Exploiting lymphatic vessels for immunomodulation: Rationale, opportunities, and challenges

Abstract

Lymphatic vessels are the primary route of communication from peripheral tissues to the immune system; as such, they represent an important component of local immunity. In addition to their transport functions, new immunomodulatory roles for lymphatic vessels and lymphatic endothelial cells have come to light in recent years, demonstrating that lymphatic vessels help shape immune responses in a variety of ways: promoting tolerance to self-antigens, archiving antigen for later presentation, dampening effector immune responses, and resolving inflammation, among others. In addition to these new biological insights, the growing field of immunoengineering has begun to explore therapeutic approaches to utilize or exploit the lymphatic system for immunotherapy.

Keywords: Cancer; Immune regulation; Immunotherapy; Lymph node targeting; Lymphangiogenesis; Nanotechnology.

Fig. 1

Antigen and cell trafficking through lymphatics. Antigens and leukocytes travel from peripheral tissue sites to the draining lymph nodes and finally back into systemic circulation via the lymphatics. In particular, antigen presenting cells like dendritic cells and lymphocytes migrate through the lymphatics via CCL19/21-mediated chemotaxis, as these cell types express the receptor CCR7. Dendritic cells also sit between lymphatic endothelial cells and appear to mediate vessel integrity in a CCR7-dependent manner. Lymphocytes can enter the LN via lymphatics, if drained from the periphery, or via high endothelial venules from the systemic circulation. This also occurs in a CCR7-dependent manner. In the LN, dendritic cells present antigens (taken up locally or peripherally) for lymphocyte education. Finally, educated lymphocytes egress from LN via efferent lymphatics and either home to the peripheral tissues or remain in the systemic circulation.

Fig. 2

Targeting the tumor-draining lymph nodes (tdLNs) with NP vaccines. TdLNs collect lymphborne tumor-associated-antigens (TAAs). Lymphatic-targeting NP vaccines can be injected into a healthy tissue (e.g. the skin) directly connected to the tdLNs via lymphatic vessels. Particulate vaccines in the 10–200 nm-range are directly uptaken into the lymphatics, most likely mainly by transcellular transport through LECs, while particles above 200 nm mostly use internalization and transport by DCs to enter the lymphatics. In the LNs, resident DCs take up NP vaccines and become activated by delivered immune adjuvants. Activated DCs can present both TAAs contained in the vaccine and TAAs already present in the tdLNs, resulting in the stimulation of T cells with multiple antigen specificities.

Fig. 3

Summary of immunomodulatory roles of lymphatic endothelial cells (LECs) during steady state and inflammation. LECs modulate immune responses both via direct interactions with immune cells, including dendritic cells and T cells, as well as through secretion of chemokines and cytokines. In the steady state, direct LEC-T cell interactions and antigen transfer to DCs can lead to increased CD4⁺ T cell apoptosis or anergy and dysfunctional CD8⁺ T cell activation. During inflammation, LECs can produce factors such as IDO and NO that inhibit T cell proliferation. LECs also upregulate adhesion molecules, MHC molecules, and other factors that aid in the maintenance of regulatory and memory T cell populations, and inhibit dendritic cell (DC) maturation. Following resolution of inflammation, LECs can retain antigens for prolonged time periods (a phenomenon called antigen archiving) and transfer them to DCs, thus contributing to the maintenance of immunological memory.