Figure 1.

Schematic diagram depicting the involvement of tumor-associated lymphatic endothelial cell (LEC) in cancer. (1) Tumor-associated upregulation of chemokine expression in lymph node (LN) LECs mediates metastasis of tumor cells expressing the cognate chemokine receptors. (2) Tumor-associated factors, cytokines, and exosome draining from the upstream tumors and afferent lymphatic induce LN lymphangiogenesis, leading to increased lymph flow, transport of tumor-derived factors, and enhanced tumor cell dissemination. (3) Tumor-associated LECs can suppress immunity and promote tolerance. Interaction between LN LECs and dendritic cells (DCs) via intercellular adhesion molecule 1 and Mac-1 inhibits DC maturation and hence limiting effective T cell activation. Tumor antigen presentation to naïve CD8⁺ T cells by LN LECs induces dysfunctional T cell activation and tolerance due to expression of inhibitory receptor programmed death ligand 1 and lack of costimulatory molecules on LEC surface. LECs activated by T cell-derived pro-inflammatory cytokines produce factors such as NO and indoleamine 2,3 dioxygenase that inhibit T cell proliferation. (4) Robust CD8⁺ T cells priming occurs in tumor-draining LN. Although tolerogenic LN microenvironment may dominate and sustain immune suppression, immune checkpoint blockades can reverse T cell exhaustion and increase effector T cell activities that may lead to tumor regression.