Developing a novel type of cancer vaccine for genetically-defined tumours
Primary Supervisor: Professor Nick La Thangue
Secondary Supervisors: Dr Geng Liu, Dr Simon Carr
Project Overview
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 and therapeutic immune response against the cancer when presented as a vaccine, and delay tumour progression in model systems. This project will expand the study across a range of tumour models and address, in particular, whether we can develop experimental vaccines for a genetically defined group of tumours, which are generally clinically difficult to treat.
The genes encoding the ‘new’ antigens are derived from a poorly annotated region of the human genome and under the control of the pRb-E2F pathway, which 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 which our studies show not only incapacitates normal control of cellular proliferation but also influences antigen presentation in the tumour. A key objective of this project will use genetically manipulated tumour cell lines (altered Rb and E2F genes) to assess the impact on antigen presentation by the MHC complex, explore the pathways involved and develop an experimental cancer vaccine for Rb-deficient tumours. We will focus on the cellular aspects of the adaptive immune response and characterise the antigen-specificity of the T cells, 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 tumours. In turn, this study will lay the foundation for developing a human cancer vaccine.
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 bioinformatics techniques like CRISPR, transcriptomics, peptidomics and chemical biology, and immunological methodologies including flow cytometry, ELIspot, ELISA, T cell growth and others by experienced members of the laboratory.
The transferrable skills programme offers courses that equip the student with relevant skills throughout the tenure of the DPhil, include bioinformatics and data science, experimental design, reproducible research, synthetic biology together with generic skills like analysis and problem solving, project management and organisation, research and information management.
References
Bate‐Eya, L.T., Albayrak, G., Carr, S.M., Shrestha, A., Kanapin, A., Samsonova, A. and La Thangue, N.B., 2024. Sustained cancer‐relevant alternative RNA splicing events driven by PRMT5 in high‐risk neuroblastoma. Molecular Oncology. https://doi.org/10.1002/1878-0261.13702
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
Liu, G., Barczak, W., Lee, L.N. et al. The HDAC inhibitor zabadinostat is a systemic regulator of adaptive immunity. Commun Biol 6, 102 (2023). https://doi.org/10.1038/s42003-023-04485-y