title: Expanding the use of monoclonal antibody therapy of cancer by using ionising radiation to upregulate antibody targets.
abstract: BACKGROUND
  Monoclonal antibody (mAb) therapy for the treatment of solid and haematologic malignancies has shown poor response rates as a monotherapy. Furthermore, its use is limited to tumours expressing certain molecular targets. It has been shown that single-dose radiation can induce immunogenic modulation that is characterised by cell-surface phenotypic changes leading to augmented tumour cell/cytotoxic T-cell interaction.
  
  
  METHODS
  We examined radiation's ability to upregulate mAb therapy targets. We also used radiation to sensitise tumour cells to antibody-dependent cell-mediated cytotoxicity (ADCC).
  
  
  RESULTS
  Radiation significantly increased cell-surface and total protein expression of mAb targets HER2, EGFR, and CD20. Focusing on HER2, targeted by trastuzumab, we observed significant upregulation of HER2 following radiation of 3 out of 3 breast cancer cell lines, one of which was triple negative, as well as in residential stem-cell populations. HER2 upregulation was sustained up to 96 h following radiation exposure and was largely dependent on intracellular reactive oxygen species. Improved ADCC and sensitisation to the antiproliferative effects of trastuzumab demonstrated the functional significance of radiation-induced HER2 upregulation.
  
  
  CONCLUSIONS
  We show that single-dose radiation enhances mAb therapy. These findings highlight a mechanism for combining radiation with immunotherapy and expand the patient population that can be treated with targeted therapy.
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room 8B13, Bethesda, MD 20892, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Wattenberg
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room 8B13, Bethesda, MD 20892, USA.
authors.forename: A R
authors.initials: AR
authors.lastname: Kwilas
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room 8B13, Bethesda, MD 20892, USA.
authors.forename: S R
authors.initials: SR
authors.lastname: Gameiro
authors.affiliation: Department of Radiation Oncology, Thomas Jefferson University, 111 S. 11th Street, Philadelphia, PA 19107, USA.
authors.forename: A P
authors.initials: AP
authors.lastname: Dicker
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room 8B13, Bethesda, MD 20892, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Hodge
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000920:Antibody-Dependent Cell Cytotoxicity / Q000528:radiation effects; D018951:Antigens, CD20 / Q000096:biosynthesis / Q000276:immunology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000532:radiotherapy*; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D066246:ErbB Receptors / Q000096:biosynthesis / Q000276:immunology; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D058990:Molecular Targeted Therapy / Q000379:methods; D014176:Protein Biosynthesis / Q000528:radiation effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000528:radiation effects; D000068878:Trastuzumab; D015854:Up-Regulation / Q000528:radiation effects
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018951:Antigens, CD20; D066246:ErbB Receptors; D017382:Reactive Oxygen Species; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C512478:EGFR protein, human; C508053:ERBB2 protein, human