Justin C. Jagodinsky, Jessica M. Vera, Won Jong Jin, Amanda G. Shea, Paul A. Clark, Raghava N. Sriramaneni, Thomas C. Havighurst, Ishan Chakravarthy, Raad H. Allawi, KyungMann Kim, Paul M. Harari, Paul M. Sondel, Michael A. Newton, Marka R. Crittenden, Michael J. Gough, Jessica R. Miller, Irene M. Ong, Zachary S. Morris
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When combined with dual immune checkpoint inhibition in murine models, heterogeneous RT generated more potent antitumor responses in distant, nonirradiated tumors compared with any homogeneous dose. The antitumor effect after heterogeneous RT required CD4 and CD8 T cells and low-dose RT to a portion of the tumor. At the 3-day post-RT time point, dose heterogeneity imprinted the targeted TME with spatial differences in immune-related gene expression, antigen presentation, and susceptibility of tumor cells to immune-mediated destruction. At a later 10-day post-RT time point, high-, moderate-, or low-RT-dose regions demonstrated distinct infiltrating immune cell populations. This was associated with an increase in the expression of effector-associated cytokines in circulating CD8 T cells. Consistent with enhanced adaptive immune priming, heterogeneous RT promoted clonal expansion of effector CD8 T cells. 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引用次数: 0
摘要
放射治疗(RT)会激活肿瘤微环境(TME)中的多种免疫效应,并观察到不同的剂量-反应关系。我们假设,与均质 RT 相比,异质 RT 剂量能同时优化激活单一 TME 中的多种免疫效应,从而产生更有效的抗肿瘤免疫反应。我们利用高剂量率近距离放射疗法,对携带合成肿瘤的小鼠进行单剂量异质RT治疗,剂量范围为2至30灰。当在小鼠模型中结合双重免疫检查点抑制时,与任何均质剂量相比,异质RT能在远处未照射的肿瘤中产生更强的抗肿瘤反应。异质 RT 后的抗肿瘤效果需要 CD4 和 CD8 T 细胞以及对部分肿瘤的低剂量 RT。在RT后3天的时间点,剂量异质性使靶向TME在免疫相关基因表达、抗原呈递和肿瘤细胞对免疫介导的破坏敏感性方面存在空间差异。在 RT 后 10 天的时间点上,高、中、低 RT 剂量区域显示出不同的浸润免疫细胞群。这与循环 CD8 T 细胞中效应相关细胞因子表达的增加有关。与增强的适应性免疫启动相一致,异质性 RT 促进了效应 CD8 T 细胞的克隆扩增。这些发现阐明了RT对TME的剂量依赖性效应的广度,以及异质RT与免疫检查点抑制剂联合使用时促进抗肿瘤免疫的能力。
Intratumoral radiation dose heterogeneity augments antitumor immunity in mice and primes responses to checkpoint blockade
Radiation therapy (RT) activates multiple immunologic effects in the tumor microenvironment (TME), with diverse dose-response relationships observed. We hypothesized that, in contrast with homogeneous RT, a heterogeneous RT dose would simultaneously optimize activation of multiple immunogenic effects in a single TME, resulting in a more effective antitumor immune response. Using high-dose-rate brachytherapy, we treated mice bearing syngeneic tumors with a single fraction of heterogeneous RT at a dose ranging from 2 to 30 gray. When combined with dual immune checkpoint inhibition in murine models, heterogeneous RT generated more potent antitumor responses in distant, nonirradiated tumors compared with any homogeneous dose. The antitumor effect after heterogeneous RT required CD4 and CD8 T cells and low-dose RT to a portion of the tumor. At the 3-day post-RT time point, dose heterogeneity imprinted the targeted TME with spatial differences in immune-related gene expression, antigen presentation, and susceptibility of tumor cells to immune-mediated destruction. At a later 10-day post-RT time point, high-, moderate-, or low-RT-dose regions demonstrated distinct infiltrating immune cell populations. This was associated with an increase in the expression of effector-associated cytokines in circulating CD8 T cells. Consistent with enhanced adaptive immune priming, heterogeneous RT promoted clonal expansion of effector CD8 T cells. These findings illuminate the breadth of dose-dependent effects of RT on the TME and the capacity of heterogeneous RT to promote antitumor immunity when combined with immune checkpoint inhibitors.
期刊介绍:
Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research.
The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases.
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