The tumor-draining lymph node as a reservoir for systemic immune surveillance

Abstract

Early in solid tumor development, antigens are presented in tumor-draining lymph nodes (tdLNs), a process that is necessary to set up immune surveillance. Recent evidence indicates that tdLNs fuel systemic tumor-specific T cell responses which may halt cancer progression and facilitate future responses to immunotherapy. These protective responses, however, are subject to progressive dysfunction exacerbated by lymph node (LN) metastasis. We discuss emerging preclinical and clinical literature indicating that the tdLN is a crucial reservoir for systemic immunity that can potentiate immune surveillance. We also discuss the impact of LN metastasis and argue that a better understanding of the relationship between LN metastasis and systemic immunity will be necessary to direct regional disease management in the era of immunotherapy.

Keywords: immune surveillance; immunotherapy; lymph node; metastasis.

Figure 1.. The tumor-draining lymph node supports systemic anti-tumor immune surveillance.

The afferent lymphatic vasculature transports tumor-derived material (e.g. antigens), leukocytes, and tumor cells from the primary tumor to the tumor draining lymph node (tdLN). Dendritic cells in the tdLN express PD-L1 and exhibit a more immature phenotype, resulting in suboptimal priming of CD8⁺ T cells, characterized by a failure to activate full effector function. Further contributing to these dysfunctional CD8⁺ T cell states, regulatory T cells (T_REG) expand in tdLNs, even before metastasis, and home to sites of tumor where they inhibit effector function. Tumor-primed CD8⁺ T cells retain a more stem-like phenotype (T_SC), self-renew, and circulate from the tdLN through the blood to sites of tumor, particularly in response to immunotherapy, where they are necessary to seed the intratumoral T cell repertoire. Within tumor, a second antigen encounter provided by local antigen presenting cells induce TSC differentiation to an effector (T_EFF) and then towards terminal differentiation and exhaustion (T_EX). CD8⁺ T cells that remain in the T_SC fate or receive only weak antigen stimulation also egress the tumor to return to the tdLN.

Figure 2.. Metastasizing tumor cells evade local mechanisms of protection and induce immune dysfunction.

Local protection. Lymph nodes harbor defense mechanisms that limit tumor cell seeding. Cytotoxic resident memory CD8⁺ T cells (TRM) and natural killer (NK) cells provide rapid cytotoxicity in response to tumor arrival, limiting tumor cell seeding and protecting the antigen-specific, stem-like CD8⁺ T cells (T_SC) that circulate and mediate primary tumor control. Metastasis. Eventual seeding of the lymph node by cancer cells may depend on upregulation of MHC Class I, allowing them to evade killing by NK cells. The seeding of tumor cells then further conditions the lymph node by expanding regulatory T cells (T_REG), in part by MHC Class II expression, and promoting a decrease in dendritic cell maturation and local antigen presentation that drives the T_SC population towards dysfunction (T_EFF/T_EX). T_REG further suppress NK cell cytotoxicity, limit the priming of effector CD8⁺ T cell responses, and recirculate to exert their suppressive function at distant tumor locations.