Departments of Medical Oncology, Beijing Key Laboratory for Therapeutic Cancer Vaccines, Capital Medical University Cancer Center, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China; Departments of Radio-Oncology, Capital Medical University Cancer Center, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China.
Departments of Medical Oncology, Beijing Key Laboratory for Therapeutic Cancer Vaccines, Capital Medical University Cancer Center, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China.
Int J Radiat Oncol Biol Phys. 2021 Oct 1;111(2):479-490. doi: 10.1016/j.ijrobp.2021.04.041. Epub 2021 May 8.
Radiation therapy (RT) modulates immune cells and cytokines, resulting in both clinically beneficial and detrimental effects. The changes in peripheral blood T lymphocyte subsets and cytokines during RT for pediatric brain tumors and the association of these changes with therapeutic outcomes have not been well described.
The study population consisted of children (n = 83, aged 3~18) with primary brain tumors (medulloblastoma, glioma, germ cell tumors (GCT), and central nervous system embryonal tumor-not otherwise specified), with or without residual or disseminated (R/D) diseases who were starting standard postoperative focal or craniospinal irradiation (CSI). Peripheral blood T lymphocyte subsets collected before and 4 weeks after RT were enumerated by flow cytometry. Plasma levels of interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor-α, interferon-γ, and IL-17A were measured by cytometric bead array.
Patients with R/D lesions receiving CSI (n = 32) had a post-RT increase in the frequency of CD3+T and CD8+T cells, a decrease in CD4+T cells, and an increase in regulatory T cells (Tregs) and CD8+CD28- suppressor cells, which was more predominantly seen in these patients than in other groups. In the CSI group with such R/D lesions, consisting of patients with medulloblastoma and germ cell tumors, 19 experienced a complete response (CR) and 13 experienced a partial response (PR) on imaging at 4 weeks after RT. The post/pre-RT ratio of Tregs (P = .0493), IL-6 (P = .0111), and IL-10 (P = .0070) was lower in the CR group than in the PR group. Multivariate analysis revealed that the post/pre-RT ratios of Treg, IL-6, and IL-10 were independent predictors of CR (P < .0001, P = .018, P < .0001, respectively). The areas under the receiver operating curves and confidence intervals were 0.7652 (0.5831-0.8964), 0.7794 (0.5980-0.9067), and 0.7085 (0.5223-0.8552) for IL-6, IL-10, and Treg, respectively. The sensitivities of IL-6, IL-10, and Treg to predict radiotherapeutic responses were 100%, 92.3%, and 61.5%, and specificity was 52.6%, 57.9%, and 84.2%, respectively.
CSI treatment to those with R/D lesions predominantly exerted an effect on antitumor immune response compared with both R/D lesion-free but exposed to focal or CSI RT and with R/D lesions and exposed to focal RT. Such CSI with R/D lesions group experiencing CR is more likely to have a decrease in immunoinhibitory molecules and cells than patients who only achieve PR. Measuring peripheral blood Treg, IL-6, and IL-10 levels could be valuable for predicting radiotherapeutic responses of pediatric brain tumors with R/D lesions to CSI for medulloblastoma and intracranial germ cell tumors.
放射治疗（RT）可调节免疫细胞和细胞因子，从而产生临床有益和有害的影响。在儿科脑肿瘤的 RT 期间外周血 T 淋巴细胞亚群和细胞因子的变化，以及这些变化与治疗结果的关系尚未得到很好的描述。
研究人群包括 83 名患有原发性脑肿瘤（髓母细胞瘤、神经胶质瘤、生殖细胞肿瘤（GCT）和中枢神经系统胚胎肿瘤-未另作说明）的儿童（年龄 3~18 岁），无论是否有残留或播散性（R/D）疾病，他们开始接受标准术后局部或颅脊髓照射（CSI）。在 RT 前后 4 周采集外周血 T 淋巴细胞亚群，并用流式细胞术进行计数。通过流式细胞术微珠阵列法测量白细胞介素（IL）-2、IL-4、IL-6、IL-10、肿瘤坏死因子-α、干扰素-γ和 IL-17A 的血浆水平。
接受 CSI（n=32）的 R/D 病变患者在 RT 后 CD3+T 和 CD8+T 细胞的频率增加，CD4+T 细胞减少，调节性 T 细胞（Tregs）和 CD8+CD28-抑制细胞增加，这种变化在这些患者中比其他组更为明显。在接受 CSI 的具有 R/D 病变的患者中（包括髓母细胞瘤和生殖细胞肿瘤患者），19 名患者在 RT 后 4 周的影像学检查中获得完全缓解（CR），13 名患者获得部分缓解（PR）。CR 组 Treg（P=.0493）、IL-6（P=.0111）和 IL-10（P=.0070）的 RT 前后比值均低于 PR 组。多变量分析显示，Treg、IL-6 和 IL-10 的 RT 前后比值是 CR 的独立预测因子（P<0.0001，P=.018，P<0.0001）。IL-6、IL-10 和 Treg 的受试者工作特征曲线下面积和置信区间分别为 0.7652（0.5831-0.8964）、0.7794（0.5980-0.9067）和 0.7085（0.5223-0.8552）。IL-6、IL-10 和 Treg 预测放射治疗反应的灵敏度分别为 100%、92.3%和 61.5%，特异性分别为 52.6%、57.9%和 84.2%。
与 R/D 病变无但暴露于局部或 CSI RT 以及 R/D 病变并暴露于局部 RT 的患者相比，CSI 治疗 R/D 病变主要对肿瘤免疫反应产生影响。经历 CR 的 CSI 治疗 R/D 病变组比仅获得 PR 的患者更有可能降低免疫抑制分子和细胞。测量外周血 Treg、IL-6 和 IL-10 水平可能有助于预测接受 CSI 治疗的小儿脑肿瘤 R/D 病变对髓母细胞瘤和颅内生殖细胞肿瘤的放射治疗反应。
