Intrinsic Properties of the Lymph Node Render It Immunologically Susceptible to Metastasis

Lymph nodes (LN) are the staging grounds for antitumor immunity; therefore, their high susceptibility to metastatic colonization is a paradox. Previous studies have suggested that extrinsic tumor-derived factors precondition the draining LN to enable tumor cell survival by promoting a state of immune suppression. In this study, we investigate whether properties of the LN itself may impede its ability to clear metastasizing tumor cells. Using multiple immunocompetent transplant models, we show that LNs possess intrinsic features, independent of preconditioning, which make them an advantageous site for tumor cells to evade T-cell control. Tumor growth in the LN is facilitated by regulatory T cells, which locally suppress the cytolytic capacity of tumor-specific CD8+ T cells by restricting IL2. These findings identify an intrinsic mechanism that contributes to the high rate of LN metastasis in solid tumors. SIGNIFICANCE: As an immune organ, the LN's paradoxical susceptibility to metastasis has been attributed to immunosuppressive conditioning by tumor-secreted factors. We identify regulatory T cell restriction of IL2 from CD8+ T cells as an intrinsic property of LNs that renders them susceptible to metastatic colonization. See related commentary Menzel and Padera, p.1780.