Bidirectional Crosstalk between Lymphatic Endothelial Cell and T Cell and Its Implications in Tumor Immunity

Abstract

Lymphatic vessels have been traditionally considered as passive transporters of fluid and lipids. However, it is apparent from recent literature that the function of lymphatic vessels is not only restricted to fluid balance homeostasis but also extends to regulation of immune cell trafficking, antigen presentation, tolerance, and immunity, all which may impact the progression of inflammatory responses and diseases such as cancer. The lymphatic system and the immune system are intimately connected, and there is emergent evidence for a crosstalk between T cell and lymphatic endothelial cell (LEC). This review describes how LECs in lymph nodes can affect multiple functional properties of T cells and the impact of these LEC-driven effects on adaptive immunity and, conversely, how T cells can modulate LEC growth. The significance of such crosstalk between T cells and LECs in cancer will also be discussed.

Keywords: T cell; cancer; cytokine; inflammation; lymph node; lymphatic endothelial cells; tolerance.

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.