Angiogenesis in Lymph Nodes Is a Critical Regulator of Immune Response and Lymphoma Growth

Abstract

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.

Lymphocyte access to lymphoma is impaired by high endothelial venule regression

“…In line, we found a strong reduction and even entire loss of HEVs in DLBCL and BL, a finding that was in strong contrast to largely intact HEVs in cHL. Different from the two aggressive B-NHL entities, cHL harbors only a minority of tumor-defining Hodgkin-Reed-Sternberg (HRS) cells, surrounded by a predominant benign immune cell infiltrate ( Menzel et al., 2020 ). Data showed that HRS-derived LTα activates ECs to enhance naive T cell recruitment by upregulating adhesion molecules and the ECM component hyaluronan ( Fhu et al., 2014 ).…”

“…Despite their origin as autochthonous LN tumors, very little is known about the fate of HEVs in the context of B cell lymphoma (BCL). An important blood vessel pathology is the angiogenic increase of the microvessel density (MVD) ( Cardesa-Salzmann et al., 2011 ; Gloger et al., 2020 ; Menzel et al., 2020 ), which is prognostically unfavorable in diffuse large BCL (DLBCL). A previous immunohistology study found reduced numbers of HEVs with a damaged appearance in high-grade B cell non-Hodgkin lymphoma (B-NHL), while in low-grade tumors, HEVs were preserved ( Pajor et al., 1990 ).…”

“…Here, we report a severe loss of HEVs in two independent aggressive lymphoma mouse models, a phenotype that we validated in human DLBCL. While it seems clear that mouse models can not exactly phenocopy B cell origin, phenotype, and genetics of defined human lymphoma entities, they are suitable to mimic features like growth kinetics, homing, migration, and dependency on a non-malignant LN infrastructure ( O’Connor et al., 2019 ; Menzel et al., 2020 ). Furthermore, they provide insight into processes at tumor onset in an in vivo setting, whereas human specimens are usually obtained from established and progressed lymphoma with a severely disturbed LN microanatomy.…”

Anlotinib: A Novel Targeted Drug for Bone and Soft Tissue Sarcoma

“…New vessels in tumor tissues are lifelines for the development of tumor cells. Through continuous angiogenesis, nutrients are continuously supplied and, at the same time, provide vascular channels for the distant local invasion and metastasis of tumor cells (14)(15)(16). Therefore, continuous angiogenesis ensures the continuation of the biological behaviors of tumors (15,16).…”

“…Through continuous angiogenesis, nutrients are continuously supplied and, at the same time, provide vascular channels for the distant local invasion and metastasis of tumor cells (14)(15)(16). Therefore, continuous angiogenesis ensures the continuation of the biological behaviors of tumors (15,16). Tumor angiogenesis (TA) also plays an essential role in tumors, especially in the malignant tumor system.…”