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

Jennifer E. Beane (), Sarah A. Mazzilli, Joshua D. Campbell, Grant Duclos, Kostyantyn Krysan, Christopher Moy, Catalina Perdomo, Michael Schaffer, Gang Liu, Sherry Zhang, Hanqiao Liu, Jessica Vick, Samjot S. Dhillon, Suso J. Platero, Steven M. Dubinett, Christopher Stevenson, Mary E. Reid, Marc E. Lenburg and Avrum E. Spira
Additional contact information
Jennifer E. Beane: Boston University School of Medicine
Sarah A. Mazzilli: Boston University School of Medicine
Joshua D. Campbell: Boston University School of Medicine
Grant Duclos: Boston University School of Medicine
Kostyantyn Krysan: David Geffen School of Medicine at UCLA
Christopher Moy: Johnson and Johnson Innovation
Catalina Perdomo: Princeton University
Michael Schaffer: Johnson and Johnson Innovation
Gang Liu: Boston University School of Medicine
Sherry Zhang: Boston University School of Medicine
Hanqiao Liu: Boston University School of Medicine
Jessica Vick: Boston University School of Medicine
Samjot S. Dhillon: Kaiser Permanente, Roseville and Sacramento
Suso J. Platero: Covance
Steven M. Dubinett: David Geffen School of Medicine at UCLA
Christopher Stevenson: Janssen Research and Development
Mary E. Reid: Roswell Park Comprehensive Cancer Center
Marc E. Lenburg: Boston University School of Medicine
Avrum E. Spira: Boston University School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-09834-2

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