Immature central tumor tertiary lymphoid structures are associated with better prognosis in non-small cell lung cancer

Abstract Background & aims Tertiary lymphoid structures (TLSs) are predictive biomarkers of favorable clinical outcomes and immunotherapy response in several solid malignancies, including non-small cell lung cancer (NSCLC). However, the relationship between TLSs and NSCLC prognosis has not been eludicated from the aspects of location, density, and maturity. This study aimed to investigate the clinicopathological and prognostic significance of TLSs in NSCLC. Methods A collection of 151 resected pulmonary nodules in patients with NSCLC was retrospectively analyzed. Two experienced pathologists reviewed hematoxylin-eosin (H&E) slides and assessed TLS scores at different anatomic subregions. Then, we analyzed their correlation with clinicopathologic parameters and CD8 staining intensity and assessed multiple clinicopathological factors affecting patient prognosis. Results CD8 expression was correlated with total (TLS-CT) ( P = 0.000), aggregates (Agg) (TLS-CT) ( P = 0.001), follicles (FOL)-I (TLS-CT) ( P = 0.025), and TLS(overall) ( P = 0.013). TLS scores in the central tumor (CT) and invasion margin (IM) areas were negatively correlated with distant metastasis and Union for International Cancer Control (UICC) stage in NSCLC patients, while TLS score in the CT area was positively correlated with CD8 expression. TLS (overall), Agg (TLS-CT), and FOL-I (TLS-CT) were positively correlated with distant metastasis, UICC stage, and CD8 expression in NSCLC patients. Agg (TLS-IM) was positively correlated with distant metastasis and UICC stage. FOL-I (TLS-IM) was positively correlated with UICC stage. FOL-II (TLS-IM) was positively correlated with distant metastasis ( P < 0.05). Multivariate Cox regression analysis showed that unfavorable independent prognostic factors were associated with metastasis status and UICC stage. Independent prognostic factors with protective effects included Agg (TLS-CT), FOL-I (TLS-CT), total (TLS-CT), and overall TLS ( P < 0.05). Conclusion Histological score assessment of H&E sections of Agg (TLS-CT), FOL-I (TLS-CT), total (TLS-CT), and overall TLS levels in NSCLC has prognostic value.