title: γ-Radiation promotes immunological recognition of cancer cells through increased expression of cancer-testis antigens in vitro and in vivo.
abstract: BACKGROUND
  γ-radiation is an effective treatment for cancer. There is evidence that radiotherapy supports tumor-specific immunity. It was described that irradiation induces de novo protein synthesis and enhances antigen presentation, we therefore investigated whether γ-radiation results in increased expression of cancer-testis (CT) antigens and MHC-I, thus allowing efficient immunological control. This is relevant because the expression of CT-antigens and MHC-I on tumor cells is often heterogeneous. We found that the changes induced by γ-radiation promote the immunological recognition of the tumor, which is illustrated by the increased infiltration by lymphocytes after radiotherapy.
  
  
  RESULTS
  We compared the expression of CT-antigens and MHC-I in various cancer cell lines and fresh biopsies before and after in vitro irradiation (20 Gy). Furthermore, we compared paired biopsies that were taken before and after radiotherapy from sarcoma patients. To investigate whether the changed expression of CT-antigens and MHC-I is specific for γ-radiation or is part of a generalized stress response, we analyzed the effect of hypoxia, hyperthermia and genotoxic stress on the expression of CT-antigens and MHC-I. In vitro irradiation of cancer cell lines and of fresh tumor biopsies induced a higher or de novo expression of different CT-antigens and a higher expression of MHC-I in a time- and dose-dependent fashion. Importantly, we show that irradiation of cancer cells enhances their recognition by tumor-specific CD8+ T cells. The analysis of paired biopsies taken from a cohort of sarcoma patients before and after radiotherapy confirmed our findings and, in addition showed that irradiation resulted in higher infiltration by lymphocytes. Other forms of stress did not have an impact on the expression of CT-antigens or MHC-I.
  
  
  CONCLUSIONS
  Our findings suggest that γ-radiation promotes the immunological recognition of the tumor. We therefore propose that combining radiotherapy with treatments that support tumor specific immunity may result in increased therapeutic efficacy.
authors.affiliation: Department of Oncology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Anu
authors.initials: A
authors.lastname: Sharma
authors.forename: Beata
authors.initials: B
authors.lastname: Bode
authors.forename: Roland H
authors.initials: RH
authors.lastname: Wenger
authors.forename: Kuno
authors.initials: K
authors.lastname: Lehmann
authors.forename: Alessandro A
authors.initials: AA
authors.lastname: Sartori
authors.forename: Holger
authors.initials: H
authors.lastname: Moch
authors.forename: Alexander
authors.initials: A
authors.lastname: Knuth
authors.forename: Lotta von
authors.initials: Lv
authors.lastname: Boehmer
authors.forename: Maries van den
authors.initials: Mv
authors.lastname: Broek
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D064007:Ataxia Telangiectasia Mutated Proteins; D001706:Biopsy; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D051747:DNA-Activated Protein Kinase / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D005720:Gamma Rays; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000528:radiation effects; D008297:Male; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000528:radiation effects; D013312:Stress, Physiological / Q000528:radiation effects; D013601:T-Lymphocytes / Q000276:immunology / Q000528:radiation effects; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D015854:Up-Regulation / Q000528:radiation effects
chemical_list: D000951:Antigens, Neoplasm; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D015395:Histocompatibility Antigens Class I; D009687:Nuclear Proteins; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases