Immune surveillance in clinical regression of pre-invasive squamous cell lung cancer

Abstract

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 ...

Early immune pressure imposed by tissue resident memory T cells sculpts tumour evolution in non-small cell lung cancer

“…Strikingly, clonal HLA LoH was only detected in ES patients in both early-stage and late-stage disease suggesting it is an early event in the evolution of ES tumours. Analysis of HLA LoH in preinvasive lung cancer lesions corroborates this observation where HLA LoH occurred in 34% of squamous carcinoma in situ in ES patients 62 , 8% of adenocarcinoma in situ/minimally invasive adenocarcinoma in ES patients and only 1% of these lesions in NS patients 51 . We propose that the TRM-rich microenvironment of ES lungs where NSCLC grows is a likely driver of this early immune evasion mechanism.…”

“…Pre-invasive LUSC 61 possess mutations in oncogenic drivers including KRAS, EGFR and KEAP1 but a number of these lesions regress to a normal-like state 62 . The presence of CD8 + T cells infiltrating pre-malignant LUSC was proposed to support the elimination of malignant cells 62 . It is tempting to speculate greater TRM-immunosurveillance induced by tobacco smoking may protect from invasive cancers induced by this same insult.…”

“…Oncogenic alterations and genomic instability are found in normal lung basal cells from heavy smokers 4,5 , yet not all ever-smokers will develop lung cancers 60 . Pre-invasive LUSC 61 possess mutations in oncogenic drivers including KRAS, EGFR and KEAP1 but a number of these lesions regress to a normal-like state 62 . The presence of CD8 + T cells infiltrating pre-malignant LUSC was proposed to support the elimination of malignant cells 62 .…”

Interrogating the Precancerous Evolution of Pathway Dysfunction in Lung Squamous Cell Carcinoma Using XTABLE

“…This potential role of CIN as biomarker of PMLs progression has been observed in low and high grade PMLs (24,25). These reports showed that high levels of copy number variations was the best predictor of progressive PMLs (24,25) and that immune response is the most likely cause of regression as these lesions contained higher levels of immune infiltration (23,27). These results are supported by transcriptomic analysis of PMLs that indicate immune evasion in the transition to invasiveness (28).…”

“…LUSC progresses through a series of premalignant stages characterized by alterations of the normal bronchial epithelium (Figure 1) (20)(21)(22)(23). These endobronchial premalignant lesions (PMLs) are classified as low-grade (squamous metaplasia, mild and moderate dysplasia) and high-grade (severe dysplasia, and carcinomas in-situ) (Figure 1).…”