Developing a novel cancer vaccine for low mutation burden tumours derived from the non-coding genome
Co-supervisors: Wojciech Barczak and Simon Carr
Our laboratory aims to understand how mutation in tumour suppressors and oncogenes causes cancer. We focus on understanding the biochemical basis of oncogene and tumour suppressor activity in order to develop new cancer therapies. In recent work, we have identified a surprising and 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. We have shown that these new antigens can foster an adaptive immune response against the cancer when presented as a vaccine, and delay tumour progression. We now wish to expand the study across a range of tumour models and address, in particular, whether we can develop experimental vaccines for low mutation burden tumours, which are clinically difficult to treat. We will focus on the cellular aspects of the adaptive immune response and characterise the T cells, and other relevant cells, that are responsible for the anti-cancer effect.
By way of background, the retinoblastoma tumour suppressor protein (pRb)-E2F pathway is a key point of control in the cell cycle and under aberrant control in the vast majority of human tumours. Consequently, 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, it has become apparent that 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, for example, genes encoding microRNA and long non-coding (lnc) RNA, often described as the non-coding genome. Typically, lncRNA genes encode small transcripts with lengths of over 200 nucleotides, most of which are believed to exist as untranslated RNAs.
In our recent work, however, we 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 found to be controlled by the pRb-E2F pathway and the PRMT5 enzyme, and thus exhibit tumour-specific expression patterns. Further, a stand-alone therapeutic vaccine composed of lncRNA-derived MHC bound peptide antigens drove a cytotoxic T lymphocyte response that resulted in delayed in tumour growth.
In this project we will assess whether the non-coding genome provides a source of cancer antigens of relevance to low mutation ‘cold’ tumours, which are usually poorly immunogenic and notoriously difficult to treat. We will interrogate the non-coding genome using genome-wide technologies coupled with immunopeptidomics on appropriate cancer cell types, to gain an understanding of the immunopeptidome and the role of the non-coding genome. An assortment of complementary reagents, including genetically manipulated knock-out cells and chemical biology tools, will enable the role of the pRb-E2F pathway and PRMT5 to be pin-pointed. The ultimate aim of the project will be to develop an experimental cancer vaccine for cold tumours that will then be validated in tumour models, and explore the nature of the anti-cancer immune response. The study will therefore lay the foundation for developing a human cancer vaccine for difficult to treat cancers.
In addition to gaining a thorough understanding of cancer biology research, students will be trained in a range of state-of-the-art molecular, biochemical, genomic and bioinformatics techniques including CRISPR gene knock-out, transcriptomics, immunopeptidomics and chemical biology, and immunological methodologies including flow cytometry, ELIspot, ELISA and others by experienced members of the laboratory.
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