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

归巢(生物学) CD86 CD80 细胞生物学 树突状细胞 T细胞 肿瘤坏死因子α 化学 免疫学 癌症研究 免疫系统 生物 细胞毒性T细胞 CD40 体外 生态学 生物化学
作者
Ziqi Zhou,Jing Zhao,Ke Hu,Xiaorong Hou,Xiansong Sun,Xiaoli Pan,Xiaohui Wang,Nan Li,Zhiwei Yang,Fuquan Zhang,Qianqian Zhou,Linsheng Zhan
出处
期刊:International Journal of Radiation Oncology Biology Physics [Elsevier BV]
卷期号:109 (1): 95-108 被引量:23
标识
DOI:10.1016/j.ijrobp.2020.07.2321
摘要

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-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. Conclusions An RT dose ≥5 Gy has distinct advantages over 2 Gy in facilitating DC homing to lymph nodes and cross-priming T cells. 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 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. 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.
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