Targeting the mRNA Export Pathway to Overcome Immune Evasion in Hypoxic Head and Neck Cancer

About the project

About the Project Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide, with approximately 800,000 new cases diagnosed annually. Recurrence rates remain as high as 50% despite aggressive multimodal therapy. Immune checkpoint blockade (ICB) has transformed outcomes for some HNSCC patients; however, its efficacy is disproportionately confined to HPV-positive disease. HPV-negative HNSCC, which carries significantly worse prognosis, consistently fails to respond to immunotherapy, driven by a profoundly immunosuppressive, immune-cold tumour microenvironment characterised by dysfunctional tumour-infiltrating lymphocytes and suppressed innate immune signalling. Strategies to convert these tumours from immune cold to immune responsive represent one of the most urgent unmet needs in head and neck oncology. All solid tumours, including HNSCC, contain regions of hypoxia (0.1–2% O₂) which are strongly associated with resistance to radiotherapy, chemotherapy, and ICB. Our group has identified a novel hypoxia-inducible RNA-binding protein in HPV-negative HNSCC, with high expression correlating with worse patient survival. This protein functions within the mRNA processing and export pathway and has been implicated in the suppression of innate immune transcripts under hypoxic conditions. We hypothesise that this factor suppresses viral mimicry, a process whereby dormant endogenous retroelements are re-expressed, generating double-stranded RNA species that activate interferon signalling and tumour immunity, thereby enabling hypoxic tumour cells to evade immune detection. Targeting this pathway may simultaneously impair hypoxic tumour cell survival and restore innate immune signalling, rendering immune-cold HPV-negative HNSCC responsive to ICB. This PhD will provide the first mechanistic characterisation of this novel hypoxia-regulated RNA-binding protein's role in immune suppression in HPV-negative HNSCC, defining its RNA interactome, upstream regulatory mechanisms, and downstream immunological consequences. This project will employ a suite of state-of-the-art molecular and cellular approaches, including: siRNA-mediated gene knockdown and CRISPR/Cas9 genome editing Clonogenic survival assays and 3D spheroid culture EF5-based hypoxia detection and immunohistochemistry RT-qPCR, immunoblotting, and confocal microscopy RNA immunoprecipitation sequencing (RIP-seq) RNA sequencing and bioinformatic analysis ELISA Immune functional assays Immunofluorescence and multiplex immunostaining Entry Requirements: You must have, or expect to achieve, at least a 2:1 honours degree, or equivalent, in an appropriate subject, including: cancer research, biomedical sciences. Candidates must have experience in relevant molecular biology techniques e.g.: mammalian cell culture, western blotting, RT-qPCR, immunofluorescence and transfection. A Masters degree (MSc or MRes) is advantageous but not essential. How to apply: Please complete a University Postgraduate Research Application form available here: www.shef.ac.uk/postgraduate/research/apply Please clearly state the prospective main supervisor in the respective box and select (School of Clinical Dentistry) as the department. Enquiries: Interested candidates should in the first instance contact Dr Hannah Bolland h.bolland@sheffield.ac.uk

Research areas