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目的 基于生物信息学方法探讨三级淋巴结构(TLS)在头颈部鳞状细胞癌(HNSCC)中的免疫功能特征及其对患者预后评估的价值，并分析其与肿瘤免疫微环境及突变特征的关系，为HNSCC治疗策略制定提供参考。方法 通过TCGA数据库获取HNSCC患者(522个肿瘤组织样本和44个正常对照组织样本)转录组数据及临床资料，筛选TLS相关基因并采用单样本基因集富集分析(ssGSEA)计算TLS评分，根据TLS评分的最佳截断值(Cut-off)将患者分为高评分TLS和低评分TLS。比较不同评分患者总生存率，并采用单因素及多因素Cox回归分析评估TLS评分的预后价值。进一步筛选不同评分的差异表达基因并进行GO及KEGG富集分析。采用CIBERSORT算法评估免疫细胞富集程度，分析不同TLS评分下免疫微环境状态。使用maftools计算肿瘤突变负荷(TMB),并分析其与TLS评分的相关性，同时比较免疫检查点基因的表达差异。结果 高评分TLS患者的总生存率高于低评分TLS患者(P<0.05),Cox回归分析显示TLS评分、年龄和分期是HNSCC患者临床预后的独立影响因素(P均<0.05)。差异表达基因主要富集于细胞因子-细胞因子受体相互作用、T细胞受体信号通路及B细胞受体信号通路等肿瘤免疫相关通路。高TLS评分与低TLS评分相比，多种抗肿瘤免疫细胞富集程度更高(P均<0.05)。TLS评分与TMB呈负相关(P<0.05),TP53、TTN、FAT1和CDKN2A等基因在HNSCC中突变频率较高，且高评分TLS中11个免疫检查点基因表达水平高于低评分TLS组(P均<0.05)。结论 TLS水平与HNSCC患者预后及肿瘤免疫微环境密切相关，TLS评分可能作为HNSCC潜在预后评估指标，并为免疫治疗及靶向治疗策略的制定提供参考。
Abstract：Objective To investigate the immune characteristics of tertiary lymphoid structure(TLS) in head and neck squamous cell carcinoma(HNSCC), their prognostic value, and their associations with the tumor immune microenvironment and mutational features, so as to provide a reference for the formulation of treatment strategies for HNSCC. Methods Transcriptomic data and clinical information of 522 tumor samples and 44 normal control samples were obtained from The Cancer Genome Atlas(TCGA) database. TLS scores were calculated using single-sample gene set enrichment analysis(ssGSEA), and patients were stratified into the high-score TLS and low-score TLS based on the optimal cut-off value. Survival analysis and Cox regression were performed to assess prognostic significance. Differentially expressed genes were subjected to Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) analyses. We evaluated the enrichment of immune cells using the Cell-type Identification by Estimating Relative Subsets of RNA Transcripts(CIBERSORT) algorithm and analyzed the status of the immune microenvironment under different TLS scores. We calculated the tumor mutation burden(TMB) with maftools and analyzed its correlation with TLS scores. Meanwhile, the expression differences of immune checkpoint genes were compared.Results Overall survival was higher in the high-score TLS than in the low-score TLS(P<0.05). TLS score, age, and stage were independent influencing factors for clinical prognosis of HNSCC patients(all P<0.05). Differentially expressed genes were mainly enriched in tumor immunity-related pathways such as cytokine-cytokine receptor interaction, T-cell receptor signaling pathway, and B-cell receptor signaling pathway. The high-score TLS showed higher infiltration levels of multiple antitumor immune cells(all P<0.05). TLS score was negatively correlated with TMB(P<0.05). TP53, TTN, FAT1, and CDKN2A had high mutation frequencies. In addition, the expression levels of 11 immune checkpoint genes in the high-score TLS group were higher than those in the lows-core TLS group(all P<0.05).Conclusions TLS is closely associated with prognosis and the tumor immune microenvironment in HNSCC. TLS score may serve as a potential prognostic biomarker and provide insights for immunotherapy and targeted therapy.
[1] WANG M,PAN M,LI Y S,et al.ANXA6/TRPV2 axis promotes lymphatic metastasis in head and neck squamous cell carcinoma by inducing autophagy[J].Exp Hematol Oncol,2023,12(1):43.
[2] HADDAD R I,HARRINGTON K,TAHARA M,et al.Nivolumab plus ipilimumab versus extreme regimen as first-line treatment for recurrent/metastatic squamous cell carcinoma of the head and neck:the final results of checkMate 651[J].J Clin Oncol,2023,41(12):2166-2180.
[3] ZHAO L Y,JIN S,WANG SH Y,et al.Tertiary lymphoid structures in diseases:immune mechanisms and therapeutic advances[J].Signal Transduct Target Ther,2024,9(1):225.
[4] SCHUMACHER T N,THOMMEN D S.Tertiary lymphoid structures in cancer[J].Science,2022,375(6576):eabf9419.
