Identification and targeting of early T cell dysfunction in pulmonary preinvasive neoplasia

癌症是由突变引起的，这些突变通常是由于暴露在环境因素中而产生的，例如紫外线或香烟烟雾。免疫系统消除了绝大多数随着我们年龄增长而发展的突变细胞，但这种防御系统的功能障碍允许一些突变细胞突破癌症。如果我们能够在早期阶段发现癌前生长，并迅速修复这种潜在的免疫功能障碍，我们就可以重新唤醒突变特异性免疫，在小肿瘤进展或完全阻止肿瘤形成之前摧毁它们。然而，我们缺乏强有力的方法来检测许多癌症类型的癌前生长，免疫系统中这些关键缺陷的身份仍然是一个谜。这带来了两个紧迫的科学挑战：1.我们如何在癌症早期或癌前阶段检测肿瘤？2.我们如何识别和修复免疫系统中允许突变细胞进展为癌症的早期缺陷？UKRI FLF应用程序提出了一个创新的研究计划，将首次以前所未有的规模和深度研究肺部癌前病变中突变细胞的免疫反应。使用一组全球独一无二的临床样本，这些样本来自“侵袭前”肺部病变患者，我将研究识别癌前生长的关键杀手“T细胞”。使用我在过去5年中开发的实验性、尖端技术，我的目标是精确定位突变特异性T细胞的缺陷，以完善一系列精确的原型药物，以恢复它们的杀手功能。与此同时，我将尝试利用杀伤T细胞的功能障碍作为肺癌早期检测的一种方法，从而将癌症前期疾病中日益衰弱的免疫系统武器化，成为一种临床策略，跟踪和瞄准危险的病变，以阻止癌症的萌芽。我自己和其他人的研究表明，这两种方法都可能是有效的临床策略，具有拯救大量生命的潜力。首先，及早发现肺癌可以减少大约25%的死亡，因为我们可以在肿瘤有机会扩散之前进行治疗。其次，在动物和人类的早期阶段修复肿瘤相关的T细胞功能障碍比晚些时候修复更有效，并且可以产生长期的、潜在的、治疗性的免疫反应，摧毁肿瘤，并可能保护患者免受未来出现的突变细胞的影响。虽然我的实验室专注于侵袭前肺部疾病的这一系列实验，但它具有更广泛的影响。例如，我们知道，在多种癌症的晚期，T细胞功能障碍是相似的，而且目前的‘免疫疗法’对几种类型的癌症都有效果。此外，我们的初步结果表明，通过血液中功能失调的T细胞追踪肿瘤是可行的。为了在侵袭性肺疾病前期进行这项研究，我将检验三个假设：1.早期T细胞功能障碍可以作为一种基于血液的方法来检测肺部的癌前生长2.杀伤T细胞识别导致癌症的突变细胞3.突变特异性杀伤T细胞中的缺陷可以被识别和修复，以恢复其功能。这项工作将为早期癌症检测和原型药物开发新的测试，以开创未来的临床策略，为我创造的早期干预免疫疗法和癌症免疫预防的癌症药物新纪元铺平道路。

Cancer is initiated by mutations that often arise from exposure to environmental factors, such as UV light or cigarette smoke. The immune system eliminates the vast majority of mutant cells that develop as we age but dysfunction of this defence allows some mutant cells to break through into cancer. If we could detect pre-cancerous growths at an early stage and rapidly repair this underlying immune dysfunction, we could reawaken mutation-specific immunity to destroy small tumours before they advance or prevent tumour formation altogether. However, we lack robust methods to detect pre-cancerous growth for many cancer types and the identity of these crucial defects in the immune system remains a mystery. This presents two urgent scientific challenges:1. How can we detect tumours in early or pre-cancerous stages?2. How can we identify and repair the early defects in our immune system that allow mutant cells to progress to cancer?This UKRI FLF application sets out an innovative research programme that will be the first to study the immune response to mutant cells in pre-cancerous lesions of the lungs at never-before-seen scale and depth. Using a globally unique set of clinical samples from patients with 'preinvasive' lung lesions I will study key killer 'T cells' which recognise pre-cancerous growths. Using experimental, cutting-edge technology I have developed over the last 5 years I aim to pinpoint defects in mutation-specific T cells to refine a portfolio of precision, prototype drugs to resurrect their killer functions. At the same time, I will attempt to hi-jack the dysfunction of killer T cells as a method of early lung cancer detection, thus weaponising the failing immune system in pre-cancerous disease into a clinical strategy to track and target dangerous lesions to stop cancer in its nascent form.My own research, and that of others has shown that both of these approaches may be potent clinical strategies with the potential to save a significant number of lives. Firstly, early detection of lung cancer reduces deaths by approximately 25%, because we can deploy treatment before tumours have a chance to spread. Secondly fixing tumour-associated T cell dysfunction at an earlier stage in animals and humans is more effective than doing so later and can generate long-lived potentially, curative immune responses that destroy tumours and may protect patients from mutated cells that arise in the future. Whilst my laboratory are focussing this series of experiments in preinvasive lung disease, it has much wider ranging impact. For example, we know that T cell dysfunction in later stages is similar across multiple cancers and that current 'immunotherapies' have an effect on several types of cancer. Moreover, we have preliminary results suggesting that tracking tumours via dysfunctional T cells in the blood is feasible. To conduct this study in preinvasive lung disease I will test three hypotheses: 1. Early T cell dysfunction can be used as a blood-based method of detecting pre-cancerous growths in the lung 2. Killer T cells recognise the mutated cells that give rise to cancer3. Defects in mutation-specific killer T cells can be identified and repaired to restore their function. This work will develop novel tests for early cancer detection and prototype drugs to pioneer future clinical strategies, paving the way for a new era of cancer medicines I have coined Early Intervention Immunotherapy and Cancer Immunoprevention.