A novel cancer vaccine derived from non-canonical antigens
Primary Supervisor: Professor Nick La Thangue
Secondary Supervisors: Dr Geng Liu & Dr Wiktoria Blaszczak
Project overview
We have identified a surprising and novel source of cryptic non-canonical cancer antigens, derived from the non-coding genome of tumour cells including long non-coding RNA (lncRNA) and aberrantly processed forms of RNA, presented to the immune system by the MHC class I complex. These genes are almost invariably under the control of a key oncogenic pathway, the retinoblastoma protein pRb and its key effector transcription factor E2F, which is subjected to oncogenic changes in the majority of human cancers. As a vaccine, the cryptic antigens can foster an adaptive immune response against the cancer which delays tumour progression in model systems. This project will aim to develop a new generation of cancer vaccines carrying immunologically optimized antigens derived from non-canonical sources identified in tumours with an aberrant pRb-E2F pathway, with the ultimate objective of testing an experimental cancer vaccine designed to target the immune response to tumours with aberrations in the pRb-E2F pathway. The genes encoding cryptic antigens are generally derived from poorly annotated regions of the cancer genome, or incompletely processed RNA transcripts which again remain poorly characterised. Thus, an additional objective will be to understand the mechanisms and pathways that give rise to the antigens, as this knowledge could allow us to devise strategies to regulate the antigenicity of tumour cells. Here, we will focus on an enzyme, PRMT5, which is a critical upstream regulator of E2F activity that is frequently subject to oncogenic control. We will use genetically manipulated tumour cell lines (altered Rb and E2F genes) and chemical biology (inhibition of PRMT5) to assess the impact on antigen presentation by the MHC complex using immunopeptidomics, and focus on the cellular aspects of the adaptive immune response and characterise the antigen-specificity of the T lymphocytes, and other relevant cells, that are responsible for the anti-cancer immune response. An assortment of complementary techniques, reagents and platforms, including genetically manipulated cells, genome-wide and single cell expression, chemical biology tools and proteomics will facilitate the ultimate goal of the project to develop experimental cancer vaccines for difficult-to-treat solid tumours. In turn, this study will lay the foundation for developing a human cancer vaccine that targets tumours with aberrant pRb-E2F.
Training Opportunities
In addition to gaining a thorough research training in cancer biology and translational science, students will be trained in a range of state-of-the-art project-specific techniques including molecular, biochemical, genomic and bioinformatic techniques like CRISPR, transcriptomics, peptidomics and chemical biology, and immunological methodologies including flow cytometry, ELISpot, ELISA, T cell proliferation assay and others by experienced members of the laboratory. The transferrable skills programme offers courses that equip the student with relevant skills throughout the course of the DPhil, include bioinformatics and data science, experimental design, reproducible research, synthetic biology together with soft skills like analysis and problem solving, project management and organisation, research and information management and communication skills.
References
Bate‐Eya, L.T., Albayrak, G., Carr, S.M., Shrestha, A., Kanapin, A., Samsonova, A. and La Thangue, N.B., 2025. Sustained cancer‐relevant alternative RNA splicing events driven by PRMT5 in high‐risk neuroblastoma. Molecular Oncology, 19(3), pp.741-763.