[5] LI J,CHEN G,LUO Y,et al.The molecular subtypes and clinical prognosis characteristic of tertiary lymphoid structures-related gene of cutaneous melanoma[J].Sci Rep,2023,13(1):23097.
[6] CHEN Q,WANG SH Y,CHEN Y,et al.Novel pretreatment nomograms based on pan-immune-inflammation value for predicting clinical outcome in patients with head and neck squamous cell carcinoma[J].Front Oncol,2024,14:1399047.
[7] SAEIDPOUR MASOULEH S,NASIRI K,OSTOVAR RAVARI A,et al.Advances and challenges in CAR-T cell therapy for head and neck squamous cell carcinoma[J].Biomark Res,2025,13(1):69.
[8] FARAH C S.Molecular landscape of head and neck cancer and implications for therapy[J].Ann Transl Med,2021,9(10):915.
[9] VAHABI M,BLANDINO G,DI AGOSTINO S.MicroRNAs in head and neck squamous cell carcinoma:a possible challenge as biomarkers,determinants for the choice of therapy and targets for personalized molecular therapies[J].Transl Cancer Res,2021,10(6):3090-3110.
[10] HELMINK B A,REDDY S M,GAO J J,et al.B cells and tertiary lymphoid structures promote immunotherapy response[J].Nature,2020,577(7791):549-555.
[11] CUI X,GU X,LI D,et al.Tertiary lymphoid structures as a biomarker in immunotherapy and beyond:advancing towards clinical application[J].Cancer Lett,2025,613:217491.
[12] MUNOZ-ERAZO L,RHODES J L,MARION V C,et al.Tertiary lymphoid structures in cancer-considerations for patient prognosis[J].Cell Mol Immunol,2020,17(6):570-575.
[13] TEILLAUD J L,HOUEL A,PANOUILLOT M,et al.Tertiary lymphoid structures in anticancer immunity[J].Nat Rev Cancer,2024,24(9):629-646.
[14] LYNCH K T,YOUNG S J,MENEVEAU M O,et al.Heterogeneity in tertiary lymphoid structure B-cells correlates with patient survival in metastatic melanoma[J].J Immunother Cancer,2021,9(6):e002273.
[15] JIANG L L,LI S,ZHOU P,et al.The germinal center-tertiary lymphoid structure after neoadjuvant chemo-immunotherapy for locally advanced lung squamous cell carcinoma can predict the disease progression[J].Front Immunol,2025,16:1579840.
[16] KAGAMU H,YAMASAKI S,KITANO S,et al.Single-cell analysis reveals a CD4+ T-cell cluster that correlates with PD-1 blockade efficacy[J].Cancer Res,2022,82(24):4641-4653.
[17] CHEN H Q,MA R,ZHOU B J,et al.Integrated immunological analysis of single-cell and bulky tissue transcriptomes reveals the role of interactions between M0 macrophages and naive CD4+ T cells in the immunosuppressive microenvironment of cervical cancer[J].Comput Biol Med,2023,163:107151.
[18] YILMAZ E,ISMAILA N,BAUMAN J E,et al.Immunotherapy and biomarker testing in recurrent and metastatic head and neck cancers:ASCO guideline[J].J Clin Oncol,2023,41(5):1132-1146.
[19] LI W J,ZHOU K ZH,LI M T,et al.Identification of SCN7A as the key gene associated with tumor mutation burden in gastric cancer[J].BMC Gastroenterol,2022,22(1):45.
[20] SPERLING A S,GUERRA V A,KENNEDY J A,et al.Lenalidomide promotes the development of TP53-mutated therapy-related myeloid neoplasms[J].Blood,2022,140(16):1753-1763.
[21] HAASE D,STEVENSON K E,NEUBERG D,et al.TP53 mutation status divides myelodysplastic syndromes with complex karyotypes into distinct prognostic subgroups[J].Leukemia,2019,33(7):1747-1758.
[22] BISHNUPURI K S,ALVARADO D M,KHOURI A N,et al.IDO1 and kynurenine pathway metabolites activate PI3K-AKT signaling in the neoplastic colon epithelium to promote cancer cell proliferation and inhibit apoptosis[J].Cancer Res,2019,79(6):1138-1150.
[23] STARZER A M,BERGHOFF A S.New emerging targets in cancer immunotherapy:CD27 (TNFRSF7)[J].ESMO Open,2020,4(Supll 3):e629.
[24] YU X,HARDEN K,GONZALEZ L C,et al.The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells[J].Nat Immunol,2009,10(1):48-57.
[25] ZHAI L J,LADOMERSKY E,LENZEN A,et al.IDO1 in cancer:a gemini of immune checkpoints[J].Cell Mol Immunol,2018,15(5):447-457.
基本信息:
中图分类号:R739.91
引用信息:
[1]王浩然,张梦琪,张宁,等.三级淋巴结构评分在头颈部鳞状细胞癌预后评估及靶向治疗中的作用分析[J].山东医药,2026,66(04):16-20.
基金信息:
山东省自然科学基金青年项目(ZR2022QH395)
2026-04-25
2026-04-25