Yuan Zongxiang, Huang Shihui, Qin Fang, Wang Fengyi, Wei Hailun, Luo Shengrui, Zhang Yukai, Liang Hao, Jiang Junjun, Ye Li
Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, 530021 Nanning, Guangxi, China.
Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-constructed by the Province and Ministry, Life Science Institute, Guangxi Medical University, 530021 Nanning, Guangxi, China.
Discov Med. 2025 Feb;37(193):299-314. doi: 10.24976/Discov.Med.202537193.24.
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 ( = 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; = 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; = 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; = 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.
尽管三级淋巴结构（TLSs）对肿瘤进展和预后具有潜在影响，但其在胃腺癌（STAD）中的作用仍不明确。
从癌症基因组图谱（TCGA）数据库中收集了362例STAD患者的数据。使用单样本基因组富集分析，基于9个基因特征对TLSs进行量化，并将患者分为TLS特征高（TLS高）组和TLS特征低（TLS低）组。评估TLS特征与预后、肿瘤微环境（TME）免疫状态、肿瘤突变负担和基因突变状态之间的关联。GSE26253队列作为外部数据集，用于验证TLS特征对STAD患者预后的预测作用。
在TCGA队列的男性STAD患者中，TLS高组的总生存期（OS）显著较低（P = 0.01）。多变量分析显示，TLS特征是I-III期STAD男性患者OS的显著独立负性预测因子（风险比（HR）：2.68；95%置信区间（CI）：1.19 - 6.00；P = 0.02）。TLS高的患者免疫细胞亚群浸润增加；然而，癌症免疫循环分析显示TME内既有抗肿瘤反应也有促肿瘤反应。相关性分析表明，TLS与免疫抑制相关细胞的关联比与抗肿瘤免疫细胞更强。此外，免疫抑制细胞募集因子、免疫抑制因子和免疫检查点受体的表达在TLS高组中高于TLS低组。尽管如此，在接受辅助治疗的I-III期STAD男性患者中，多变量分析确定TLS特征是GSE26253队列中无复发生存的显著独立正性预测因子（HR：0.61；95%CI：0.38 - 0.97；P = 0.04）。TLS特征与辅助治疗的相互作用对这些患者的OS产生了显著的正性影响（HR：0.41；95%CI：0.17 - 0.97；P = 0.04）。
在TCGA队列中，TLS特征是I-III期STAD男性患者的独立不良预后因素，且与免疫抑制性TME相关，二者相互作用影响患者预后。然而，辅助治疗可能会影响TLS对I-III期STAD男性患者预后的预测作用。
