title: Immunological low-dose radiation modulates the pediatric medulloblastoma antigens and enhances antibody-dependent cellular cytotoxicity.
abstract: BACKGROUND
  Immunotherapy can be an effective treatment for pediatric medulloblastoma (MB) patients. However, major subpopulations do not respond to immunotherapy, due to the lack of antigenic mutations or the immune-evasive properties of MB cells. Clinical observations suggest that radiation therapy (RT) may expand the therapeutic reach of immunotherapy. The aim of the present investigation is to study the effect of low-dose X-ray radiation (LDXR, 1 Gy) on the functional immunological responses of MB cells (DAOY, D283, and D341).
  
  
  METHODS
  Induction of MB cell death was examined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Production of reactive oxygen species (ROS) was measured by fluorescent probes. Changes in the expression of  human leukocyte antigen (HLA) molecules and caspase-3 activities during treatment were analyzed using Western blotting and caspase-3 assay.
  
  
  RESULTS
  Western blot analysis demonstrated that LDXR upregulated the expression of HLA class I and HLA II molecules by more than 20% compared with control and high-dose (12 Gy) groups in vitro. Several of these HLA subtypes, such as MAGE C1, CD137, and ICAM-1, have demonstrated upregulation. In addition, LDXR increases ROS production in association with phosphorylation of NF-κB and cell surface expression of mAb target molecules (HER2 and VEGF). These data suggest that a combined LDXR and mAb therapy can create a synergistic effect in vitro.
  
  
  CONCLUSIONS
  These results suggest that LDXR modulates HLA molecules, leading to alterations in T-cell/tumor-cell interaction and enhancement of T-cell-mediated MB cell death. Also, low-dose radiotherapy combined with monoclonal antibody therapy may one day augment the standard treatment for MB, but more investigation is needed to prove its utility as a new therapeutic combination for MB patients.
authors.affiliation: Department of Neurosurgery and MUSC Brain and Spine Tumor Program CSB 310, Medical University of South Carolina, Charleston, SC, 29425, USA. dasa@musc.edu.
authors.forename: Arabinda
authors.initials: A
authors.lastname: Das
authors.affiliation: Department of Radiation Oncology, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: McDonald
authors.affiliation: Department of Neurosurgery and MUSC Brain and Spine Tumor Program CSB 310, Medical University of South Carolina, Charleston, SC, 29425, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Lowe
authors.affiliation: Department of Neurosurgery and MUSC Brain and Spine Tumor Program CSB 310, Medical University of South Carolina, Charleston, SC, 29425, USA.|Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Amy-Lee
authors.initials: AL
authors.lastname: Bredlau
authors.affiliation: Department of Radiation Oncology, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Vanek
authors.affiliation: Department of Neurosurgery and MUSC Brain and Spine Tumor Program CSB 310, Medical University of South Carolina, Charleston, SC, 29425, USA.
authors.forename: Sunil J
authors.initials: SJ
authors.lastname: Patel
authors.affiliation: Department of Pediatric Neurosurgery Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Cheshier
authors.affiliation: Department of Neurosurgery and MUSC Brain and Spine Tumor Program CSB 310, Medical University of South Carolina, Charleston, SC, 29425, USA. eskandar@musc.edu.|Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA. eskandar@musc.edu.
authors.forename: Ramin
authors.initials: R
authors.lastname: Eskandari
mesh_terms: D053330:4-1BB Ligand / Q000378:metabolism; D000704:Analysis of Variance; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor / Q000528:radiation effects*; D002470:Cell Survival / Q000187:drug effects; D004307:Dose-Response Relationship, Radiation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects*; D006680:HLA Antigens / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008527:Medulloblastoma / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D011827:Radiation; D017382:Reactive Oxygen Species / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology
chemical_list: D053330:4-1BB Ligand; D000911:Antibodies, Monoclonal; D053148:Caspase 3; D006680:HLA Antigens; D018799:Intercellular Adhesion Molecule-1; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D018719:Erb-b2 Receptor Tyrosine Kinases; D042461:Vascular Endothelial Growth Factor A; C505974:TNFSF9 protein, human; C508053:ERBB2 protein, human
keywords: HLA; Immunomodulation; Medulloblastoma; Radiation; mAb