Growth and Immune Evasion of Lymph Node Metastasis

Abstract

Cancer patients with lymph node (LN) metastases have a worse prognosis than those without nodal disease. However, why LN metastases correlate with reduced patient survival is poorly understood. Recent findings provide insight into mechanisms underlying tumor growth in LNs. Tumor cells and their secreted molecules engage stromal, myeloid, and lymphoid cells within primary tumors and in the lymphatic system, decreasing antitumor immunity and promoting tumor growth. Understanding the mechanisms of cancer survival and growth in LNs is key to designing effective therapy for the eradication of LN metastases. In addition, uncovering the implications of LN metastasis for systemic tumor burden will inform treatment decisions. In this review, we discuss the current knowledge of the seeding, growth, and further dissemination of LN metastases.

Keywords: immunity; lymph node; lymphatics; metastasis; tumor.

Figure 1

Progression of lymphatic metastasis from primary tumor to tumor-draining LN (TDLN). Primary tumors induce lymphangiogenesis to facilitate lymphatic metastasis and release of immunomodulatory molecules, including exosomes, which lead to immunosuppression of TDLNs. Lymph node (LN) lymphatic endothelial cells (LECs) capture tumor antigen and tolerize T cells via programmed death-ligand 1 expression. Tumor-associated lymphatic vessels and tertiary lymphoid organs have been implicated in immune suppression and immune activation. High endothelial venules found in primary tumors can allow infiltration of naive T cells that may further differentiate into effector T cells. Tumor-associated lymphatic vessels recruit both cancer cells and immune cells by releasing chemoattractants (see Figure 2). Cancer cells, T cells, and dendritic cells enter lymphatic capillaries and migrate through collecting lymphatic vessels to LNs. Cancer cells in lymphatic vessels can attach to the lymphatic endothelium en route to LNs. Active mechanisms, such as CCL1/CCR8 signaling, control cancer cell entry into the LN. Polyclonal cancer cells proliferate to form a metastatic lesion that invades deeper into the LN parenchyma, where it can grow and replace LN tissue in the absence of new blood vessel growth. The immune response to a growing metastatic lesion is limited; some immune cells are excluded from LN lesions, while other immune cells are present, but unable to eliminate cancer cells (not shown). Some cancer cells may exit through the efferent lymphatic vessel and seed secondary draining LNs. Recent evidence suggests LEC sphingosine-1-phosphate (S1P) helps shape the antitumor immune response.

Figure 2

Tumor-associated lymphatic vessels promote metastasis and cancer progression. (i) Tumor-associated macrophages and cancer cells secrete VEGF-C and VEGF-D, which binds to VEGFR-2/3 on lymphatic capillaries to mediate lymphangiogenesis. VEGF-C upregulates CCL21 production by lymphatic endothelial cells (LECs). CCL21 attracts cancer cells, T cells, and dendritic cells (DCs), which express CCR7, a receptor for CCL21. VEGF-C has also been shown to upregulate CXCR4 expression on LECs. The CXCL12–CXCR4 axis can stimulate lymphangiogenesis to promote cancer cell migration. Alternatively, LECs promote the migration of CXCR4-positive cancer cells by secretion of CXCL12. Tumor antigen is delivered to the tumor-draining lymph nodes, where it is presented to T cells by DCs and LECs. (ii) Binding of LEC programmed death-ligand 1 (PD-L1) with T cell PD-1 receptor induces CD8 T cell tolerance to tumor antigens.