Immunomodulatory Roles of Lymphatic Vessels in Cancer Progression

Melody A. Swartz

doi:10.1158/2326-6066.CIR-14-0115

DOI: 10.1158/2326-6066.CIR-14-0115 Published August 2014

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Figure 1.
Several domains of lymphatic research that evolved for the most part independently have recently begun to overlap and merge. A, lymph was first discovered in the mesenteric vessels draining the small intestine after a lipid-rich meal, as they absorb and transport lipids in the form of chylomicrons. Shown is an overlaid bright-field image of the mesentery with a fluorescence image of a lymphatic collecting vessel (arrow) and surrounding mesenteric adipose tissue (MAT) in the small intestine after feeding a fluorescently labeled lipid to a mouse; image courtesy of Ryan Oliver (EPFL, Lausanne, Switzerland.) B, interstitial fluid balance, whereby osmotic and hydrostatic pressure forces are considered to drive plasma out of blood capillaries and into lymphatic vessels with small net driving forces, has been the subject of a great deal of quantitative investigation over the past 50 years. C, a valve separating two lymphangions in a collecting lymphatic vessel. The pump function and valve system of collecting lymphatics have received substantial research attention over the past few decades, and genes critical for valve development have been found to be mutated in congenital lymphedema. Image adapted from Figure 5A of ref. (43). D, the molecular regulation of tumor lymphangiogenesis has greatly improved our understanding of molecular cross-talk and signaling involved in lymphatic proliferation. E, until very recently, lymphatic research in immunology was mostly limited to its roles in antigen and cell transport and cell–cell communication necessary for adaptive immune responses, i.e., from peripheral tissues to the lymph node, and within various compartments of the lymph node. Drawings in B, D, and E are courtesy of Katie Hubbell, University College London, UK.
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Figure 2.
This is a schematic diagram incorporating results from recent work that identified multiple complementary mechanisms by which tumor-associated lymphatic vessels may promote immune escape. (i) Many solid tumors induce increased lymphatic drainage, delivering tumor antigens and tumor-secreted exosomes to the DLN. Because lymphatic drainage plays important roles in adaptive tolerance to newly introduced antigens, increased tumor drainage may exploit the natural mechanisms of self-tolerance in the lymph node. (ii) Tumor-associated LECs can directly scavenge and cross-present tumor antigen in the absence of costimulatory molecules and in the presence of inhibitory ligands such as PD-L1 to drive CD8⁺ T-cell apoptosis. (iii) VEGF-C, secreted by tumor-associated macrophages, upregulates LEC expression of the lymphoid chemokine CCL21, which attracts naïve and regulatory T cells and drives the transformation of lymphoid-like stroma that facilitates T-cell education. VEGF-C also induces TGFβ secretion by LECs (J. Munson and M. Swartz, unpublished data), which can promote regulatory T-cell education and drives fibroblast-to-myofibroblast transformation and stromal stiffening. Finally, increased interstitial flow in the tumor stroma due to high pressure gradients at the tumor margin also promotes TGFβ activation, myofibroblast transformation, and stromal stiffening (44), and promote fibroblast-led tumor-cell invasion (45). Drawings are courtesy of Katie Hubbell, University College London, UK.