Lymph node biophysical remodeling is associated with melanoma lymphatic drainage

Abstract

Tissue remodeling is a characteristic of many solid tumor malignancies including melanoma. By virtue of tumor lymphatic transport, remodeling pathways active within the local tumor microenvironment have the potential to be operational within lymph nodes (LNs) draining the tumor interstitium. Here, we show that lymphatic drainage from murine B16 melanomas in syngeneic, immune-competent C57Bl/6 mice is associated with LN enlargement as well as nonuniform increases in bulk tissue elasticity and viscoelasticity, as measured by the response of whole LNs to compression. These remodeling responses, which quickly manifest in tumor-draining lymph nodes (TDLNs) after tumor inoculation and before apparent metastasis, were accompanied by changes in matrix composition, including up to 3-fold increases in the abundance of soluble collagen and hyaluronic acid. Intranodal pressures were also significantly increased in TDLNs (+1 cmH2O) relative to both non-tumor-draining LNs (-1 cmH2O) and LNs from naive animals (-1 to 2 cmH2O). These data suggest that the reorganization of matrix structure, composition, and fluid microenvironment within LNs associated with tumor lymphatic drainage parallels remodeling seen in primary malignancies and has the potential to regulate the adhesion, proliferation, and signaling function of LN-resident cells involved in directing melanoma disease progression.

Implications of Lymphatic Transport to Lymph Nodes in Immunity and Immunotherapy

“…For example, sentinel, or tumor-draining, lymph nodes are exposed to a high concentration of lymph-transported molecules from the tumor interstitium by virtue of their proximity to growing tumors (Figure 1) (7, 8). Signaling pathways active within the local tumor microenvironment that result in tissue remodeling associated with cancer cell survival (44), invasion (45–47), and immune suppression (5) could therefore operate within tumor-draining lymph nodes.…”

“…Signaling pathways active within the local tumor microenvironment that result in tissue remodeling associated with cancer cell survival (44), invasion (45–47), and immune suppression (5) could therefore operate within tumor-draining lymph nodes. We recently analyzed lymph nodes from B16 melanoma–bearing mice with respect to tumor stage and found that melanoma lymphatic drainage was associated with alterations in lymph node hyaluronic acid and collagen content corresponding with physical adaptations that manifest in tumors (44, 48, 49), including increased intranodal pressures (7, 50, 51) and increased lymph node tissue stiffness and viscoelasticity (7). The potential for these and other remodeling responses to influence critical cellular processes in the lymph node, including cell proliferation, migration, and lymphocyte homing, is discussed below.…”

“…Low–molecular weight hyaluronic acid induces an increase in the proliferation of lymphatic endothelial cells and triggers their migration and organization into tubelike structures (57). Alterations in lymph node hyaluronic acid content, which were previously demonstrated to be associated with melanoma lymphatic drainage (7), therefore have the potential to influence the survival, proliferation, and functionality of lymph node resident cells.…”

“…Indeed, lymph drainage affects more than just tissue edema. For example, lymph drainage facilitates both exogenous and self-antigen transport to lymph nodes to tune humoral response to immunization as well as regulatory T (T reg ) cell function and immune tolerance (4); locally dampens antitumor immunity (5); and directs the remodeling of draining lymph nodes (4, 6, 7), tissues whose microstructure orchestrates the comingling of lymph and lymphocytes to facilitate adaptive immune response. The transport role of the lymphatics is thus intrinsically linked to lymphatic function in immune physiology.…”

Progress and opportunities for enhancing the delivery and efficacy of checkpoint inhibitors for cancer immunotherapy

“…Furthermore, tumor-draining lymph nodes often display altered immunological microenvironments relative to non-tumor associated lymph nodes, suggesting active regulation of the tumor-draining lymph node microenvironment by the tumor to suppress anti-tumor immunity. We and others have noted lymph node remodeling associated with tumor lymphatic drainage [17,18,83–85], effects that may alter antigen, cytokine, growth factor, or even therapeutic agent accumulation within and distribution throughout tumor-draining lymph nodes to alter their signaling activity [18]. Furthermore, increased frequencies of regulatory T cells [86] and low densities of CD169 + subcapsular sinus macrophages [87] within tumor-draining lymph nodes predicts poor patient outcome in melanoma [86].…”