Sequencing data have been deposited at the European Genome-Phenome Archive (http://www.ebi.ac.uk/ega/) under accession numbers EGAD00001005193. Somatic mutation calls, including single base substitutions, indels and structural variants, from all 632 samples have been deposited on Mendeley Data with the identifier: http://dx.doi.org/10.17632/b53h2kwpyy.2. Code Availability Detailed method and custom R scripts for the analysis of mutational burden in bronchial epithelium are available in Supplementary Code. Other packages used in the analysis are listed below:

Squamous cell carcinoma of the lung arises from preinvasive progenitors in the central airways. The archetypal model appears to be a stepwise morphological progression until there is invasion of the basement membrane. However, not every lesion appears to follow this course and many individuals can have stable disease, or indeed regress to normal epithelium. From our increased understanding of the molecular pathology it is becoming apparent that the respiratory epithelium accumulates progressive genetic and epigenetic insults in response to carcinogens. Still, little is known about how to predict those 'at risk' of progression, and it is likely that in the future molecular signatures will underpin prediction models of developing invasive lung cancer. Currently, autofluorescence bronchoscopy gives us the ability to follow the natural history of these lesions, with the prospect that detecting and treating lesions early may improve survival. However, treatment remains controversial, and radical therapies are offered to individuals with carcinoma in situ who may never develop invasive cancer. This has paved the way for the use of minimally invasive bronchoscopic treatments, which, while apparently effective, have not been tested in randomised controlled trials. In this paper we describe the known biology and natural history of preinvasive lesions and review the current treatment strategies.

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Before squamous cell lung cancer develops, pre-cancerous lesions can be found in the airways. From longitudinal monitoring, we know that only half of such lesions become cancer, whereas a third spontaneously regress. While recent studies have described the presence of an active immune response in high-grade lesions, the mechanisms underpinning clinical regression of pre-cancerous lesions remain unknown. Here, we show that host immune surveillance is strongly implicated in lesion regression. Using bronchoscopic biopsies from human subjects, we find that regressive carcinoma in-situ lesions harbour more infiltrating immune cells than those that progress to cancer. Moreover, molecular profiling of these lesions identifies potential immune escape mechanisms specifically in those that progress to cancer: antigen presentation is impaired by genomic and epigenetic changes, TGF-beta signalling is overactive, and the immunomodulator TNFSF9 is downregulated. Changes appear intrinsic to the CIS lesions as the adjacent stroma of progressive and regressive lesions are transcriptomically similar. This study identifies mechanisms by which pre-cancerous lesions evade immune detection during the earliest stages of carcinogenesis and forms a basis for new therapeutic strategies that treat or prevent early stage lung cancer.Correspondence: s.janes@ucl.ac.uk, nicholas.mcgranahan.10@ucl.ac.uk Before the development of lung squamous cell carcinoma (LUSC), pre-invasive lesions can be observed in the airways. These evolve stepwise, progressing through mild and moderate dysplasia (low-grade lesions) to severe dysplasia and carcinoma in-situ (CIS; high-grade lesions), before the development of invasive cancer(1). Markers of immune sensing and escape have been associated with increasing grade(2). However, longitudinal bronchoscopic surveillance of such le-sions has shown that progression of pre-invasive lesions to cancer is not inevitable; only half of high-grade CIS lesions will progress to cancer within two years, whereas a third will spontaneously regress(3). Here, we integrate genomic, transcriptomic, epigenetic and imaging data across carefully phenotyped airway CIS lesions and adjacent stroma (Table S1; Extended Data Figure 1) to assess the role of immune surveillance in lesion regression. We identify key immune escape mechanisms enriched in pre-invasive lesions which later progressed to cancer. Understanding these mechanisms may offer new therapeutic strategies to induce regression and prevent the development of invasive disease. To assess our hypothesis that lesion regression is driven by immune surveillance, we first performed immunohistochemistry (IHC) on 28 progressive and 16 regressive CIS lesions (Figure 1a-b). Regressive lesions showed higher concentrations of intra-lesional cytotoxic CD8+ (p=0.037; Figure 1c) but not CD4+ (p=0.25) or regulatory FOXP3+ (p=0.41) T cells. We then quantified immune cells in stromal regions adjacent to CIS lesions, but found no significant differences between progressive and regressive lesions ...