High endothelial venules abundance in tertiary lymphoid structures: a prognostic biomarker in non-small cell lung cancer with neoadjuvant immunochemotherapy

BACKGROUND: High endothelial venules (HEV) in tertiary lymphoid structures (TLS) are associated with favorable prognoses in malignancies. However, regarding neoadjuvant immunochemotherapy for non-small cell lung cancer (NSCLC), HEV production and its relationship with therapeutic response are poorly elucidated. This study aims to investigate the discrepancy in HEV abundance among NSCLC patients receiving neoadjuvant therapy, as well as the value of the HEV/TLS index as an innovative prognostic marker. METHODS: Eighty-eight formalin-fixed paraffin-embedded (FFPE) tissues were retrospectively collected from patients with NSCLC and divided into two cohorts: neoadjuvant immunochemotherapy (N = 48) and neoadjuvant chemotherapy (N = 40). We analyzed the differences in HEV abundance score between the cohorts and their relationship with the prognosis. Kaplan–Meier method was used to explore the effect of each indicator on recurrence-free survival (RFS) and overall survival (OS). Receiver operating characteristic (ROC) curves including HEV abundance and HEV/TLS index were plotted to compare the predictive effects of different indicators by area under curve (AUC). RESULTS: HEV were mostly commonly found in the peripheral region (94.2%) within TLS and rarely in the geminal centers compartment (5.8%). The neoadjuvant immunochemotherapy cohort had higher levels of major pathological response (MPR) rate and pathological complete response (pCR) rate than neoadjuvant chemotherapy cohort (MPR: 29.1% vs. 15.0%; pCR: 29.1% vs. 5.0%). Furthermore, neoadjuvant immunochemotherapy exhibited higher HEV abundance score (p < 0.001) and significantly better prognostic RFS (p = 0.0321) and OS (p = 0.0319). Multivariate analysis demonstrated that HEV abundance score remains the most prominent immunological prognostic factor affecting RFS (hazard ratio [HR] = 0.113) and OS (HR = 0.009) after adjusting variables. We found that the predictive accuracy of the combined HEV/TLS index was superior to that of HEV abundance score alone. CONCLUSION: The HEV/TLS index was more effective than HEV abundance score in predicting patients’ prognosis. Therefore, the induction of HEV formation within TLS to increase their abundance may be a potential strategy to enhance the efficacy of neoadjuvant immunochemotherapy in NSCLC.