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

非小细胞肺癌（NSCLC）的晚期诊断是癌症死亡的主要原因。目前的筛查方法既繁琐又无效，因此迫切需要改进早期检测。目前的筛查方案往往依赖于基于成像的技术，因此有过度诊断的风险，并给卫生保健提供者带来沉重的资源负担。其他方法可能是侵入性的，导致公众出勤和吸收问题。早期检测领域的研究工作现在主要是为了发现液体活检的潜力。这可以提供一种更具成本效益和更容易获得的筛选方法，既可以与现有方法结合使用，也可以作为单独的测试。我们和其他人最近发现，抗肿瘤免疫反应在肿瘤中产生不同的功能失调T细胞分化模式。初步数据表明，该信号可在非小细胞肺癌患者和气道高级侵袭前病变患者的血液中检测到，为早期癌症检测的创新新策略提供了基础。我们将通过对发展中的肿瘤患者的独特队列的血液样本进行T细胞组学分析来验证和扩展我们的观察结果。我们的目标是利用这些数据来设计一种临床可实施的早期检测血液测试。我们假设循环外周T细胞分化状态的变化可用于检测正在进行的肺肿瘤发展。具体来说，发展中的肿瘤的存在表现为循环T细胞的可量化变化，与肿瘤抗原驱动的分化增加相一致，即细胞表型的改变，T细胞受体库结构的改变和表观遗传重编程。该项目为一种全新的非侵入性多癌早期检测方法铺平了道路，重塑了未来的临床实践。

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.