Changes in peripheral blood regulatory T cells, and IL−6 and IL−10 levels predict response of pediatric medulloblastoma and germ cell tumors with residual or disseminated disease to craniospinal irradiation

Abstract Purpose Radiotherapy modulates immune cells and cytokines resulting in both clinically beneficial and detrimental effects. The changes in peripheral blood T lymphocyte subsets and cytokines during radiotherapy for pediatric brain tumors and the association of these changes with therapeutic outcomes have not been well described. Methods and Materials The study population consisted of children (n=83, ages 3∼18) with primary brain tumors (medulloblastoma, glioma, germ cell tumors, and CNS embryonal tumor-NOS), with or without residual or disseminated (R/D) diseases who were starting standard post-operative focal or craniospinal-irradiation (CSI). Peripheral blood T lymphocyte subsets collected before and 4 weeks after radiotherapy were enumerated by flow cytometry. Plasma levels of IL—2, IL—4, IL—6, IL—10, TNF—α, IFN—γ, and IL—17A were measured by cytometric bead array. Results Patients with R/D lesions receiving CSI (n=32) had a post-radiotherapy increase in the frequency of CD3+T cell and CD8+T cells, a decrease in CD4+ T cells, and an increase in Tregs and CD8+CD28- suppressor cells which were predominantly seen than other groups. In such R/D lesions exposed to CSI group, 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 following radiotherapy. The post/pre-radiotherapy ratio of Tregs (P =0.0493), IL−6 (P=0.0111) and IL−10 (P=0.0070) was lower in the CR group than the PR group. Multivariate analysis revealed that the post/pre-radiotherapy ratios of Treg, IL−6 and IL−10 were independent predictors of CR (P Conclusions CSI treatment to those with R/D lesions exerted a predominantly effect on anti-tumor immune response compared with both R/D lesions-free but exposed to focal or CSI radiotherapy and with R/D lesions for focal radiotherapy. 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 with CSI for medulloblastoma and intracranial germ cell tumors.