title: Synergy between the ectoenzymes CD39 and CD73 contributes to adenosinergic immunosuppression in human malignant gliomas.
abstract: BACKGROUND
  The importance of ectoenzymes CD39 and CD73 in mediating adenosinergic immunosuppression has been recognized, but their roles in human malignant glioma-associated immunosuppression remain largely unknown.
  
  
  METHODS
  In this study, the ectoenzyme characteristics of malignant glioma cells and infiltrating CD4(+) T lymphocytes isolated from newly diagnosed malignant glioma patients were investigated. The ectoenzyme activities of both cell populations were determined by nucleotide hydrolysis assay. The immunosuppressive property of the CD39-CD73 synergic effect was evaluated via responder T-cell proliferation assay.
  
  
  RESULTS
  We observed that CD39(-)CD73(+) glioma cells and infiltrating CD4(+)CD39(high)CD73(low) T lymphocytes exhibited 2 distinct but complementary ectoenzyme phenotypes, which were further verified by enzyme activity assay. The nucleotide hydrolysis cascade was incomplete unless CD39 derived from T lymphocytes and CD73 collaborated synergistically. We demonstrated that increased suppression of responder CD4(+) T-cell proliferation suppression was induced by CD4(+)CD39(+) T cells in the presence of CD73(+) glioma cells, which could be alleviated by the CD39 inhibitor ARL67156, the CD73 inhibitor APCP, or the adenosine receptor A2aR antagonist SCH58261. In addition, survival analysis suggested that CD73 downregulation was a positive prognostic factor related to the extended disease-free survival of glioblastoma patients.
  
  
  CONCLUSIONS
  Our data indicate that glioma-derived CD73 contributes to local adenosine-mediated immunosuppression in synergy with CD39 from infiltrating CD4(+)CD39(+) T lymphocytes, which could become a potential therapeutic target for treatment of malignant glioma and other immunosuppressive diseases.
authors.affiliation: Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China.
authors.forename: Shuo
authors.initials: S
authors.lastname: Xu
authors.forename: Qian-Qian
authors.initials: QQ
authors.lastname: Shao
authors.forename: Jin-Tang
authors.initials: JT
authors.lastname: Sun
authors.forename: Ning
authors.initials: N
authors.lastname: Yang
authors.forename: Qi
authors.initials: Q
authors.lastname: Xie
authors.forename: Dong-Hai
authors.initials: DH
authors.lastname: Wang
authors.forename: Qi-Bing
authors.initials: QB
authors.lastname: Huang
authors.forename: Bin
authors.initials: B
authors.lastname: Huang
authors.forename: Xin-Yu
authors.initials: XY
authors.lastname: Wang
authors.forename: Xin-Gang
authors.initials: XG
authors.lastname: Li
authors.forename: Xun
authors.initials: X
authors.lastname: Qu
mesh_terms: D015720:5'-Nucleotidase / Q000378:metabolism*; D000241:Adenosine / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism*; D001081:Apyrase / Q000378:metabolism*; D001932:Brain Neoplasms / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology* / Q000276:immunology; D045744:Cell Line, Tumor; D005910:Glioma / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D016246:Lymphocytes, Tumor-Infiltrating / Q000201:enzymology / Q000276:immunology
chemical_list: D015703:Antigens, CD; D015720:5'-Nucleotidase; D001081:Apyrase; C067869:CD39 antigen; D000241:Adenosine
keywords: CD39-CD73-adenosinergic immunosuppression; glioma microenvironment; infiltrating T lymphocytes; malignant glioma; synergic effect