Qin Chao, Cheng Shumin, Ma Jingyun, Li Lujing, Leng Yun, Zheng Lei, Chen Huiying, Mo Hui, Li Shi, Liang Yuhong, Zhang Yi, Li Wenxia, Liang Jing, Liu Yuxuan, Mai Junxuan, Hou Linlin, Wang Di, Zhu Ke, Huang Bihui
Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China.
Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
Front Immunol. 2025 Sep 1;16:1662573. doi: 10.3389/fimmu.2025.1662573. eCollection 2025.
mutations are prevalent in colorectal cancer (CRC) and generally confer a poor prognosis. Tertiary lymphoid structures (TLS), a critical component of the tumor immune microenvironment, exist in various malignancies and often correlate with improved immunotherapy response and survival. However, whether TLS can counteract the adverse prognostic effects of mutations in CRC remains unexplored. This study characterizes TLS features (location, number, maturity) as well as correlation to the mutation status and clinicopathological characteristics in CRC, and specifically evaluates the potential role of TLS in mitigating the negative prognostic impact of mutations.
Single-cell RNA sequencing data from GSE146771, GSE146771, GSE200997, GSE205506, and GSE231559, along with bulk RNA-seq data from the TCGA CRC cohort, were analyzed. Prognostic genes were identified using univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression, and subsequently used to construct TLS-related prognostic signatures. Kaplan-Meier survival analysis and receiver operating characteristic (ROC) curve analysis were used to evaluate the predictive performance of the signature. Immune infiltration was assessed using the ESTIMATE and CIBERSORT algorithms. Histopathological evaluation of TLS was conducted in tissue sections from 200 CRC patients. Clinicopathological features were compared between the wild-type (BRAF) and mutant (BRAF) groups. Associations between BRAF mutation status and TLS location, number, maturity, as well as overall survival (OS), were analyzed.
TLS displayed distinct expression patterns within the CRC tumor microenvironment. A 10-gene prognostic model was developed based on LASSO regression analysis. Patients with BRAF CRC exhibited unfavorable clinicopathological characteristics, including poor differentiation, advanced T stage, and lymph node metastasis. Meanwhile, BRAF CRC was associated with a greater number and higher maturity of TLS. Notably, patients with BRAF, TLS-high (TLS, and BRAF-TLS subgroups showed significantly improved OS compared to other groups.
TLS-related prognostic signatures serve as effective tools for predicting CRC outcomes. Moreover, intratumorally TLS may enhance the prognosis of patients with BRAF CRC, highlighting its potential as a therapeutic and prognostic biomarker. Colorectal cancer, mutation, tertiary lymphoid structures, tumor microenvironment, prognosis.
突变在结直肠癌（CRC）中普遍存在，通常预示着不良预后。三级淋巴结构（TLS）是肿瘤免疫微环境的关键组成部分，存在于多种恶性肿瘤中，且常与免疫治疗反应改善和生存期延长相关。然而，TLS是否能抵消CRC中突变的不良预后影响仍未得到探索。本研究对CRC中TLS的特征（位置、数量、成熟度）以及与突变状态和临床病理特征的相关性进行了表征，并特别评估了TLS在减轻突变的负面预后影响方面的潜在作用。
分析了来自GSE146771、GSE146771、GSE200997、GSE205506和GSE231559的单细胞RNA测序数据，以及来自TCGA CRC队列的批量RNA-seq数据。使用单变量Cox回归和最小绝对收缩和选择算子（LASSO）回归鉴定预后基因，随后用于构建与TLS相关的预后特征。采用Kaplan-Meier生存分析和受试者工作特征（ROC）曲线分析来评估该特征的预测性能。使用ESTIMATE和CIBERSORT算法评估免疫浸润情况。对200例CRC患者的组织切片进行了TLS的组织病理学评估。比较了野生型（BRAF）和突变型（BRAF）组的临床病理特征。分析了BRAF突变状态与TLS位置、数量、成熟度以及总生存期（OS）之间的关联。
TLS在CRC肿瘤微环境中表现出不同的表达模式。基于LASSO回归分析建立了一个包含10个基因的预后模型。BRAF CRC患者表现出不利的临床病理特征，包括低分化、T分期较晚和淋巴结转移。同时，BRAF CRC与更多数量和更高成熟度的TLS相关。值得注意的是，BRAF、TLS高（TLS）和BRAF-TLS亚组的患者与其他组相比，OS显著改善。
与TLS相关的预后特征是预测CRC预后的有效工具。此外，肿瘤内TLS可能改善BRAF CRC患者的预后，突出了其作为治疗和预后生物标志物的潜力。结直肠癌、突变、三级淋巴结构、肿瘤微环境、预后。
