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

Abstract

BackgroundLung 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.MethodsClinical 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.ResultsTLS 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.ConclusionThis 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.

The Presence of Tertiary Lymphoid Structures Provides New Insight Into the Clinicopathological Features and Prognosis of Patients With Breast Cancer

“…Recently, several gene signatures detecting TLSs identified from transcriptomic analysis were proven to be feasible in the quantification of TLSs. The 9-gene TLS signature mainly represented the B cells and T cells in TLSs, which was thought to be more representative of TLS-associated gene expression than the 12-chemokine signature ( 32 ). The 9-gene signature has been used for TLS quantification in a variety of solid tumors such as lung adenocarcinoma and melanoma, conveying significant prognostic and predictive value ( 15 , 32 ).…”

“…The 9-gene TLS signature mainly represented the B cells and T cells in TLSs, which was thought to be more representative of TLS-associated gene expression than the 12-chemokine signature ( 32 ). The 9-gene signature has been used for TLS quantification in a variety of solid tumors such as lung adenocarcinoma and melanoma, conveying significant prognostic and predictive value ( 15 , 32 ). First, we comparatively assessed the differential expression of 9 genes between tumor and normal tissues in the TCGA BC cohort ( Figure S1 ).…”

Tertiary lymphoid structures in lung adenocarcinoma: characteristics and related factors

“…[11][12][13][14] The beneficial effect of TLSs on tumors positively correlates with their density and maturity in the tumor area; however, due to their remarkable heterogeneity, no effective method was found to predict TLSs. 13,[15][16][17][18] Although TLSs have been extensively studied in NSCLC, only a handful of studies have been carried out on their role in lung adenocarcinoma (LAC). Furthermore, those studies have mainly focused either on the function of TLSs components, such as protective B cells, 19 infiltrating T cells, 20 and immuno-suppressive regulatory T cells 21 or on the possible strategies to modulate TLSs.…”

“… 11 , 12 , 13 , 14 The beneficial effect of TLSs on tumors positively correlates with their density and maturity in the tumor area; however, due to their remarkable heterogeneity, no effective method was found to predict TLSs. 13 , 15 , 16 , 17 , 18 …”

“…TLSs have been proven to improve antitumor responses and predict the efficacy of immunotherapy 11–14 . The beneficial effect of TLSs on tumors positively correlates with their density and maturity in the tumor area; however, due to their remarkable heterogeneity, no effective method was found to predict TLSs 13,15–18 …”