Translational Tumorimmunology, Max-Delbrück-Center for Molecular Medicine Berlin, Germany, 13125 Berlin, Germany.
Microenvironmental Regulation in Autoimmunity and Cancer, Max-Delbrück-Center for Molecular Medicine Berlin, 13125 Berlin, Germany.
Cell Rep. 2021 Oct 26;37(4):109878. doi: 10.1016/j.celrep.2021.109878.
Blood endothelial cells display remarkable plasticity depending on the demands of a malignant microenvironment. While studies in solid tumors focus on their role in metabolic adaptations, formation of high endothelial venules (HEVs) in lymph nodes extends their role to the organization of immune cell interactions. As a response to lymphoma growth, blood vessel density increases; however, the fate of HEVs remains elusive. Here, we report that lymphoma causes severe HEV regression in mouse models that phenocopies aggressive human B cell lymphomas. HEV dedifferentiation occurrs as a consequence of a disrupted lymph-carrying conduit system. Mechanosensitive fibroblastic reticular cells then deregulate CCL21 migration paths, followed by deterioration of dendritic cell proximity to HEVs. Loss of this crosstalk deprives HEVs of lymphotoxin-β-receptor (LTβR) signaling, which is indispensable for their differentiation and lymphocyte transmigration. Collectively, this study reveals a remodeling cascade of the lymph node microenvironment that is detrimental for immune cell trafficking in lymphoma.
血液内皮细胞具有显著的可塑性，这取决于恶性微环境的需求。虽然在实体瘤中的研究集中在它们在代谢适应中的作用，但淋巴结中高内皮静脉（HEV）的形成将它们的作用扩展到了免疫细胞相互作用的组织上。作为对淋巴瘤生长的反应，血管密度增加；然而，HEV 的命运仍然难以捉摸。在这里，我们报告说，淋巴瘤导致小鼠模型中严重的 HEV 退化，这种现象类似于侵袭性人类 B 细胞淋巴瘤。HEV 去分化是由于淋巴管输送系统的破坏。然后，机械敏感的纤维状网状细胞使 CCL21 的迁移路径失调，随后树突状细胞与 HEV 接近的情况恶化。这种串扰的丧失剥夺了 HEV 的淋巴毒素-β-受体（LTβR）信号，这对于它们的分化和淋巴细胞迁移是必不可少的。总的来说，这项研究揭示了淋巴结微环境的重塑级联反应，这对淋巴瘤中免疫细胞的迁移是有害的。
