In-vivo and in-vitro impact of high-dose rate radiotherapy using flattening-filter-free beams on the anti-tumor immune response
In-vivo and in-vitro impact of high-dose rate radiotherapy using flattening-filter-free beams on the anti-tumor immune response
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DOI：
10.1016/j.ctro.2020.07.004
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发表时间：
2020-09-01
影响因子：
3.1
通讯作者：
Mirjolet, C.
中科院分区：
文献类型：
--
作者：
Laurent, P. A.;Kownacka, A.;Mirjolet, C.
简介：现代加速器具有“无平坦滤波器”（FFF）技术，以中等高剂量率提供RT，目前用于有限的临床适应症。目前尚无关于这种高剂量率对抗肿瘤免疫反应可能产生的影响的科学数据。材料和方法：在体外，CT 26细胞在Varian TrueBeam（R）直线加速器上以3种不同的剂量率（4、12或24戈伊/min）使用FFF模式照射。通过RT-qPCR分析I型干扰素途径基因的诱导，并通过研究免疫原性死亡生物标志物的诱导，评价抗肿瘤免疫应答的激活。在体内，在携带CT 26同源肿瘤的免疫活性Balb/c小鼠中进行了以2种不同剂量率递送16.5戈伊的RT的功效研究，以及通过流式细胞术分析的免疫监测和使用RNA测序的转录组学分析。使用非参数tests.Results进行统计分析：在体外，没有显着影响的FFF剂量率的增加被证明为诱导的基因的I型干扰素途径，以及为研究的免疫原性死亡标志物（HMGB 1分泌）。在体内，证明了所使用的2种剂量率之间的肿瘤生长迟缓方面没有差异，以及肿瘤微环境内免疫细胞浸润的组成和免疫监测和RNAseq中免疫检查点的表达方面也没有差异。在这项涉及CT 26模型的研究中，未证实FFF技术中的中等高剂量率对抗肿瘤免疫应答的影响，这将使RT和检查点抑制剂之间的关联的研究适合于这种RT技术。然而，使用其他细胞模型的进一步探索似乎是令人感兴趣的。(c)2020年，任作家。由Elsevier B. V.代表欧洲放射治疗和肿瘤学会发表。
Introduction: Modern accelerators have the "flattening filter-free" (FFF) technique to deliver RT with a moderate high-dose rate, currently used in limited clinical indications. No scientifically established data are currently available on the possible effects of this high dose rate on the anti-tumor immune response. We therefore propose here to study these effects in a preclinical CT26 murine colorectal tumor model.Material and methods: In-vitro, CT26 cells were irradiated on a Varian TrueBeam (R) linac at 3 different dose rates (4; 12 or 24 Gy/min) using the FFF mode. Activation of the anti-tumor immune response was evaluated by the analysis of induction of genes of the type I interferon pathway by RT-qPCR, and by the study of the induction of immunogenic death biomarkers. In-vivo, an efficacy study of RT delivering 16.5 Gy at 2 different dose rates was performed in immunocompetent Balb/c mice carrying CT26 syngeneic tumors, as well as an immunomonitoring analysed by flow cytometry and a transcriptomic analysis using RNA sequencing. Statistical analyzes were performed using non-parametric tests.Results: In-vitro, no significant influence of an increase in FFF dose rate was shown for the induction of genes of the type I interferon pathway as well as for the studied immunogenic death markers (HMGB1 secretion). In-vivo, no difference in terms of tumor growth retardation between the 2 dose rates used was demonstrated, as well as for the composition of immune cell infiltrates within tumor microenvironment and the expression of immune checkpoints in immunomonitoring and RNAseq.Conclusion: In this study involving the CT26 model, no influence of a moderate high dose rate in FFF technique on the anti-tumor immune response was demonstrated, which would make studies of associations between RT and checkpoint inhibitors fit with this technique of RT. However, further explorations using other cellular models seem to be of interest. (c) 2020 The Authors. Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.