立体定向消融放疗诱导外周血免疫表型的系统差异，取决于照射部位。
Stereotactic Ablative Radiation Therapy Induces Systemic Differences in Peripheral Blood Immunophenotype Dependent on Irradiated Site.
机构信息
Department of Radiation Oncology, University of California, Davis, Comprehensive Cancer Center, Davis, California; Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, New York.
Department of Radiation Oncology, University of California, Davis, Comprehensive Cancer Center, Davis, California.
出版信息
Int J Radiat Oncol Biol Phys. 2018 Aug 1;101(5):1259-1270. doi: 10.1016/j.ijrobp.2018.04.038. Epub 2018 Apr 22.
PURPOSE
Despite the strong interest in combining stereotactic ablative radiation therapy (SAR) with immunotherapy, limited data characterizing the systemic immune response after SAR are available. We hypothesized that the systemic immune response to SAR would differ by irradiated site owing to inherent differences in the microenvironment of various organs.
METHODS AND MATERIALS
Patients receiving SAR to any organ underwent prospective blood banking before and 1 to 2 weeks after SAR. Peripheral blood mononuclear cells (PBMCs) and serum were isolated. PBMCs were stained with fluorophore-conjugated antibodies against T and natural killer (NK) cell markers. Cells were interrogated by flow cytometry, and the results were analyzed using FlowJo software. Serum cytokine and chemokine levels were measured using Luminex. We analyzed the changes from before to after therapy using paired t tests or 1-way analysis of variance (ANOVA) with Bonferroni's post-test.
RESULTS
A total of 31 patients had evaluable PBMCs for flow cytometry and 37 had evaluable serum samples for Luminex analysis. The total number of NK cells and cytotoxic (CD56CD16) NK cells decreased (P = .02) and T-cell immunoglobulin- and mucin domain-containing molecule-3-positive (TIM3) NK cells increased (P = .04) after SAR to parenchymal sites (lung and liver) but not to bone or brain. The total memory CD4 T cells, activated inducible co-stimulator-positive and CD25CD4 memory T cells, and activated CD25CD8 memory T cells increased after SAR to parenchymal sites but not bone or brain. The circulating levels of tumor necrosis factor-α (P = .04) and multiple chemokines, including RANTES (P = .04), decreased after SAR to parenchymal sites but not bone or brain.
CONCLUSIONS
Our data suggest SAR to parenchymal sites induces systemic immune changes, including a decrease in total and cytotoxic NK cells, an increase in TIM3 NK cells, and an increase in activated memory CD4 and CD8 T cells. SAR to nonparenchymal sites did not induce these changes. By comparing the immune response after radiation to different organs, our data suggest SAR induces systemic immunologic changes that are dependent on the irradiated site.
目的
尽管人们对立体定向消融放疗（SAR）与免疫疗法相结合非常感兴趣，但目前仅有有限的数据可用于描述 SAR 后的全身免疫反应。我们假设，由于各种器官的微环境存在固有差异，SAR 后的全身免疫反应会因照射部位的不同而有所不同。
方法与材料
入组的每位接受 SAR 治疗任意器官的患者均在 SAR 治疗前和治疗后 1 至 2 周进行前瞻性血样采集。分离外周血单个核细胞（PBMC）和血清。使用荧光标记的抗体对 T 细胞和自然杀伤（NK）细胞标志物对 PBMC 进行染色。通过流式细胞术对细胞进行检测，并使用 FlowJo 软件对结果进行分析。使用 Luminex 检测血清细胞因子和趋化因子水平。我们采用配对 t 检验或单因素方差分析（ANOVA）与 Bonferroni 事后检验，分析治疗前后的变化。
结果
共有 31 例患者可用于流式细胞术评估 PBMC，37 例患者可用于 Luminex 分析评估血清样本。SAR 治疗实质脏器（肺和肝）后，NK 细胞总数和细胞毒性（CD56CD16）NK 细胞减少（P=.02），T 细胞免疫球蛋白和粘蛋白结构域 3 阳性（TIM3）NK 细胞增加（P=.04），但 SAR 治疗骨或脑时无此变化。SAR 治疗实质脏器后，总记忆 CD4 T 细胞、活化诱导共刺激分子阳性和 CD25CD4 记忆 T 细胞、活化 CD25CD8 记忆 T 细胞增加，但 SAR 治疗骨或脑时无此变化。SAR 治疗实质脏器后，肿瘤坏死因子-α（P=.04）和包括 RANTES（P=.04）在内的多种趋化因子的循环水平降低，但 SAR 治疗骨或脑时无此变化。
结论
我们的数据表明，SAR 治疗实质脏器会引起全身免疫变化，包括 NK 细胞总数和细胞毒性减少、TIM3 NK 细胞增加以及 CD4 和 CD8 记忆 T 细胞激活增加。SAR 治疗非实质脏器不会引起这些变化。通过比较不同器官接受放疗后的免疫反应，我们的数据表明，SAR 诱导的全身免疫变化取决于照射部位。
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