A preinvasive regulatory T cell axis for lung cancer interception

Late-stage non-small cell lung cancer (NSCLC) is rarely curable¹, 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.