Lymphocyte access to lymphoma is impaired by high endothelial venule regression

ABSTRACT: Summary 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. Graphical abstract Highlights • Aggressive B-cell-lymphoma-induced immunosuppressive niche in lymph nodes• Lymphoma causes a vascular remodeling cascade within the lymph node stroma• Loss of DC-HEV crosstalk deprives blood endothelial cells of LTβR signaling• Lymphoma-induced HEV dedifferentiation is detrimental for immune cell trafficking Menzel et al. report high endothelial venules (HEVs) regression that is detrimental for immune cell trafficking in lymph nodes with lymphoma. HEV dedifferentiation occurs as a consequence of a disrupted conduit system and impairment of chemokine-guided lymphocyte migration. Loss of dendritic cell-HEV interaction abrogates lymphotoxin β-receptor signaling, required for HEV maintenance.

SUBMITTER: Menzel L 

PROVIDER: S-EPMC8567313 | biostudies-literature |

REPOSITORIES: biostudies-literature