Molecular subtyping reveals immune alterations associated with progression of bronchial premalignant lesions

• Published in: Nature communications Vol. 10; no. 1; pp. 1856 - 13
• Main Authors: Beane, Jennifer E., Mazzilli, Sarah A., Campbell, Joshua D., Duclos, Grant, Krysan, Kostyantyn, Moy, Christopher, Perdomo, Catalina, Schaffer, Michael, Liu, Gang, Zhang, Sherry, Liu, Hanqiao, Vick, Jessica, Dhillon, Samjot S., Platero, Suso J., Dubinett, Steven M., Stevenson, Christopher, Reid, Mary E., Lenburg, Marc E., Spira, Avrum E.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.04.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/51; 38/91; 45/91; 631/114; 631/67/1612; 631/67/1857; 64/60; Antigen presentation; Antigen processing; Antigens; Antineoplastic Agents, Immunological - pharmacology; Antineoplastic Agents, Immunological - therapeutic use; Biomarkers; Biomarkers, Tumor - genetics; Biomarkers, Tumor - immunology; Biopsy; Bronchi - diagnostic imaging; Bronchi - immunology; Bronchi - pathology; Bronchoscopy; Carcinoma, Bronchogenic - genetics; Carcinoma, Bronchogenic - immunology; Carcinoma, Bronchogenic - pathology; Carcinoma, Bronchogenic - prevention & control; Cell cycle; Cohort Studies; Datasets as Topic; Depletion; Disease Progression; Dysplasia; Early Detection of Cancer - methods; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - immunology; Gene Regulatory Networks - genetics; Gene Regulatory Networks - immunology; Gene sequencing; Humanities and Social Sciences; Humans; Immune system; Immunity, Cellular - drug effects; Immunity, Cellular - genetics; Immunofluorescence; Information processing; Interferon; Lesions; Lung cancer; Lung carcinoma; Lung Neoplasms - genetics; Lung Neoplasms - immunology; Lung Neoplasms - pathology; Lung Neoplasms - prevention & control; Mass Screening - methods; Middle Aged; multidisciplinary; Precancerous Conditions - diagnostic imaging; Precancerous Conditions - genetics; Precancerous Conditions - immunology; Precancerous Conditions - pathology; Respiratory Mucosa - cytology; Respiratory Mucosa - diagnostic imaging; Respiratory Mucosa - immunology; Respiratory Mucosa - pathology; Respiratory tract; Ribonucleic acid; Risk; RNA; RNA, Messenger - genetics; Science; Science (multidisciplinary); Sequence Analysis, RNA; Skin cancer; Smoking; Squamous cell carcinoma; T-Lymphocytes - immunology; Tomography, X-Ray Computed; Up-Regulation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-09834-2

Bronchial premalignant lesions (PMLs) are precursors of lung squamous cell carcinoma, but have variable outcome, and we lack tools to identify and treat PMLs at risk for progression to cancer. Here we report the identification of four molecular subtypes of PMLs with distinct differences in epithelial and immune processes based on RNA-Seq profiling of endobronchial biopsies from high-risk smokers. The Proliferative subtype is enriched with bronchial dysplasia and exhibits up-regulation of metabolic and cell cycle pathways. A Proliferative subtype-associated gene signature identifies subjects with Proliferative PMLs from normal-appearing uninvolved large airway brushings with high specificity. In progressive/persistent Proliferative lesions expression of interferon signaling and antigen processing/presentation pathways decrease and immunofluorescence indicates a depletion of innate and adaptive immune cells compared with regressive lesions. Molecular biomarkers measured in PMLs or the uninvolved airway can enhance histopathological grading and suggest immunoprevention strategies for intercepting the progression of PMLs to lung cancer. Bronchial premalignant lesions can potentially progress to lung squamous cell carcinoma. Here, the authors profile bronchial biopsies from high-risk smokers by RNA sequencing and identify four molecular subtypes of premalignant lesions and an immune molecular signature that associates with lesion progression.