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.

中文翻译：

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瘤内辐射剂量异质性增强了小鼠的抗肿瘤免疫力并引发了对检查点阻断的反应


放射治疗 （RT） 激活肿瘤微环境 （TME） 中的多种免疫作用，观察到不同的剂量反应关系。我们假设，与均相 RT 相比，异质性 RT 剂量将同时优化单个 TME 中多种免疫原性效应的激活，从而产生更有效的抗肿瘤免疫反应。使用高剂量率近距离放射治疗，我们用剂量为 2 至 30 戈瑞的单分异质性 RT 治疗携带同基因肿瘤的小鼠。当与小鼠模型中的双重免疫检查点抑制相结合时，与任何均质剂量相比，异质性 RT 在远处、未照射的肿瘤中产生更有效的抗肿瘤反应。异质性 RT 后的抗肿瘤作用需要 CD4 和 CD8 T 细胞和对部分肿瘤的低剂量 RT。在 RT 后 3 天的时间点，剂量异质性印记了靶向 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的易感性方面存在空间差异。在 RT 后 10 天的较晚时间点，高、中或低剂量 RT 区域表现出明显的浸润免疫细胞群。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 的剂量依赖性作用的广度，以及异质性 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。