Glioblastoma cancer-initiating cells inhibit T-cell proliferation and effector responses by the signal transducers and activators of transcription 3 pathway.
Glioblastoma multiforme (GBM) is a lethal cancer that responds poorly to radiotherapy and chemotherapy. Glioma cancer-initiating cells have been shown to recapitulate the characteristic features of GBM and mediate chemotherapy and radiation resistance. However, it is unknown whether the cancer-initiating cells contribute to the profound immune suppression in GBM patients. Recent studies have found that the activated form of signal transducer and activator of transcription 3 (STAT3) is a key mediator in GBM immunosuppression. We isolated and generated CD133+ cancer-initiating single colonies from GBM patients and investigated their immune-suppressive properties. We found that the cancer-initiating cells inhibited T-cell proliferation and activation, induced regulatory T cells, and triggered T-cell apoptosis. The STAT3 pathway is constitutively active in these clones and the immunosuppressive properties were markedly diminished when the STAT3 pathway was blocked in the cancer-initiating cells. These findings indicate that cancer-initiating cells contribute to the immune evasion of GBM and that blockade of the STAT3 pathway has therapeutic potential.
Wei
Jun
J
Department of Neurosurgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77230-1402, USA.
Barr
Jason
J
Kong
Ling-Yuan
LY
Wang
Yongtao
Y
Wu
Adam
A
Sharma
Amit K
AK
Gumin
Joy
J
Henry
Verlene
V
Colman
Howard
H
Priebe
Waldemar
W
Sawaya
Raymond
R
Lang
Frederick F
FF
Heimberger
Amy B
AB
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002469:Cell Separation; D018925:Chemokines / Q000378:metabolism; D005909:Glioblastoma / Q000378:metabolism* / 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*; D010750:Phosphoproteins / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D018925:Chemokines; D010750:Phosphoproteins; D050796:STAT3 Transcription Factor