The Lymphatic Endothelium in the Context of Radioimmuno-Oncology

Abstract

The study of lymphatic tumor vasculature has been gaining interest in the context of cancer immunotherapy. These vessels constitute conduits for immune cells' transit toward the lymph nodes, and they endow tumors with routes to metastasize to the lymph nodes and, from them, toward distant sites. In addition, this vasculature participates in the modulation of the immune response directly through the interaction with tumor-infiltrating leukocytes and indirectly through the secretion of cytokines and chemokines that attract leukocytes and tumor cells. Radiotherapy constitutes the therapeutic option for more than 50% of solid tumors. Besides impacting transformed cells, RT affects stromal cells such as endothelial and immune cells. Mature lymphatic endothelial cells are resistant to RT, but we do not know to what extent RT may affect tumor-aberrant lymphatics. RT compromises lymphatic integrity and functionality, and it is a risk factor to the onset of lymphedema, a condition characterized by deficient lymphatic drainage and compromised tissue homeostasis. This review aims to provide evidence of RT's effects on tumor vessels, particularly on lymphatic endothelial cell physiology and immune properties. We will also explore the therapeutic options available so far to modulate signaling through lymphatic endothelial cell receptors and their repercussions on tumor immune cells in the context of cancer. There is a need for careful consideration of the RT dosage to come to terms with the participation of the lymphatic vasculature in anti-tumor response. Here, we provide new approaches to enhance the contribution of the lymphatic endothelium to radioimmuno-oncology.

Keywords: lymphatic system; lymphedema; radioimmuno-oncology; radioresistance; vasculature.

Figure 1

An overview of the Antitumorigenic and Pro-Tumorigenic effects of Radiotherapy. Basis of radiation-induced immunogenic cell death (A). Irradiation induces an increase in both ROS and MHC-I molecules in the tumor microenvironment, leading to DNA damage and more permissive antitumor activity by enhancing innate and adaptive cell activation. DNA damage induces apoptosis in tumor cells with the consequent release of ATP, DAMP and TAA which, through interaction with TLRs in DCs, cause their maturation. These mature DCs will migrate to the LN where they will cross-present Ag through MHC-I and II to CD8 and CD4 T cells, respectively, and trigger the clonal expansion of B lymphocytes. Barriers to radiation-induced immunogenic cell death (B). Irradiation can also induce the release of immunosuppressive molecules: TGFβ release can inhibit DC maturation, suppress immune effector functions and enhance DNA repair; SDF-1, CSF-1 and CCL2 attract myeloid-derived suppressor cells and induce neovascularization; PDL-1 on the tumor surface can interact with its PD-1 counterpart on T cells, leading to their inactivation. Point arrows mean activation while blunt arrows mean inhibition. ROS reactive oxygen species; DC, dendritic cell; DAMPs, damage-associated molecular patterns; TAA, tumor associated antigens; TLR, toll-like receptor; TCR, T cell receptor; MHC, major histocompatibility complex; TNFα, tumor necrosis factor; IL, interleukin; LN, lymph node; BMSCs, born marrow stromal cells; CAFs, cancer associated fibroblast; TGFβ, transforming growth factor receptor; NK, natural killers; SDF-1 stromal cell-derived factor 1; CCL2, C-C motif chemokine ligand 2; CSF-1, colony-stimulating factor 1; PDL-1, programmed death ligand 1; MDSc, myeloid derived suppressor cells.

Figure 2

Effects of Ionizing Radiation on the Blood (A) and Lymphatic vasculature (B). IR, irradiation; HIF-1α, hypoxia-inducible factor 1; M1, macrophage type 1; M2, macrophage type 2; BM, basal membrane; EC, endothelial cell; LEC, lymphatic endothelial cell; ROS, radical oxygen species; ICAM-1, intercellular adhesion molecule 1; V-CAM, vascular cell adhesion molecule 1; TNFα, necrosis tumoral alfa; IL, interleukin; ATP, adenosine triphosphate; VEGFC, vascular endothelial growth factor C; VEGFD, vascular endothelial growth factor D; COX2, cyclooxygenase-2; DC, dendritic cell.

Figure 3

The Ying and Yang of the Lymphatic Vasculature in the Context of Tumor Microenvironment. Whereas the lymphatic system is essential in maintenance of internal homeostasis, it could also favor tumor cell metastasis: 1. Fluid and particle absorption through lymphatic capillaries; 2. Chemoattractant migration gradient of immune and tumoral cells driven by CCR7-CCL21/CCl19 interaction; 3. Macrophage transdifferentiation into LECs; 4. IL1β and VEGFC induce LEC proliferation and migration; 5. Tumor cells can acquire a senescence state while migrating through the lymphatic system; 6. IDO and NO factors released from LECs can lead to T cell proliferation inhibition; 7. MAC-1 and ICAM-1 interaction induce DC maturation inhibition; 8. Lymph pressure, together with muscles and valves on contractile collectors, impulse cells into LN; 9. B cell maturation and activation takes place on LN together with T cell activation, expansion and migration; 10. VEGFC/D ligands released by some tumoral, fibroblastic and immune cells, generate an increment in permeability, lymphangiogenesis and metastasis while interacting with VEGFR3 receptors on lymphatic vessels’ surfaces; 11. LECs can express PDL1 on each surface, playing a fundamental role in peripheral tolerance balance; 12. Leukocyte migration under inflammation is driven by LFA-1 and ICAM-1 interaction; 13. Some inflammatory cytokines such as IL1β, TNFα and IL10 can attract VEGFC-secreting leukocytes. TAMs, tumor associated macrophages; VEGFC/D, vascular endothelial growth factor C/D; LEC, lymphatic endothelial cell; IDO, indoleamine-pyrrole 2,3-dioxygenase; NO, nitric oxide; MAC-1, macrophage-1 antigen; ICAM-1, intercellular adhesion molecule 1; VEGFR3, vascular endothelial growth factor receptor 3; LN, lymph node; Bc, B cells; Fc, follicular cells; Pc, plasma cells; TNFα, tumor necrosis factor; IL1β, interleukin 1β; IL10, interleukin 10; NK, natural killer cell; LFA-1, lymphocyte function-associated antigen-1; TCR, T-cell receptor; MHC-I, major histocompatibility complex I; PD1/PDL1, programmed death-1/programmed death ligand-1; CCR7, C-C chemokine receptor type 7; CCL21/19, C-C chemokine ligand 21/19; DCs, dendritic cells; CAFs, cancer associated fibroblasts.