Correlation between preoperative T-cell receptor profile characteristics and postoperative pathological stage/treatment response in non-small cell lung cancer: a prospective cohort study

BACKGROUND: Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide, with a substantial proportion of patients diagnosed at advanced stages and recurring after surgery. Traditional prognostic tools like TNM staging do not fully account for the host immune response. T-cell receptor (TCR) repertoire profiling, which reflects T-cell diversity and clonality, shows promise as a biomarker for predicting disease progression and therapy response. This study investigates the correlation between preoperative peripheral blood TCRβ repertoire characteristics and postoperative pathological stage, survival outcomes, and response to adjuvant therapies in NSCLC. MATERIALS AND METHODS: A prospective cohort of 120 treatment-naïve NSCLC patients scheduled for curative surgical resection was enrolled. Peripheral blood mononuclear cells were collected preoperatively to perform high-throughput sequencing of the TCRβ complementarity-determining region 3 (CDR3). TCR repertoire diversity, clonality, CDR3 length distribution, and clonotype sharing were quantified. Clinical data including postoperative pathological staging and treatment responses were collected. Statistical analyses included correlation tests, survival analyses (Kaplan-Meier, Cox regression), hierarchical clustering, and ROC curve analyses to evaluate prognostic performance. RESULTS: As expected, pathological stage demonstrated strong prognostic value for both DFS and OS (log-rank P < 0.001). TCR diversity was significantly lower in advanced-stage NSCLC (III-IV) compared to early stages (I-II), while clonality positively correlated with higher pathological stage. High TCR clonality (≥ 0.35) independently predicted worse progression-free survival (DFS; adjusted HR = 1.7, P = 0.04) and overall survival (OS; adjusted HR = 1.9, P = 0.02). Time-dependent ROC analyses showed TCR clonality outperformed pathological stage and PD-L1 status in 2-year OS prediction (AUC = 0.72). CDR3 length distribution skewed toward shorter lengths in advanced stages, correlating with higher clonality and poorer survival. Hierarchical clustering identified distinct TCR repertoire patterns segregating early and advanced stages, with three public clonotypes enriched in stage III-IV patients. Among treatment subgroups, high TCR diversity predicted better DFS in patients receiving immunotherapy (HR = 0.29, P = 0.02) but not in chemotherapy or targeted therapy groups. CONCLUSION: Preoperative peripheral blood TCRβ repertoire profiling provides valuable prognostic and predictive biomarkers in NSCLC. Reduced TCR diversity and increased clonality correlate with advanced pathological stage and poorer survival, while preserved diversity identifies patients likely to benefit from immunotherapy. These findings support the potential of preoperative TCR repertoire analysis as a baseline for post-operative monitoring and a component for refining risk stratification models, which could guide adjuvant therapy intensity and selection.