Single High-Dose Radiation Enhances Dendritic Cell Homing and T Cell Priming by Promoting Reactive Oxygen Species-Induced Cytoskeletal Reorganization

Abstract

Radiation therapy (RT) affects tumor-infiltrating immune cells, cooperatively driving tumor growth inhibition. However, there is still no absolute consensus on whether the homing ability of dendritic cells (DCs) is affected by direct x-ray irradiation. Most importantly, the underlying mechanisms are poorly understood. Using noninvasive imaging, we systematically examined the dose effect of RT on the invivo homing and distribution of bone marrow-derived DCs and elucidated the detailed mechanisms underlying these events. After exposure to 2, 5, 10, 15, and 20 Gy, DCs were analyzed for maturation, invivo homing ability, and T cell priming. At ranges of 2 to 20 Gy, irradiation did not cause direct cellular apoptosis or necrosis, but it induced mitochondrial damage in DCs independent of dose. In addition, upregulation of CD40, CD80, CD86, CXCR4, and CCR7 were detected on irradiated DCs. Secretion of IL-1β and IL-12p70 remained unchanged, whereas decreased secretion of IL-6 and promotion of tumor necrosis factor α secretion were observed. In particular, the homing ability of both the local residual and blood circulating DCs to lymphoid tissues was significantly higher in groups that received ≥5 Gy radiation than in the group that received 2 Gy. Furthermore, improved homing ability was associated with rearrangement of the cytoskeleton, which was regulated by reactive oxygen species accumulation through the RhoA/ROCK1 signaling pathway. Finally, more robust T cell activation was observed in mice inoculated with 20 Gy-treated DCs than in those inoculated with 2 Gy-irradiated DCs, and T cell activation also correlated with reactive oxygen species production. An RT dose ≥5 Gy has distinct advantages over 2 Gy in facilitating DC homing to lymph nodes and cross-priming T cells.