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.
Conclusion
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.
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Acknowledgements
This investigation was supported by the Department of Neurosurgery (MUSC) and also by the South Carolina Clinical and Translational Research (SCTR) Institute, with an academic home at the Medical University of South Carolina, NIH/NCATS Grant Number UL1TR001450. The final systematic editing for language and style, together with preparation for manuscript, was made by Alyssa Pierce.
Author contributions
Conception and Design: Arabinda Das and Ramin Eskandari. Acquisition of data: Arabinda Das and Daniel McDonald. Interpretation of data: Arabinda Das, Stephen Lowe, Amy-Lee Bredlau, and Ramin Eskandari. Manuscript preparation and revision: Arabinda Das, Stephen Lowe, Amy-Lee Bredlau, Daniel McDonald, Kenneth Vanek, Sunil J. Patel, Samuel Cheshier, and Ramin Eskandari.
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Amy-Lee Bredlau is a consultant for Borvo-Lennus Pharmaceuticals Inc.and Azevan Pharmaceuticals, Inc. No other author has a conflict of interest.
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Das, A., McDonald, D., Lowe, S. et al. Immunological low-dose radiation modulates the pediatric medulloblastoma antigens and enhances antibody-dependent cellular cytotoxicity. Childs Nerv Syst 33, 429–436 (2017). https://doi.org/10.1007/s00381-016-3305-x
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DOI: https://doi.org/10.1007/s00381-016-3305-x