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Background  Lung adenocarcinoma (LUAD) is a highly mortal cancer. Tertiary lymphoid structures (TLS) are ectopic lymphoid organs with similar morphological and molecular characters to secondary lymphoid organ. The aim of this study is to investigate the prognostic effect of a gene signature associated with TLSs, including B-cell-specific genes.    Methods  Clinical data of 515 LUAD patients in the TGCA cohort were used to examine the relationship of TLS signature with immune microenvironment, tumor mutational burden (TMB), and driver gene mutations. Patients were divided into the TLS signature high group and TLS signature low group, and comparative analysis of survival and its influencing factors between the two groups was performed. The resulting data were then validated in the GSE37745 cohort.    Results  TLS signature high group had significantly better overall survival (OS) and progression-free interval (PFI) as well as significantly higher infiltration of immune cell subsets, cancer immune cycle (CIC) signature except for immunogram score2 (IGS2), and expression of major checkpoint genes than the TLS signature low group. Notably, while TLS signature was not markedly associated with TMB and mutation frequencies of driver genes, there were significant differences in overall survival of patients with given mutation status of  EGFR ,  KRAS ,  BRAF  and  TP53  genes between the TLS signature high and low groups.    Conclusion  This study provided evidence that LUAD patients with high TLS signature had a favorable immune microenvironment and better prognosis, suggesting that TLS signature is an independent positive prognostic factor for LUAD patients.

Prognostic Significance of Gene Signature of Tertiary Lymphoid Structures in Patients With Lung Adenocarcinoma