Lymphocyte access to lymphoma is impaired by high endothelial venule regression

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-beta-receptor (LTbR) 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.

Automated summary

The study demonstrates that lymphoma leads to severe regression of high endothelial venules (HEVs) in the lymph nodes, disrupting immune cell trafficking and interactions in the microenvironment. This cascade of events involves the disruption of the lymph-carrying conduit system, deregulation of CCL21 migration paths, and loss of lymphotoxin-beta-receptor (LTbR) signaling, ultimately affecting HEV differentiation and lymphocyte transmigration.