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

晚期诊断的非小细胞肺癌(NSCLC)是导致癌症死亡的主要原因。目前的筛查方法繁琐且无效，突显出迫切需要改进早期发现。目前的筛查项目往往依赖于基于成像的技术，因此存在过度诊断的风险，并给医疗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，导致公众的参与和接受方面的问题。早期检测领域的研究努力现在主要针对发现液体活组织检查的潜力。这可以提供一种更具成本效益和更容易获得的筛查方法，既可以与现有方法结合使用，也可以作为单独的测试使用。我们和其他人最近发现，抗肿瘤免疫反应在肿瘤中产生了不同的功能失调的T细胞分化模式。初步数据表明，在非小细胞肺癌患者和高度侵袭前呼吸道病变患者的血液中可以检测到这一信号，为创新的早期癌症检测新策略提供了基础。我们将通过对发展中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上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以用来检测正在进行的肺癌的发展。具体地说，发展中肿瘤的存在表现为循环中T细胞的可量化变化，这与肿瘤抗原驱动的分化增加一致，即细胞表型的转变，T细胞受体体系结构的改变，以及表观遗传重新编程。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，以重塑未来的临床实践。

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.