The impact of tertiary lymphoid structures on clinicopathological, genetic and gene expression characteristics in lung adenocarcinoma

Introduction: Tertiary lymphoid structures (TLS) are observed in several cancers and are associated with favorable prognosis. This study aimed to examine the clinicopathological, genetic, and gene expression profiles of lung adenocarcinoma patients with TLS. Methods: A total of 112 patients with pathological stage IB lung adenocarcinoma who underwent complete resection between 2011 and 2015 were enrolled in this study. We investigated whether TLS correlated with prognosis and programmed death-ligand 1 (PD-L1) expression. Furthermore, the correlation of TLS with tumor mutation burden (TMB) and genetic mutations was evaluated in patients for whom whole-exon sequencing data were available. In addition, using the Cancer Genome Atlas Lung Adenocarcinoma (TCGA-LUAD) dataset, gene expression analysis according to the TLS status was performed. Results: Among the 112 patients, 49 were TLS-positive (TLS+). TLS+ correlated with longer recurrence-free survival (RFS) than TLS-negative cases (TLS−) (hazard ratio [HR], 0.47; 95 % confidence interval [CI]: 0.23–0.88, p = 0.02). In the multivariate analysis, TLS was a better independent prognostic factor for RFS (HR 0.37, 95 %CI 0.18–0.72, p < 0.01). PD-L1 expression was not significantly different between TLS+ and TLS− patients (p = 0.54). TMB in TLS+ was similar to that in TLS− patients (p = 0.39); however, it tended to be lower than that in TLS− especially among smokers (p = 0.07). In gene expression analysis, RNA expression of chemokines related to lymph node formation, such as CXCL13, CCL19 and CCL21, was significantly higher, and biological processes such as positive regulation of humoral immune response and regulation of antigen receptor-mediated signaling pathway were enhanced in TLS+. Conclusions: TLS was a favorable prognostic factor and was not associated with PD-L1 expression in patients with lung adenocarcainoma. Moreover, gene expression analysis indicated that TLS is a site for the generation and regulation of antitumor immune responses.