a Division of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands;
Radiat Res. 2014 Aug;182(2):219-29. doi: 10.1667/RR13511.1. Epub 2014 Jun 24.
Radiotherapy is a successful treatment modality for localized cancer. Our group has been exploring radiotherapy in combination with immunotherapy (radioimmunotherapy) to enhance systemic antitumor responses. Previously, we have shown that when local radiotherapy was combined with monoclonal antibodies (mAbs) (that enable T-cell responses by engaging costimulation [anti (α)-CD137] and blocking coinhibition [α-PD-1] [corrected], up to 100% of mice bearing established syngeneic AT-3 mammary tumors were cured, but single modality treatments were not curative. Here, we investigated the molecular mechanisms underlying responses to this radioimmunotherapy approach. We observed that inhibition of signaling through the mammalian target of rapamycin (mTOR) pathway during the first 10 days of treatment severely impaired the curative effect of radioimmunotherapy, at least in part by reducing MHC class I expression on tumor cells, reducing dendritic cell (DC) activation status and CD8+ T-cell function. This data indicates that the efficacy of this type of radioimmunotherapy approach involves mTOR signaling and therefore, mTOR inhibitory drugs may impede the efficacy of similar radioimmunotherapy approaches in humans.
放射疗法是治疗局部癌症的一种成功方法。我们的团队一直在探索放射疗法与免疫疗法（放射免疫疗法）相结合，以增强全身抗肿瘤反应。以前，我们已经表明，当局部放射治疗与单克隆抗体（mAbs）联合使用时（通过结合共刺激[抗（α）-CD137]和阻断共抑制[α-PD-1]来增强 T 细胞反应），高达 100%患有已建立的同源 AT-3 乳腺肿瘤的小鼠被治愈，但单一模式治疗不能治愈。在这里，我们研究了这种放射免疫治疗方法的反应的分子机制。我们观察到，在治疗的前 10 天内抑制雷帕霉素（mTOR）途径的信号传导严重损害了放射免疫治疗的疗效，至少部分原因是降低了肿瘤细胞上 MHC 类 I 表达，降低了树突状细胞（DC）激活状态和 CD8+T 细胞功能。这些数据表明，这种放射免疫治疗方法的疗效涉及 mTOR 信号传导，因此，mTOR 抑制剂可能会阻碍人类类似放射免疫治疗方法的疗效。
