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Abstract
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.
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1 University of California San Francisco, Department of Surgery, Division of Cardiothoracic Surgery, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California San Francisco, Thoracic Oncology Laboratory, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California San Francisco, ImmunoX Initiative, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811)
2 University of California San Francisco, Department of Surgery, Division of Cardiothoracic Surgery, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California San Francisco, Thoracic Oncology Laboratory, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811)
3 University of California San Francisco, ImmunoX Initiative, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California San Francisco, Department of Pathology, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California San Francisco, UCSF CoLabs, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811)
4 University of California San Francisco, ImmunoX Initiative, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California San Francisco, Department of Pathology, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California San Francisco, UCSF CoLabs, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California San Francisco, Department of Microbiology and Immunology, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811)
5 University of California San Francisco, ImmunoX Initiative, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California San Francisco, Department of Pathology, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811)