Background
The high mortality of non-small cell lung cancer (NSCLC) is largely attributable to late-stage presentation and treatment. Mounting evidence suggests that anti-tumour CD4 T cell responses are initiated but rapidly dysregulated during pulmonary tumorigenesis.

 
Objectives
We set out to test the hypotheiss that tracking and targeting preinvasive CD4 T cell dysregulation may inform new approaches to detect and intercept lung cancer development.

Methods
Here, we explored how the T cell network is remodelled during preinvasive progression of NSCLC via multi-omic, cross-tissue profiling in patients with preinvasive lung lesions detected by abnormal signals at autofluorescence bronchoscopy (AFB) and chest-computed tomography (CT) surveillance and autochthonous mouse models. We harnessed scRNAseq, TCRseq, single cell spatial transcriptomics, bulk RNAseq, spectral cytometry and in vivo functional assays. 

Results
Potently suppressive effector regulatory CD4 T cells expressing Basic leucine zipper-like ATF Transcription Factor (BATF+ Tregs) accumulated in high-grade preinvasive airway lesions, whilst clonally related CD39+ effector Tregs increased in the circulation and tracked NSCLC development. Emergence of this systemic-pulmonary effector Treg circuit defined early disease progression in CT screen detected early NSCLC.
 
In vivo, carcinogen-driven airway tumorigenesis was sufficient to induce the preinvasive effector-Treg axis; expanding effector Tregs in the blood and drainig lymph nodes, which seeded local Batf+Tregs in peri-bronchial immature tertiary lymphoid structures (iTLS). Pharmacological immune-interception prevented formation of Treg-rich iTLS, diminished preinvasive airway Tregs and reduced lung tumour development.
 
Conclusions
These data reveal a conserved, systemic-bronchial effector Treg circuit that emerges during pulmonary tumorigenesis which may inform strategies for lung cancer interception.