Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
Front Immunol. 2021 May 13;12:690105. doi: 10.3389/fimmu.2021.690105. eCollection 2021.
Tertiary lymphoid structures (TLS), also known as ectopic lymphoid structures (ELS) or tertiary lymphoid organs (TLO), represent a unique subset of lymphoid tissues noted for their architectural similarity to lymph nodes, but which conditionally form in peripheral tissues in a milieu of sustained inflammation. TLS serve as regional sites for induction and expansion of the host B and T cell repertoires an operational paradigm involving mature dendritic cells (DC) and specialized endothelial cells (i.e. high endothelial venules; HEV) in a process directed by TLS-associated cytokines and chemokines. Recent clinical correlations have been reported for the presence of TLS within tumor biopsies with overall patient survival and responsiveness to interventional immunotherapy. Hence, therapeutic strategies to conditionally reinforce TLS formation within the tumor microenvironment (TME) the targeting of DC, vascular endothelial cells (VEC) and local cytokine/chemokine profiles are actively being developed and tested in translational tumor models and early phase clinical trials. In this regard, a subset of agents that promote tumor vascular normalization (VN) have been observed to coordinately support the development of a pro-inflammatory TME, maturation of DC and VEC, local production of TLS-inducing cytokines and chemokines, and therapeutic TLS formation. This mini-review will focus on STING agonists, which were originally developed as anti-angiogenic agents, but which have recently been shown to be effective in promoting VN and TLS formation within the therapeutic TME. Future application of these drugs in combination immunotherapy approaches for greater therapeutic efficacy is further discussed.
三级淋巴结构（TLS），也称为异位淋巴结构（ELS）或三级淋巴器官（TLO），是一种独特的淋巴组织亚群，其结构与淋巴结相似，但在持续炎症的环境中，可在周围组织中条件性形成。TLS 作为诱导和扩增宿主 B 细胞和 T 细胞库的区域性位点，涉及成熟树突状细胞（DC）和专门的内皮细胞（即高内皮静脉；HEV），这一过程由与 TLS 相关的细胞因子和趋化因子指导。最近有报道称，肿瘤活检中存在 TLS 与患者的总体生存和对干预性免疫治疗的反应性相关。因此，在肿瘤微环境（TME）中条件性增强 TLS 形成的治疗策略，包括针对 DC、血管内皮细胞（VEC）和局部细胞因子/趋化因子谱的靶向治疗，正在转化肿瘤模型和早期临床试验中得到积极开发和测试。在这方面，一些促进肿瘤血管正常化（VN）的药物已被观察到可协同支持促炎 TME 的发展、DC 和 VEC 的成熟、TLS 诱导细胞因子和趋化因子的局部产生以及治疗性 TLS 的形成。本综述将重点介绍 STING 激动剂，它们最初被开发为抗血管生成剂，但最近已被证明可有效促进治疗性 TME 中的 VN 和 TLS 形成。进一步讨论了这些药物在联合免疫治疗方法中的未来应用，以提高治疗效果。
