Department of Radiation Oncology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, 11794, USA.
Department of Pharmacological Sciences, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, 11794, USA.
Sci Rep. 2021 Mar 3;11(1):5057. doi: 10.1038/s41598-021-84600-3.
The efficacy of combining radiation therapy with immune checkpoint inhibitor blockade to treat brain tumors is currently the subject of multiple investigations and holds significant therapeutic promise. However, the long-term effects of this combination therapy on the normal brain tissue are unknown. Here, we examined mice that were intracranially implanted with murine glioma cell line and became long-term survivors after treatment with a combination of 10 Gy cranial irradiation (RT) and anti-PD-1 checkpoint blockade (aPD-1). Post-mortem analysis of the cerebral hemisphere contralateral to tumor implantation showed complete abolishment of hippocampal neurogenesis, but neural stem cells were well preserved in subventricular zone. In addition, we observed a drastic reduction in the number of mature oligodendrocytes in the subcortical white matter. Importantly, this observation was evident specifically in the combined (RT + aPD-1) treatment group but not in the single treatment arm of either RT alone or aPD-1 alone. Elimination of microglia with a small molecule inhibitor of colony stimulated factor-1 receptor (PLX5622) prevented the loss of mature oligodendrocytes. These results identify for the first time a unique pattern of normal tissue changes in the brain secondary to combination treatment with radiotherapy and immunotherapy. The results also suggest a role for microglia as key mediators of the adverse treatment effect.
联合放射治疗和免疫检查点抑制剂阻断治疗脑肿瘤的疗效目前是多项研究的主题，具有重要的治疗前景。然而，这种联合治疗对正常脑组织的长期影响尚不清楚。在这里，我们研究了颅内植入小鼠胶质瘤细胞系的小鼠，这些小鼠在接受 10Gy 颅脑照射（RT）和抗 PD-1 检查点阻断（aPD-1）联合治疗后成为长期幸存者。对肿瘤植入对侧大脑半球的死后分析显示，海马神经发生完全被消除，但神经干细胞在侧脑室下区得到很好的保留。此外，我们观察到皮质下白质中成熟少突胶质细胞的数量急剧减少。重要的是，这种观察结果仅在联合（RT+aPD-1）治疗组中明显，而在单独 RT 或单独 aPD-1 治疗组中则不明显。用集落刺激因子-1 受体（CSF-1R）小分子抑制剂 PLX5622 消除小胶质细胞可防止成熟少突胶质细胞的丢失。这些结果首次确定了放射治疗和免疫治疗联合治疗后大脑正常组织变化的独特模式。结果还表明，小胶质细胞作为治疗不良反应的关键介质发挥作用。
