Lung cancer develops through a series of precancerous lung spots called pulmonary premalignant lesions, and this project will map the immune system's failure to eliminate them. Non-small cell lung cancer kills more people in the UK than any other cancer, largely because it is caught late. Screening programmes now detect these precancerous lesions more often, but doctors have no guidelines for treating them. The researcher will use a technique called spatial transcriptomics to create detailed maps of the immune cells inside these lesions and very early tumours, drawn from a unique patient cohort at University College London Hospitals. The goal is to pinpoint exactly which immune signalling pathways allow the lesions to escape destruction by tumour-reactive T cells. If the team identifies the right molecular targets, the work could lead to immunotherapies that intercept lung cancer before it becomes invasive. The project will also test how modulating these early immune pathways affects the response to personalised neoantigen vaccines, potentially making preventive cancer vaccines more effective. Because immune evasion is a universal feature of cancer, the findings may apply to other tumour types as well.
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Context Non-small cell lung cancer (NSCLC) is the leading cause of cancer death in the UK. Poor survival rates are principally due to late symptom onset and diagnosis, although long-term outcomes remain disappointing even for early-stage disease. NSCLC develops through the stepwise progression of pulmonary premalignant lesions (PMLs). Advances in imaging and screening programmes have led to more frequent detection of PMLs in high-risk individuals. This has created an unprecedented window to understand how the disease develops and intervene before it is established, a strategy known as cancer interception. However, there are currently no treatment guidelines to eliminate PMLs, representing a missed opportunity to prevent invasive disease. A hallmark of cancer is the ability to evade immune elimination, despite the expression of neoantigens, mutated proteins that would normally be recognised as ‘foreign’. In lung cancer and beyond, immune evasion precedes development of invasive disease and occurs via discrete, targetable mechanisms of immune regulation. Interceptive immunotherapies that can target early immune regulation to halt the progression of PMLs hold promise to reduce NSCLC incidence and mortality. Challenge the project addresses This project aims to identify key immune signalling pathways in lung carcinogenesis that can be targeted for cancer interception. I will use cutting-edge spatial transcriptomics (ST) technology to create detailed maps of the cellular phenotypes in PMLs and early NSCLC, from a globally unique patient cohort at UCLH undergoing lung cancer surveillance. A key focus is on identifying tumour-reactive T cells, immune cells that can recognise and potentially eliminate cancer cells and PMLs. We hypothesise that dysfunction of these cells is a critical failure allowing NSCLC development from PMLs, in both its squamous (LUSC) and adenocarcinoma (LUAD) subtypes. Pinpointing and validating the targetable immunosuppressive pathways that restrain these cells holds potential for cancer interception. In parallel, I will explore how modulating these early immune regulatory pathways impacts the response to neoantigen vaccines. This will provide me with a model to scrutinise tumour-specific T cells and understand how we might condition the pre- and early invasive lung microenvironment to maximise efficacy of preventive cancer vaccines about to enter clinical evaluation. Aims and objectives The study has three main aims: Identify high-confidence regulatory targets posing a barrier to tumour-specific T cell activation in premalignancy and early malignancy in NSCLC using ST technology. Predict and synthesise personalised neoantigen cocktails through the use of whole exome sequencing (WES) on tumour samples. Functionally validate high-confidence interception targets (Aim 1) in the presence and absence of personalised neoantigen stimulation (Aim 2) in patient-derived tumour fragments (PDTFs). Potential applications and benefits Understanding the molecular determinants of immune evasion during lung carcinogenesis will fill a fundamental knowledge gap and has transformative clinical potential for lung cancer prevention. This project could lead to strategies for preventing NSCLC in high-risk individuals and may also improve perioperative immunotherapies for established disease. The exploration of factors that condition the nascent tumour microenvironment (TME) for optimal cancer vaccine responses could enable rational combination treatment approaches to maximise early immune protection. The project promises to build an unprecedented spatial subcellular gallery of carcinogenesis and a library of actionable immune targets for future research. The findings are likely to have multi-cancer applicability, due to the universal role of the immune system in cancer biology.
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