Translational Tumor Immunology, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
Microenvironmental Regulation in Autoimmunity and Cancer, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
Front Immunol. 2020 Dec 3;11:591741. doi: 10.3389/fimmu.2020.591741. eCollection 2020.
Tumor-induced remodeling of the microenvironment in lymph nodes (LNs) includes the formation of blood vessels, which goes beyond the regulation of metabolism, and shaping a survival niche for tumor cells. In contrast to solid tumors, which primarily rely on neo-angiogenesis, hematopoietic malignancies usually grow within pre-vascularized autochthonous niches in secondary lymphatic organs or the bone marrow. The mechanisms of vascular remodeling in expanding LNs during infection-induced responses have been studied in more detail; in contrast, insights into the conditions of lymphoma growth and lodging remain enigmatic. Based on previous murine studies and clinical trials in human, we conclude that there is not a universal LN-specific angiogenic program applicable. Instead, signaling pathways that are tightly connected to autochthonous and infiltrating cell types contribute variably to LN vascular expansion. Inflammation related angiogenesis within LNs relies on dendritic cell derived pro-inflammatory cytokines stimulating vascular endothelial growth factor-A (VEGF-A) expression in fibroblastic reticular cells, which in turn triggers vessel growth. In high-grade B cell lymphoma, angiogenesis correlates with poor prognosis. Lymphoma cells immigrate and grow in LNs and provide pro-angiogenic growth factors themselves. In contrast to infectious stimuli that impact on LN vasculature, they do not trigger the typical inflammatory and hypoxia-related stroma-remodeling cascade. Blood vessels in LNs are unique in selective recruitment of lymphocytes via high endothelial venules (HEVs). The dissemination routes of neoplastic lymphocytes are usually disease stage dependent. Early seeding via the blood stream requires the expression of the homeostatic chemokine receptor CCR7 and of L-selectin, both cooperate to facilitate transmigration of tumor and also of protective tumor-reactive lymphocytes via HEV structures. In this view, the HEV route is not only relevant for lymphoma cell homing, but also for a continuous immunosurveillance. We envision that HEV functional and structural alterations during lymphomagenesis are not only key to vascular remodeling, but also impact on tumor cell accessibility when targeted by T cell-mediated immunotherapies.
肿瘤诱导的淋巴结（LN）微环境重塑包括血管的形成，这超出了代谢的调节范围，并为肿瘤细胞塑造了一个生存小生境。与主要依赖新血管生成的实体瘤不同，造血恶性肿瘤通常在次级淋巴器官或骨髓中的预先血管化的同源龛中生长。在感染诱导的反应中，扩张 LN 中的血管重塑机制已被更详细地研究；相比之下，对淋巴瘤生长和驻留的条件仍知之甚少。基于以前的小鼠研究和人类临床试验，我们得出结论，不存在适用于普遍 LN 特异性血管生成的程序。相反，与同源和浸润细胞类型紧密相连的信号通路不同程度地促进 LN 血管扩张。LN 中的炎症相关血管生成依赖于树突状细胞衍生的促炎细胞因子刺激成纤维细胞网状细胞中血管内皮生长因子-A（VEGF-A）的表达，进而触发血管生长。在高级别 B 细胞淋巴瘤中，血管生成与预后不良相关。淋巴瘤细胞在 LN 中迁移和生长，并自身提供促血管生成的生长因子。与影响 LN 血管的感染性刺激不同，它们不会触发典型的炎症和缺氧相关的基质重塑级联反应。LN 中的血管通过高内皮小静脉（HEV）选择性招募淋巴细胞是独特的。肿瘤淋巴细胞的传播途径通常取决于疾病阶段。早期通过血流播种需要稳态趋化因子受体 CCR7 和 L-选择素的表达，两者共同促进肿瘤以及保护性肿瘤反应性淋巴细胞通过 HEV 结构的迁移。从这个角度来看，HEV 途径不仅与淋巴瘤细胞归巢有关，而且在针对 T 细胞介导的免疫疗法时，对肿瘤细胞的可及性也有影响。我们设想，在淋巴瘤发生过程中，HEV 的功能和结构改变不仅是血管重塑的关键，而且还会影响肿瘤细胞的可及性。
