Article Figures & Data
Figures
- Figure 1.
Structure and function of initial and collecting lymphatic vessels. A, the lymphatic vessels of skin are composed of two plexuses, one superficial which extends into the dermal papillae near the subpapillary arterial network, which drains vertically into the deep lymphatic plexus below the second arterial network. B, initial lymphatic capillaries are blind-ended vessels with discontinuous basement membrane and no associated smooth muscle cells (SMC). At resting state, the lymphatic endothelial cells that comprise the initial capillaries are characterized by unique overlapping, button-like junctions that allow for passive flow and leukocyte trafficking through interendothelial gaps in an integrin-independent manner. Local inflammation results in vascular leakiness driving increased IFP and enhanced flows. At least in the mouse respiratory tract, inflammation is associated with a remodeling of the interendothelial junctions of initial capillaries into tight, zipper-like junctions. Lymphatic capillaries are anchored directly to the ECM through anchoring filaments, such that under high levels of IFP, stretching of ECM results in distension of initial capillaries and enhanced fluid flows and cellular trafficking both by intercellular and transcellular mechanisms. C, collecting vessels are larger vessels that have both a continuous basement membrane and SMC coverage. Collecting vessels are notably defined by the presence of a system of valves, which separates the vessel into functional units or lymphangions. SMCs mediate contraction of individual lymphangions that drives the opening of downstream valves while closing valves immediately upstream. This system of local contraction and relaxation drives unidirectional fluid flows from peripheral tissues to draining LNs.
- Figure 2.
Lymphatic vessels, inflammation, and immunity. A, homeostatic lymphatic capillaries support immune surveillance through steady-state homing of resident immune cells, including DCs and some subsets of memory T cells. B, local inflammation and damage activate a series of danger signaling as well as increased IFPs that activate initial lymphatic capillaries, resulting in remodeling (either proliferative or nonproliferative), upregulation of adhesion molecules, and enhanced expression of the homing chemokine C–C motif ligand 21 (CCL21). Altered adhesions and CCL21 coordinate to facilitate entry of activated CCR7+ DCs into afferent lymphatic vessels and migration toward draining LNs where they interact with and activate naïve T cells. The decoy receptor D6 ensures proper presentation of homeostatic chemokines by lymphatic endothelial cells (LEC) by scavenging inflammatory chemokines to specifically facilitate mature over immature DC migration. Changes in lymphatic flows that result from altered signaling in both initial capillaries and collecting vessels may influence accumulation of inflammatory cytokines that help to perpetuate local inflammation leading to infiltration and accumulation of leukocytes in tissue, which further drive lymphatic remodeling. C, although important for immune induction, evidence also indicates that lymphatic capillaries importantly regulate resolution of local inflammation and immunity through leukocyte egress and chemokine sequestration. Both macrophages and some T cells exit peripheral tissue through draining lymphatic capillaries using CCL21 and sphingosine kinase (SPHK) conversion of sphingosine into sphingosine-1-phosphate (S1P) as signals for their exit, all produced by initial lymphatic vessels. Cellular exit is required for resolution of disease. ICAM1, intracellular adhesion molecule 1; LFA1, lymphocyte function associated antigen 1. D, novel immunomodulatory roles of LECs have been described, largely in the context of lymphoid organs. LECs inhibit both antigen-dependent and independent T-cell activation through production of nitric oxide (NO) and nonspecific inhibition of DC–T-cell interactions. Inflamed LECs inhibit maturation of DCs through ICAM1 and receive peptide-loaded MHCII complexes from mature DCs. In addition, LECs promiscuously present endogenous and scavenge exogenous antigen for cross-presentation on MHCI molecules and direct deletion of antigen-specific CD8+ T cells.
- Figure 3.
Deregulation of lymphatic vessel function, inflammation, and skin carcinogenesis by environmental factors. Environmental factors that predispose to skin cancer (UVR, infection, and surgery or physical trauma) simultaneously affect lymphatic vessel dysfunction. Lymphatic remodeling as a result of ultraviolet exposure, infection, or surgery may result in altered fluid flows and local inflammation that generate a local microenvironment more permissive to the oncogenic effects of the agents.
- Figure 4.
Proposed model for feedback between lymphatic vessels, inflammation, and skin carcinogenesis: implications for immunotherapy. A, tumor-promoting inflammation induces the initiation and progression of skin cancer as well as remodeling of local lymphatic vessels, which, in turn, may be further tumor-promoting by facilitating the resolution response characterized by immune suppressive leukocyte infiltrates and local tolerance. Lymphatic remodeling results in enhanced fluid flows to draining LNs, facilitating metastatic progression of developing skin cancers. Furthermore, in addition to the protumor, suppressive inflammation, lymphatic vessels may directly inhibit antitumor immunity, preventing local control of the growing tumor, although whether this would occur in tumor microenvironments or their draining LNs remains unknown. B, immunotherapy endeavors to switch the balance in this network toward antitumor immunity through methods of both direct and indirect activation of adaptive immune responses against tumors. Enhanced antitumor immunity will control primary growth but may also influence local remodeling of lymphatic vessels through an IFNγ-dependent mechanism. Mechanisms of resistance to this approach have already been described where infiltrating leukocytes impair local T-cell infiltration and function. Given the novel immunomodulatory roles of lymphatic vessels, it remains to be seen whether their status may be additionally predictive of response or alternatively a targetable mechanism of resistance.
Volume 6, Issue 1
Jump to section
- Article
- Abstract
- Introduction
- Inflammation and Cancer
- Skin Inflammation and Cancer
- Lymphatic Vessels and Regional Inflammation
- Environmental Agents and Lymphatic Function
- Lymphatic Vessels, Inflammation, and Metastasis
- Therapeutic Implications
- Conclusions
- Disclosure of Potential Conflicts of Interest
- Grant Support
- References
- Figures & Data
- Info & Metrics