Abstract
SummaryBlood 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.
Highlights
Lymph nodes (LNs) integrate two vascular systems to maintain homeostasis, comprising blood and lymphatic vessels (Drayton et al, 2006; Liao and Ruddle, 2006)
high endothelial venules (HEVs) are postcapillary venules, which furnish lymphocyte transmigration routes. To fulfill their pivotal role in lymphocyte homing, mature HEVs must be equipped with peripheral node addressin (PNAd), which engages with lymphocyte-expressed L-selectin, followed by a process referred to as tethering and rolling (Girard et al, 2012)
Lymphoma-induced LN expansion relies on differential induction of blood endothelial cells (BECs) subsets The mechanisms and kinetics of inflammation-induced LN expansion are well described, whereas lymphoma-associated LN expansion correlating with tumor progression remains to be elucidated
Summary
Lymph nodes (LNs) integrate two vascular systems to maintain homeostasis, comprising blood and lymphatic vessels (Drayton et al, 2006; Liao and Ruddle, 2006). HEVs are postcapillary venules, which furnish lymphocyte transmigration routes To fulfill their pivotal role in lymphocyte homing, mature HEVs must be equipped with peripheral node addressin (PNAd), which engages with lymphocyte-expressed L-selectin, followed by a process referred to as tethering and rolling (Girard et al, 2012). The homeostatic chemokine CCL21 expressed and immobilized on HEVs recruits naive and central memory T cells via the CCR7 receptor. This leads to integrin aLb2 (LFA-1) affinity enhancement, lymphocyte arrest, and transendothelial migration (Girard et al, 2012). The importance of this dynamic system has been elucidated under homeostatic conditions, and further insights into the remodeling and molecular factors involved were obtained from infection models (Guarda et al, 2007; Veerman et al, 2019)
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