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Abstract

Abstract Late-stage non-small cell lung cancer (NSCLC) is rarely curable 1 , underscoring a need to intervene earlier in the disease process. Growing evidence suggests that antitumour T cell responses are mounted but become progressively dysregulated during early tumorigenesis 2,3 . Tracking and targeting preinvasive T cell regulation may inform new approaches to detect and intercept lung cancer development. Here we explore how the T cell network is remodelled during NSCLC development via multi-omic, cross-tissue immune profiling in patients with preinvasive lung lesions surveilled by autofluorescence bronchoscopy and computed tomography (CT) imaging. Effector regulatory CD4 + T cells (eT reg cells) expressing basic leucine zipper ATF-like transcription factor (BATF) accumulated in high-grade premalignant airway lesions and were clonally related to circulating eT reg cells. Circulating eT reg cells were increasingly elevated during preinvasive progression, enabling lung tumorigenesis to be tracked through analysis of peripheral blood. Emergence of this clonally coordinated eT reg cell circuit defined rapid progression in patients with early-stage NSCLC detected during CT screening. In mice, carcinogen-driven lung tumorigenesis triggered an analogous preinvasive eT reg cell axis across the blood, airways and draining lymph nodes (dLNs). This culminated in an expansion of lung BATF + T reg cells and T reg  cell-rich peribronchial immature tertiary lymphoid structures (iTLSs). Immune interception via phosphoinositide 3-kinase-δ (PI3Kδ) inhibition abrogated formation of T reg cell-rich iTLSs, reduced circulating and pulmonary T reg cells, increased local conventional type 1 dendritic cells (cDC1s) and reduced lung tumour incidence and size. These data reveal a conserved eT reg cell network that emerges across tissues during early pulmonary tumorigenesis and provide a theranostic framework to track and target preinvasive immune regulation for lung cancer interception.