Genetic and immunologic features of recurrent stage I lung adenocarcinoma

• Published in: Scientific reports 2021-12, Vol.11 (1), p.23690-23690, Article 23690
• Main Authors: Kratz, Johannes R., Li, Jack Z., Tsui, Jessica, Lee, Jen C., Ding, Vivianne W., Rao, Arjun A., Mann, Michael J., Chan, Vincent, Combes, Alexis J., Krummel, Matthew F., Jablons, David M.
• Format: Article
• Language: English
• Subjects: 631/67/1612/1350; 631/67/580; Adaptive immunity; Adenocarcinoma; Adenocarcinoma of Lung - diagnosis; Adenocarcinoma of Lung - genetics; Adenocarcinoma of Lung - immunology; Antigen presentation; Biomarkers, Tumor; Cell cycle; Computational Biology - methods; Cytolytic activity; Cytometry; Disease Susceptibility; Epigenesis, Genetic; Epigenetics; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genetic Variation; Genomic instability; Humanities and Social Sciences; Humans; Immune response; Immunosurveillance; Lung cancer; Lymphocytes T; Male; Microenvironments; multidisciplinary; Mutation; Neoplasm Recurrence, Local; Neoplasm Staging; Patients; Prognosis; Proportional Hazards Models; Science; Science (multidisciplinary); Surgery; Tumor Microenvironment - genetics; Tumors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-02946-0

Although surgery for early-stage lung cancer offers the best chance of cure, recurrence still occurs between 30 and 50% of the time. Why patients frequently recur after complete resection of early-stage lung cancer remains unclear. Using a large cohort of stage I lung adenocarcinoma patients, distinct genetic, genomic, epigenetic, and immunologic profiles of recurrent tumors were analyzed using a novel recurrence classifier. To characterize the tumor immune microenvironment of recurrent stage I tumors, unique tumor-infiltrating immune population markers were identified using single cell RNA-seq on a separate cohort of patients undergoing stage I lung adenocarcinoma resection and applied to a large study cohort using digital cytometry. Recurrent stage I lung adenocarcinomas demonstrated higher mutation and lower methylation burden than non-recurrent tumors, as well as widespread activation of known cancer and cell cycle pathways. Simultaneously, recurrent tumors displayed downregulation of immune response pathways including antigen presentation and Th1/Th2 activation. Recurrent tumors were depleted in adaptive immune populations, and depletion of adaptive immune populations and low cytolytic activity were prognostic of stage I recurrence. Genomic instability and impaired adaptive immune responses are key features of stage I lung adenocarcinoma immunosurveillance escape and recurrence after surgery.