Dysregulated Immune and Metabolic Microenvironment Is Associated with the Post-Operative Relapse in Stage I Non-Small Cell Lung Cancer

SIMPLE SUMMARY: The underlying mechanism of post-operative relapse of non-small cell lung cancer (NSCLC) remained poorly understood. This study highlights that both tumors and adjacent tissues from stage I NSCLC with relapse show a dysregulated immune and metabolic environment. Immune response shifts from an active state in primary tumors to a suppressive state in recurrent tumors. A model based on the enriched biological features in the primary tumors with relapse could effectively predict recurrence for stage I NSCLC. These results provide insights into the underpinning of the post-operative relapse and suggest that identifying NSCLC patients with a high risk of relapse could help the clinical decision of applying appropriate therapeutic interventions. ABSTRACT: The underlying mechanism of post-operative relapse of non-small cell lung cancer (NSCLC) remains poorly understood. We enrolled 57 stage I NSCLC patients with or without relapse and performed whole-exome sequencing (WES) and RNA sequencing (RNA-seq) on available primary and recurrent tumors, as well as on matched tumor-adjacent tissues (TATs). The WES analysis revealed that primary tumors from patients with relapse were enriched with USH2A mutation and 2q31.1 amplification. RNA-seq data showed that the relapse risk was associated with aberrant immune response and metabolism in the microenvironment of primary lesions. TATs from the patients with relapse showed an immunosuppression state. Moreover, recurrent lesions exhibited downregulated immune response compared with their paired primary tumors. Genomic and transcriptomic features were further subjected to build a prediction model classifying patients into groups with different relapse risks. We show that the recurrence risk of stage I NSCLC could be ascribed to the altered immune and metabolic microenvironment. TATs might be affected by cancer cells and facilitate the invasion of tumors. The immune microenvironment in the recurrent lesions is suppressed. Patients with a high risk of relapse need active post-operative intervention.