Tumor-draining lymph nodes: At the crossroads of metastasis and immunity

Abstract

Early engagement of the lymphatic system by solid tumors in peripheral, nonlymphoid tissues is a clinical hallmark of cancer and often forecasts poor prognosis. The significance of lymph node metastasis for distant spread, however, has been questioned by large-scale lymph node dissection trials and the likely prevalence of direct hematogenous metastasis. Still, an emerging appreciation for the immunological role of the tumor-draining lymph node has renewed interest in its basic biology, role in metastatic progression, antitumor immunity, and patient outcomes. In this review, we discuss our current understanding of the early mechanisms through which tumors engage lymphatic transport and condition tumor-draining lymph nodes, the significance of these changes for both metastasis and immunity, and potential implications of the tumor-draining lymph node for immunotherapy.

Lymphocytes in tumor-draining lymph nodes co-cultured with autologous tumor cells for adoptive cell therapy

“…TDLNs, where anti-tumor immune activity is primarily induced, play pivotal roles to effectively generate anti-tumor T cell responses [ 18 , 19 , 35 ]. TDLNs are usually excised during surgery along with a primary tumor(s) to remove possible residual tumor cells and are examined for diagnosis with/without metastatic tumor cells in these lymph nodes [ 36 ].…”

T cell Egress via Lymphatic Vessels Limits the Intratumoral T cell Repertoire in Melanoma

“…In the setting of inflamed malignant lesions, however, lymphatic vessels may also contribute to local immune suppression and limit therapeutic response. Tumor-associated lymphatic vessels can act as antigen-presenting cells to induce CD8 + T cell dysfunction 5, 44 and expand regulatory T cells 6 , activate inhibitory ligand expression in response to cytotoxic activity 7 , and induce immune suppression in LNs 45 , altogether dampening local tumor control. In addition, our study now indicates that lymphatic vessels remove tumor-specific effector CD8 + T cells from tumors and thereby limit their accumulation and target engagement.…”

Standing Watch: Immune Activation and Failure in Melanoma Sentinel Lymph Nodes

“…The SLN is the most proximal to a primary lesion, identified by lymphatic mapping at time of wide excision, and therefore the most likely first site of regional metastasis. Tumor-draining LNs are also critical sites of antigen presentation and anti-tumor adaptive immune activation, and yet how an immunological organ is simultaneously a critical site for tumor antigen and permissive for tumor metastasis has remained incompletely understood (2). Studies to date describe a series of immunological changes in the SLN that associate with metastasis, including a reduction in both the number and activated state of dendritic cell populations and an increase in regulatory T cells (2).…”

“…Tumor-draining LNs are also critical sites of antigen presentation and anti-tumor adaptive immune activation, and yet how an immunological organ is simultaneously a critical site for tumor antigen and permissive for tumor metastasis has remained incompletely understood (2). Studies to date describe a series of immunological changes in the SLN that associate with metastasis, including a reduction in both the number and activated state of dendritic cell populations and an increase in regulatory T cells (2). These observations support the presumption that the SLN undergoes a progressive failure of immune control that permits tumor seeding and may further impact systemic immune surveillance.…”