positive locally-advanced oropharyngeal, cervical, and anal carcinomas treated with chemoradiation, aiming to identify specific characteristics associated with treatment response. The understanding of systemic immune dynamics is further expanded in a cohort of locally-advanced head and neck carcinomas treated with chemoradiation through a multi-omic characterisation that integrates intra-tumoural and peripheral TCR sequencing, circulating HPV16 DNA analysis, and peripheral immune profiling. Lastly, the HPV genome status and tumour microenvironment are interrogated in a large cohort of locally-advanced head and neck cancers, providing valuable insights into the interplay between