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

Purpose: 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. Methods and Materials: Using noninvasive imaging, we systematically examined the dose effect of RT on the in vivo 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, in vivo homing ability, and T cell priming. Results: 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-1 beta and IL-12p70 remained unchanged, whereas decreased secretion of IL-6 and promotion of tumor necrosis factor alpha 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. Conclusions: An RT dose >= 5 Gy has distinct advantages over 2 Gy in facilitating DC homing to lymph nodes and cross-priming T cells. (C) 2020 Published by Elsevier Inc.

Automated summary

This study systematically examined the dose effect of radiation therapy on the in vivo homing and distribution of bone marrow-derived dendritic cells using noninvasive imaging. The results showed that radiation did not directly cause cellular apoptosis or necrosis in DCs, but induced mitochondrial damage and upregulation of certain receptors. Higher radiation doses (>= 5 Gy) significantly increased the homing ability of DCs to lymphoid tissues, and this improvement was associated with reactive oxygen species accumulation. Enhanced T cell activation was also observed in mice inoculated with higher radiation dose-treated DCs, indicating the advantages of >= 5 Gy radiation in facilitating DC homing and T cell priming.