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

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 cancer 3. 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.