Tissue and Blood Immune Status Predicts Risk of Recurrence in Resected Non-small Cell Lung Cancer

BACKGROUND The integration of Immune checkpoint inhibitors(ICIs) into perioperative strategies for early-stage non-small-cell lung cancer(NSCLC) has shown promising survival benefits; however, reliable biomarkers to predict response and recurrence risk remain limited. The aim of the study was to determine whether a comprehensive immune profiling, including tumor immune microenvironment(TIME) at tissue level and peripheral blood(PB), might unveil immune-biological grounds and improve prognostic stratification in resected NSCLC. METHODS We prospectively analyzed 115 patients with resected stage I–IIIA NSCLC. Comprehensive immune profiling was performed on tumor tissue using digital microscopy, and on paired PB samples by Fluorescence-Activated-Cell-Sorting(FACS). The microarchitecture of tumor-infiltrating lymphocytes(TILs) subtypes, and levels of circulating lymphocytes were correlated with clinicopathological features and recurrence-free survival(RFS). RESULTS Immune profiling of patients with node-negative disease showed a TIME with high density of CD4+( p =0.01) and CD8+( p =0.05) TILs. Stage I disease compared to stage II-III, had increased densities of CD3+( p =0.004), stromal -CD4+( p <0.001), and intratumoral -CD8+ TILs( p =0.002) and, in PB higher levels of CD3+( p =0.01) and CD4+( p =0.03) circulating lymphocytes. At log-rank test, improved RFS was documented in patients carrying high stromal- CD4+(p<0.001; HR 0.24, 95%CI 0.11-0.52) and intratumoral- CD8+(p<0.001; HR 0.24, 95%CI 0.11-0.53) TILs. TIME with PD-1-to-CD8 ratio 0.5 was associated with a high risk of relapse (p<0.001; HR 3.62, 95%CI 1.77-7.41). Multivariate analysis confirmed histology, intratumoral CD8+ TILs and PD-1-to-CD8 ratio as independent prognostic factors of RFS. CONCLUSIONS Our findings suggest that both tissue and blood immune profiles reflect tumor immune status and may serve as prognostic markers in resectable NSCLC. Integrated immune profiling could enhance patient stratification and optimize perioperative immunotherapy strategies.