Radiation fosters dose-dependent and chemotherapy-induced immunogenic cell death.
Radiation fosters dose-dependent and chemotherapy-induced immunogenic cell death.
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DOI：
10.4161/onci.28518
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发表时间：
2014
期刊：
影响因子：
7.2
通讯作者：
Formenti SC
中科院分区：
文献类型：
--
作者：
Golden EB;Frances D;Pellicciotta I;Demaria S;Helen Barcellos-Hoff M;Formenti SC
已建立的肿瘤的典型特征是免疫抑制的微环境。与这种自然发生的现象相反，新出现的证据表明，辐射促进了肿瘤内的免疫原环境，能够刺激宿主癌症特异性免疫反应。细胞毒剂诱导的细胞死亡有三个隐蔽的免疫原性成分，即钙网蛋白细胞表面暴露、高迁移率族蛋白1(HMGB1)蛋白的释放和ATP的释放，这些成分对树突状细胞(DC)的激活和效应性T细胞的启动至关重要。因此，这些免疫动员成分通常预示着肿瘤对治疗的排斥反应。我们最初提出的假设是辐射诱导的免疫原性细胞死亡(ICD)是剂量依赖的。接下来，我们假设当同时给予化疗时，放射治疗会增加化疗引起的ICD，正如在类似的同步放化疗方案中观察到的良好的临床结果所表明的那样。因此，我们设计了一种体外试验，在临床相关的辐射剂量下检查ICD的三个特征。然后，我们测试了放射联合卡铂或紫杉醇的免疫致死诱导作用，重点是这些组合模拟分别用于早期三阴性[NCT0128953/NYU-10-01969]和局部晚期[NYU-06209]乳腺癌患者的临床试验中实际使用的放化疗方案。尽管体外模型有明显的局限性，放射治疗对ICD的诱导和化疗均有剂量依赖性的促进作用。这些发现提供了初步的证据，表明无论是单独的大剂量放射治疗还是同步放化疗方案所刺激的ICD，都可能有助于瘤周免疫原环境的建立。
Established tumors are typified by an immunosuppresive microenvironment. Countering this naturally occurring phenomenon, emerging evidence suggests that radiation promotes a proimmunogenic milieu within the tumor capable of stimulating host cancer-specific immune responses. Three cryptic immunogenic components of cytotoxic-agent induced cell death—namely, calreticulin cell surface exposure, the release of high mobility group box 1 (HMGB1) protein, and the liberation of ATP—have been previously shown to be critical for dendritic cell (DC) activation and effector T-cell priming. Thus, these immune-mobilizing components commonly presage tumor rejection in response to treatment. We initially set out to address the hypothesis that radiation-induced immunogenic cell death (ICD) is dose-dependent. Next, we hypothesized that radiation would enhance chemotherapy-induced ICD when given concomitantly, as suggested by the favorable clinical outcomes observed in response to analogous concurrent chemoradiation regimens. Thus, we designed an in vitro assay to examine the 3 hallmark features of ICD at clinically relevant doses of radiation. We then tested the immunogenic-death inducing effects of radiation combined with carboplatin or paclitaxel, focusing on these combinations to mimic chemoradiation regimens actually used in clinical trials of early stage triple negative [NCT0128953/NYU-10–01969] and locally advanced [NYU-06209] breast cancer patients, respectively. Despite the obvious limitations of an in vitro model, radiotherapy produced both a dose-dependent induction and chemotherapeutic enhancement of ICD. These findings provide preliminary evidence that ICD stimulated by either high-dose radiotherapy alone, or concurrent chemoradiation regimens, may contribute to the establishment of a peritumoral proimmunogenic milieu.
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影响因子：
4.7
作者：
Golden EB;Pellicciotta I;Demaria S;Barcellos-Hoff MH;Formenti SC
通讯作者：
Formenti SC
DOI：
10.1158/1078-0432.ccr-09-0265
发表时间：
2009-09-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Dewan MZ;Galloway AE;Kawashima N;Dewyngaert JK;Babb JS;Formenti SC;Demaria S
通讯作者：
Demaria S
DOI：
10.1111/j.1749-6632.2010.05763.x
发表时间：
2010-01-01
期刊：
CLEARANCE OF DYING CELLS IN HEALTHY AND DISEASED IMMUNE SYSTEMS
影响因子：
--
作者：
Locher, Clara;Conforti, Rosa;Zitvogel, Laurence
通讯作者：
Zitvogel, Laurence
影响因子：
7.2
作者：
Kroemer G;Zitvogel L
通讯作者：
Zitvogel L
影响因子：
51.1
作者：
Formenti, Silvia C.;Demaria, Sandra
通讯作者：
Demaria, Sandra