Dynamic alterations in the irradiated draining lymph node

Tumor-draining lymph nodes (DLNs) are crucial for the development of anti-tumor immunity upon irradiation. However, in radiotherapy, DLNs are frequently co-irradiated, which impairs their function. Here, we examine the consequences of DLN irradiation on anti-tumor immunity, focusing on the recently described radiotherapy-induced disruption of the CCR7-CCL19/CCL21 axis, which governs tumor-to-DLN trafficking. We use in vivo irradiated murine LNs and in vitro assays to assess irradiation-induced structural and functional changes in the DLNs. DLN-infiltrating lymphocytes and CCL19/CCL21 chemokines were depleted early after irradiation in a dose-dependent manner. Lymphocyte numbers recovered only in DLNs irradiated with 5 Gy or less. Lymphopenia persisted in DLNs irradiated with 15 Gy, with few surviving lymphocytes showing a compensatory increase in proliferation. Irradiation-deregulated secretion of CCL19 could be related to lymphodepletion and/or direct irradiation-induced processes in stromal cells. In conclusion, radiotherapy depletes DLNs, and impairs stromal function and chemokine signaling, thereby compromising anti-tumor immunity.