Prognostic Significance of a 9-Gene Signature Related to Tertiary Lymphoid Structures in Male Stomach Adenocarcinoma Patients

The role of tertiary lymphoid structures (TLSs) in stomach adenocarcinoma (STAD) remains unclear despite their known potential effects on tumor progression and prognosis. Data were collected from 362 patients with STAD from The Cancer Genome Atlas (TCGA) database. Using single-sample genomic enrichment analysis, TLSs were quantified based on a 9-gene signature, and the patients were categorized into TLS-signature high (TLS-high) and TLS-signature low (TLS-low) groups. The association of TLS signature with prognosis, tumor microenvironment (TME) immune status, tumor mutation burden, and gene mutation status was evaluated. The GSE26253 cohort served as an external dataset to validate the prognostic predictive effect of the TLS signature in patients with STAD. The TLS-high group exhibited notably lower overall survival (OS) among male patients with STAD from the TCGA cohort (p = 0.01). Multivariate analysis revealed that the TLS signature was a significant independent negative predictor of OS in male patients with stage I-III STAD (hazard ratio (HR): 2.68; 95% confidence interval (CI): 1.19-6.00; p = 0.02). The TLS-high patients exhibited increased infiltration of immune cell subsets; however, cancer-immunity cycle analysis revealed both antitumor and protumor responses within the TME. Correlation analyses indicated that TLS was more strongly associated with immunosuppression-related cells than with antitumor immune cells. Furthermore, expressions of immunosuppressive cell-recruitment factors, immunosuppressive factors, and immune checkpoint receptors were higher in the TLS-high group than in the TLS-low group. Nonetheless, among male patients with stage I-III STAD who received adjuvant therapy, multivariate analysis identified TLS trait as a significant independent positive predictor of relapse-free survival in the GSE26253 cohort (HR: 0.61; 95% CI: 0.38-0.97; p = 0.04). Interaction of the TLS signature with adjuvant therapy exerted a significant positive effect on OS in these patients (HR: 0.41; 95% CI: 0.17-0.97; p = 0.04). In the TCGA cohort, the TLS signature acted as an independent adverse prognostic factor for male patients with stage I-III STAD and was associated with immunosuppressive TME, which interacted to affect patient prognosis. However, adjuvant therapy may affect the prognostic predictive effect of TLS in male patients with stage I-III STAD.