T cell focused early detection of pre-invasive lung neoplasia.

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Late diagnosis of non-small cell lung cancer (NSCLC) is a major cause of cancer mortality. Current screening methods are burdensome and ineffective, underscoring an urgent need to improve early detection. Current screening programmes often rely on imaging-based techniques, therefore risking overdiagnosis and placing a heavy resource burden on healthcare providers. Other methods can be invasive, contributing to problems with attendance and uptake by the general public. Research efforts in the field of early detection are now largely directed towards discovering the potential of liquid biopsies. This could provide a far more cost effective and accessible method of screening, to be used either in conjunction with existing methods or as a standalone test. We and others recently discovered that anti-tumour immune responses generate distinct patterns of dysfunctional T cell differentiation in the tumour. Preliminary data demonstrates that this signal is detectable in the blood of patients with NSCLC and high-grade pre-invasive lesions of the airway, providing the basis for an innovative new strategy for early cancer detection. We will validate and extend our observations by conducting T cell-omics analysis in blood samples from unique cohorts of patients with developing neoplasia. We aim to leverage these data to design a clinically implementable early detection blood test. We hypothesise that changes in the differentiation state of circulating peripheral T cells can be used to detect ongoing lung tumour development. Specifically, that the presence of a developing tumour manifests in quantifiable changes to circulating T cells, consistent with increased tumour antigen-driven differentiation, namely a shift in cellular phenotype, changes to T cell receptor repertoire architecture, and epigenetic reprogramming. This project paves the way for a radically new class of non-invasive multi-cancer early detection methodologies to reshape future clinical practise.