title: Glioma-associated cancer-initiating cells induce immunosuppression.
abstract: OBJECTIVE
  Glioblastoma multiforme is a lethal cancer that responds poorly to therapy. Glioblastoma multiforme cancer-initiating cells have been shown to mediate resistance to both chemotherapy and radiation; however, it is unknown to what extent these cells contribute to the profound immunosuppression in glioblastoma multiforme patients and if strategies that alter their differentiation state can reduce this immunosuppression.
  
  
  METHODS
  We isolated a subpopulation of cells from glioblastoma multiforme that possessed the capacity for self-renewal, formed neurospheres in vitro, were capable of pluripotent differentiation, and could initiate tumors in vivo. The immune phenotype of these cells was characterized including the elaboration of immunosuppressive cytokines and chemokines by ELISA. Functional immunosuppressive properties were characterized based on the inhibition of T-cell proliferation and effector responses, triggering of T-cell apoptosis, and induction of FoxP3(+) regulatory T cells. On altering their differentiation state, the immunosuppressive phenotype and functional assays were reevaluated.
  
  
  RESULTS
  We found that the cancer-initiating cells markedly inhibited T-cell proliferation and activation, induced regulatory T cells, and triggered T-cell apoptosis that was mediated by B7-H1 and soluble Galectin-3. These immunosuppressive properties were diminished on altering the differentiation of the cancer-initiating cells.
  
  
  CONCLUSIONS
  Cancer-initiating cells contribute to tumor evasion of the immunosurveillance and approaches that alter the differentiation state may have immunotherapeutic potential.
authors.affiliation: Department of Neurosurgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Wei
authors.forename: Jason
authors.initials: J
authors.lastname: Barr
authors.forename: Ling-Yuan
authors.initials: LY
authors.lastname: Kong
authors.forename: Yongtao
authors.initials: Y
authors.lastname: Wang
authors.forename: Adam
authors.initials: A
authors.lastname: Wu
authors.forename: Amit K
authors.initials: AK
authors.lastname: Sharma
authors.forename: Joy
authors.initials: J
authors.lastname: Gumin
authors.forename: Verlene
authors.initials: V
authors.lastname: Henry
authors.forename: Howard
authors.initials: H
authors.lastname: Colman
authors.forename: Raymond
authors.initials: R
authors.lastname: Sawaya
authors.forename: Frederick F
authors.initials: FF
authors.lastname: Lang
authors.forename: Amy B
authors.initials: AB
authors.lastname: Heimberger
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001932:Brain Neoplasms / Q000097:blood / Q000276:immunology / Q000473:pathology*; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005909:Glioblastoma / Q000097:blood / Q000276:immunology / Q000473:pathology*; D006801:Humans; D007108:Immune Tolerance; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000276:immunology / Q000473:pathology* / Q000502:physiology* / Q000637:transplantation; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000502:physiology; D014183:Transplantation, Heterologous; D019139:Tumor Escape / Q000276:immunology / Q000502:physiology