Enhancing immunogenicity in non-viral low mutation burden tumours

在过去的十年里，免疫疗法已经成为癌症治疗的新支柱，提高了十几种不同肿瘤类型的生存率。免疫疗法的一个关键优势是生存时间，一些患者经历了长期持久的癌症缓解。虽然这在某些个体中会导致异常积极的结果，但并非所有接受免疫治疗的患者都能获益，事实上，大多数患者（~60-80%）对治疗没有反应。我们现在越来越了解免疫疗法治疗失败的原因，其中一个关键因素是一些肿瘤没有突变到足以让免疫系统识别和攻击。识别过程包括肿瘤细胞展示其受损的内容物以供通过的免疫细胞识别（这一过程称为“新抗原呈递”），当信号足够强时，免疫疗法就可以起作用。但当损伤程度较低或中等时，免疫识别无法激活。该项目旨在利用一种新颖的方法来克服这一挑战，这种方法本质上是阻止癌细胞内的损伤清理过程。缺乏清理使得受损分子在癌细胞中积累到更高的水平，从而超过激活免疫识别所需的损伤水平。这种方法的一个关键好处是，它适用于那些肿瘤损伤不足，目前免疫疗法无法发挥作用的患者（占所有病例的80%），因为它不需要潜在的损伤水平很高。相反，通过阻止损伤清除，即使开始的损伤水平很低，突变分子的水平也可以上升到更高的水平。本项目研究的特定损伤清除过程包括无义介导的衰变、不间断衰变、不去衰变和未折叠的蛋白质反应途径。这些途径的选择基于先前的证据，实验室实验和对患者临床试验数据的分析已经证实了它们作为免疫治疗开发的新候选药物的潜力。此外，癌细胞通常严重依赖这些过程来处理癌症基因组中的突变负担，因此靶向这些过程对正常（非癌）细胞的损害风险较低。该项目有四个不同的目标，第一个是使用先进的成像技术来观察癌细胞内部，以确切地了解阻断损伤清除如何影响免疫识别。在进行治疗开发工作之前，这一目标对于理解这些过程的分子工作至关重要。第二个目标是详细研究损伤清除过程在癌变细胞和正常细胞以及不同器官类型中如何不同地运作。这对于确定一种对癌细胞影响最大但对正常健康组织毒性最小的药物靶向策略非常重要。第三个目标是通过肿瘤特异性调节损伤清理过程诱导抗肿瘤免疫反应。前三个目标特别关注最有希望的损伤清除途径，即无义介导的衰变，因此第四个目标是将工作扩展到其他损伤清除途径（不间断衰变，不去衰变和未折叠的蛋白质反应）。这项工作的结果将首先增加我们对损伤清理过程如何影响癌细胞免疫识别的生物学理解。其次，这项工作旨在支持开发新的免疫疗法，用于肿瘤损伤不足的患者，使当前的免疫疗法有效。

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.