PhD Studentship in Developing a Novel Cancer Vaccine for Low Mutation Burden Tumours Derived from the Non-coding Genome

Project Description: Our laboratory focus is on the biochemical basis of oncogene and tumour suppressor activity. We have identified a novel source of cancer antigens derived from the non-coding ‘dark’ genome of tumour cells, which are under the control of the key oncogenic pathway, pRb-E2F. These new antigens can foster an adaptive immune response against the cancer when presented as a vaccine. We will expand the study across a range of tumour models to develop experimental vaccines for low mutation, clinically-challenging burden tumours. We will focus on the cellular aspects of the adaptive immune response and characterise the T and other relevant cells responsible for the anti cancer effect.

The retinoblastoma tumour suppressor protein (pRb)-E2F pathway is a key control in the cell cycle and under aberrant control in the vast majority of human tumours. Mutation in the pRb-E2F pathway is widely regarded as a ‘hallmark’ of cancer. Classically, pRb is viewed as a negative regulator of E2F transcription factors, where E2F acts as a transcriptional hub through which pRb exerts its effects on cell cycle control. However, the pRb-E2F pathway regulates a much broader spectrum of genes than originally envisaged, mediated in part by the protein arginine methyltransferase (PRMT)5. PRMT5 alters the biological properties of E2F, switching it from a primary role in cell cycle control to one with a much broader influence on gene expression and biological processes.

Most of the human genome consists of non-classical genes, including genes encoding microRNA and long non-coding (lnc) RNA. Typically, lncRNA genes encode small transcripts with lengths of over 200 nucleotides, most of which are believed to exist as untranslated RNAs.

We recently described a group of lncRNA genes that are translated and further processed into small antigenic peptides presented on MHC class I protein complexes to cytotoxic T cells. Many lncRNA genes were controlled by the pRb-E2F pathway and the PRMT5 enzyme, and thus exhibit tumour specific expression patterns. A stand-alone therapeutic vaccine composed of lncRNA-derived MHC bound peptide antigens drove a cytotoxic T lymphocyte response resulting in delayed in tumour growth.

This project will assess whether the non-coding genome provides a source of cancer antigens relevant to low mutation ‘cold’ tumours. The aim is to develop an experimental cancer vaccine for cold tumours to be validated in tumour models, and explore the nature of the anti-cancer immune response. The study will lay the foundation for developing a human cancer vaccine for difficult-to treat cancers.

Relevant Publications: Barczak, W., Carr, S. M., Liu, G., Munro, S., Nicastri, A., Lee, L. N., Hutchings, C., Ternette, N., Klenerman, P., Kanapin, A., Samsonova, A., & La Thangue, N. B. (2023). Long non-coding RNA-derived peptides are immunogenic and drive a potent anti-tumour response. Nature Communications, 14(1), 1078. https://doi.org/10.1038/s41467-023-36826-0

Funding: competition funded. Entry Requirements and How to Apply: first-class or strong upper second-class undergraduate degree (or predicted) in a biological, medical, mathematical or physical science or international equivalent. Enquire: Prof Nick LaThangue nick.lathangue@oncology.ox.ac.uk

Project Link - Dept Oncology website

General Enquiries: graduate.studies@oncology.ox.ac.uk

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