三级淋巴结构:肿瘤免疫治疗的预后因素与新兴靶点

Tertiary lymphoid structures:prognostic factors and emerging targets for tumor immunotherapy

三级淋巴结构(TLS)是指非生理条件下由于长期发生炎症而形成的异位淋巴组织,是架构在成纤维细胞网络上的淋巴细胞聚集体,包含两个重要的结构区域——T细胞区和滤泡B细胞区。TLS在肿瘤中以不同的成熟状态存在,最终形成生发中心,其内含有T滤泡辅助细胞和滤泡树突状细胞,并且与B细胞紧密联系。近年研究明确了新生的TLS的关键特征、相关的生物标志物及检测手段,进一步阐述了TLS通过刺激相关的肿瘤抗原调控淋巴细胞的浸润,以增强抗肿瘤免疫效应的作用机制。对TLS与肿瘤患者临床获益之间的相关性研究结果表明,TLS可作为包括免疫治疗在内的生物治疗的良好预后和预测因素。目前,研究者正在开发诱导TLS形成的技术,包括使用趋化因子、细胞因子、抗体、抗原提呈细胞或合成支架等。在“冷肿瘤”和“热肿瘤”中诱导TLS新生联合抑制炎性环境的治疗剂或免疫检查点抑制剂的方案,代表了肿瘤治疗的新希望。

Tertiary lymphoid structure(TLS)refers to ectopic lymphoid tissue formed at long-term inflammatory sites in nonphysiological conditions.It is a lymphocyte aggregate constructed on the fibroblast network and contains two important structural regions-the T cell region and the follicular B cell region.TLS exists in different mature states in tumors,and finally forms germinal centers.Germinal centers contain T follicular helper cells and follicular dendritic cells,and are closely related to B cells.Recent studies have identified the main features,biomarkers and detection methods of newborn TLS,further expounding the mechanism that TLSs can enhance the effect of anti-tumor immune response by stimulating related tumor antigens and regulating lymphocyte infiltration.Studies on the relevance between TLSs and clinical benefits of cancer patients show that TLSs can be used as a good prognosis and predictive factor for biotherapies including immunotherapy.Several methods to induce TLS formation are currently being developed,including the use of chemokines,cytokines,antibodies,antigen presenting cells or synthetic scaffolds.The regimen of inducing TLS neogenesis in cold tumors and hot tumors in combination with therapeutic agents for inflammatory environment suppression or immune checkpoint inhibitors,represents a new hope for cancer treatment.