Bazyar Soha, O'Brien Edward Timothy, Benefield Thad, Roberts Victoria R, Kumar Rashmi J, Gupta Gaorav P, Zhou Otto, Lee Yueh Z
Department of Radiation Oncology, University of Maryland, Maryland, MD 21201, USA.
Department of Physics and Astronomy, The University of North Carolina, Chapel Hill, NC 27514, USA.
Cancers (Basel). 2021 Dec 29;14(1):155. doi: 10.3390/cancers14010155.
Spatially fractionated radiotherapy has been shown to have effects on the immune system that differ from conventional radiotherapy (CRT). We compared several aspects of the immune response to CRT relative to a model of spatially fractionated radiotherapy (RT), termed microplanar radiotherapy (MRT). MRT delivers hundreds of grays of radiation in submillimeter beams (peak), separated by non-radiated volumes (valley). We have developed a preclinical method to apply MRT by a commercial small animal irradiator. Using a B16-F10 murine melanoma model, we first evaluated the in vitro and in vivo effect of MRT, which demonstrated significant treatment superiority relative to CRT. Interestingly, we observed insignificant treatment responses when MRT was applied to Rag and CD8-depleted mice. An immuno-histological analysis showed that MRT recruited cytotoxic lymphocytes (CD8), while suppressing the number of regulatory T cells (Tregs). Using RT-qPCR, we observed that, compared to CRT, MRT, up to the dose that we applied, significantly increased and did not saturate CXCL9 expression, a cytokine that plays a crucial role in the attraction of activated T cells. Finally, MRT combined with anti-CTLA-4 ablated the tumor in half of the cases, and induced prolonged systemic antitumor immunity.
空间分割放疗已被证明对免疫系统有不同于传统放疗（CRT）的影响。我们比较了相对于一种称为微平面放疗（MRT）的空间分割放疗模型，对CRT免疫反应的几个方面。MRT在亚毫米束（峰值）中传递数百戈瑞的辐射，由未辐射体积（谷值）隔开。我们已经开发出一种通过商业小动物辐照器应用MRT的临床前方法。使用B16-F10小鼠黑色素瘤模型，我们首先评估了MRT的体外和体内效果，结果表明其相对于CRT具有显著的治疗优势。有趣的是，当将MRT应用于Rag和CD8缺失的小鼠时，我们观察到治疗反应不明显。免疫组织学分析表明，MRT招募了细胞毒性淋巴细胞（CD8），同时抑制了调节性T细胞（Tregs）的数量。使用RT-qPCR，我们观察到，与CRT相比，在我们应用的剂量范围内，MRT显著增加且未使CXCL9表达饱和，CXCL9是一种在活化T细胞吸引中起关键作用的细胞因子。最后，MRT联合抗CTLA-4在一半的病例中消除了肿瘤，并诱导了长期的全身抗肿瘤免疫。
