Genomic and transcriptomic profiles reveal the immune landscape and the potential prognostic biomarkers in lung cancer patients with lymph node metastasis

Lung cancer is a leading cause of cancer-related mortality worldwide, with metastasis being a critical factor of poor prognosis. However, the mechanisms underlying lymph node (LN) metastasis and its impact on cancer progression remain poorly understood. This study prospectively conducted DNA sequencing and bulk RNA-seq on primary tumors and matched LN metastases (in N1 or N2 stations) from 20 resectable non-small cell lung cancer (NSCLC) patients, followed by a median of 14.75 months of follow-up. We observed the N2 LN metastases shared more genetic mutations with the matched primary tumor than N1 (18.6% vs. 5.7%, p = 0.002), along with a more extensive infiltration of plasma B cells in N2. Additionally, the infiltration of plasma B cells in lymph nodes was significantly correlated with the mutational concordance with primary tumors. The diversity of the TCR, rather than the BCR, showed a potential association with early recurrence. Furthermore, SBS1 and SBS6 activities showed potential associations with favorable and unfavorable outcomes, respectively. Among the immune cell types, activated NK cells were enriched in metastatic lymph nodes and associated with reduced disease recurrence. Our findings shed light on the interplay between tumor mutations, immune responses, and clinical outcomes in NSCLC with LN metastasis, providing insights into potential molecular features and immune mechanisms that may guide future biomarker development and therapeutic exploration.