Immunomodulatory Roles of Lymphatic Vessels in Cancer Progression

Abstract

Lymphatic vessels in the tumor microenvironment are known to foster tumor metastasis in many cancers, and they can undergo activation, hyperplasia, and lymphangiogenesis in the tumor microenvironment and in the tumor-draining lymph node. The mechanism underlying this correlation was originally considered as lymphatic vessels providing a physical route for tumor cell dissemination, but recent studies have highlighted new roles of the lymphatic endothelium in regulating host immunity. These include indirectly suppressing T-cell function by secreting immunosuppressive factors and inhibiting dendritic cell (DC) maturation, as well as directly driving Tcell tolerance by antigen presentation in the presence of inhibitory ligands.

Tumor-associated Lymphatic Endothelial Cells Promote Lymphatic Metastasis By Highly Expressing and Secreting SEMA4C

“…However, recent studies on the immunoregulatory function of lymphatic endothelial cells (LEC) in inflammation (i.e., in wound healing and tumor metastasis) have included a new focus on LECs. In addition to providing a physical route for leukocyte transport, LECs have emerged as active players that control transport functions and directly communicate with immune cells (5)(6)(7). Nevertheless, whether and how LECs actively regulate lymphangiogenesis or communicate with tumor cells remains unclear.…”

Prognostic Significance of CD169+ Lymph Node Sinus Macrophages in Patients with Malignant Melanoma

“…In tumor immunology, the regional lymph nodes (RLN) that drain various malignant tumors, including malignant melanoma, are primary sites of the innate immune response (4). Fragmented dead tumor cells flow into the sinus area of the lymph node through lymphatic vessels (5) and are endocytosed by specific resident macrophages known as sinus macrophages. Sinus macrophages internalize, process, and present antigens on MHC I and induce the activation of the tumor antigen-specific lymphocyte response (6,7).…”

From T cell “exhaustion” to anti-cancer immunity

“…Their cytotoxic activity and cytokine production is attenuated as compared to acute infections. Multiple factors in the TME contribute to this attenuation (reviewed in [40][41][42][43][44][45][46][47]). Similar to unresolved (chronic) viral infections such as human immunodeficiency virus (HIV) or hepatitis, the immune response is mitigated and establishes an equilibrium of immune activation and attenuation.…”

“…These factors may directly inhibit immune defense mechanisms, or disrupt immune activatory pathways. Due to space limitations we cannot cover the entire field and therefore refer to the literature [40][41][42][43][44][45][46][47]. In this review, we will focus on two areas, namely (i) inhibitory lymphocyte receptors, and (ii) T cell signaling and transcriptional regulation.…”