Tertiary lymphoid structures in the tumor immune microenvironment of EGFR mutation–positive lung cancer are associated with prognosis: a retrospective review

Abstract Background The tumor immune microenvironment (TME) of epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC) remains poorly characterized. We hypothesized that a higher abundance of tertiary lymphoid structures (TLSs) is associated with improved disease-free survival (DFS) and that TLS abundance differs across major EGFR mutation subtypes. Methods We retrospectively analyzed the medical records of 213 patients with EGFR mutation-positive NSCLC who underwent surgical resection between 2007 and 2015. TLS was defined as the presence of lymphocyte aggregates containing peripheral nodal addressin-positive endothelial venules. Clinicopathological factors, prognosis, and spatial immune profiles were assessed using imaging mass cytometry. Results Tumors with high TLS abundance were more frequent in the L858R than in Exon19del cases (57% vs. 37%, P = 0.011). In stage II–III disease, high TLS abundance remained prognostic ( P = 0.003), particularly in L858R tumors. Univariate analysis revealed that TLS abundance is an independent prognostic factor. Imaging mass cytometry showed a higher density of granzyme B-positive cytotoxic lymphocytes in tumors with high TLS abundance. Conclusions Higher TLS abundance was associated with improved DFS in EGFR mutation-positive NSCLC, especially in L858R tumors. TLS abundance may reflect a more active cytotoxic immune niche and contribute to differential therapeutic responses; however, mechanistic interpretations require further validation.