Enhancing immunogenicity in non-viral low mutation burden tumours

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Over the last decade, immunotherapy has become a new pillar of treatment in cancer, improving survival rates in over a dozen different tumour types. A key strength of immunotherapy is the duration of survival, with some patients experiencing long-term durable remission from cancer. While this leads to exceptionally positive outcome in some individuals, not all patients treated with immunotherapy experience benefit, and in fact most patients (~60-80%) do not respond to therapy. We now increasingly understand the reasons for therapeutic failure of immunotherapy, and a key factor is that some tumours are not mutated enough for the immune system to recognise and attack. The process of recognition involves tumour cells displaying their damaged contents for passing immune cells to recognize (a process called "neoantigen presentation"), and when the signal is strong enough immunotherapy can work. But when the extent of damage is low or moderate, immune recognition fails to activate.This project aims to overcome this challenge using a novel approach, which is essentially blocking damage clean-up processes within cancer cells. The lack of clean-up allows damaged molecules to accumulate to higher levels in the cancer cell, and thus surpass the level of damage needed to activate immune recognition. A key benefit of this approach is that it serves to benefit patients whose tumours have insufficient damage for current immunotherapies to be effective (which is up to ~80% of all cases), as it doesn't require the underlying level of damage to be high. Instead by blocking damage clean-up, the level of mutated molecules can build up to higher levels even if the starting level of damage is low. The particular damage clean-up processes to be investigated in this project include the nonsense mediated decay, non-stop decay, no-go decay and unfolded protein response pathways. The choice of these pathways is based on prior evidence, where laboratory experiments and analysis of patient clinical trial data have validated their potential as novel candidates for immunotherapeutic development. In addition, cancer cells often rely heavily on these processes to deal with the burden of mutations within the cancer genome, so targeting these processes poses a lower risk of damage to normal (non-cancerous) cells. The project has four distinct objectives, the first is to use advanced imaging techniques to look inside cancer cells to understand exactly how blocking damage clean-up impacts immune recognition. This objective will be critical in understanding the molecular workings of the these processes before therapeutic development work is undertaken. The second objective is study in detail how the processes of damage clean-up operate differently in cancerous and normal cells, and across different organ types. This is important in identifying a drug targeting strategy that has maximal impact on cancer cells but minimal toxicity to normal healthy tissue. The third objective is to induce anti-tumour immune response via tumour specific modulation of damage clean-up processes. The first three objectives are specifically focused on the most promising damage clean-up pathway, which is called nonsense mediated decay, so the fourth objective is to then broaden the work to the other damage clean-up pathways (non-stop decay, no-go decay and unfolded protein response). The results from this work will firstly increase our biological understanding of how damage clean-up processes impact immune recognition of cancer cells. Secondly, this work aims to support the development of novel immunotherapies for patients whose tumours have insufficient damage for current immunotherapies to be effective.