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PMID: 20667896 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Glioma cancer stem cells induce immunosuppressive macrophages/microglia.

Neuro-oncology ·Vol. 12 ·No. 11 ·2010-11-00 ·Pages 1113-25

Wu A, Wei J, Kong LY, Wang Y, Priebe W, Qiao W, Sawaya R, Heimberger AB

Abstract

Macrophages (MΦs)/microglia that constitute the dominant tumor-infiltrating immune cells in glioblastoma are recruited by tumor-secreted factors and are induced to become immunosuppressive and tumor supportive (M2). Glioma cancer stem cells (gCSCs) have been shown to suppress adaptive immunity, but their role in innate immunity with respect to the recruitment and polarization of MΦs/microglia is unknown. The innate immunosuppressive properties of the gCSCs were characterized based on elaborated MΦ inhibitory cytokine-1 (MIC-1), transforming growth factor (TGF-β1), soluble colony-stimulating factor (sCSF), recruitment of monocytes, inhibition of MΦ/microglia phagocytosis, induction of MΦ/microglia cytokine secretion, and the inhibition of T-cell proliferation. The role of the signal transducer and activator of transcription 3 (STAT3) in mediating innate immune suppression was evaluated in the context of the functional assays. The gCSCs produced sCSF-1, TGF-β1, and MIC-1, cytokines known to recruit and polarize the MΦs/microglia to become immunosuppressive. The gCSC-conditioned medium polarized the MΦ/microglia to an M2 phenotype, inhibited MΦ/microglia phagocytosis, induced the secretion of the immunosuppressive cytokines interleukin-10 (IL-10) and TGF-β1 by the MΦs/microglia, and enhanced the capacity of MΦs/microglia to inhibit T-cell proliferation. The inhibition of phagocytosis and the secretion of IL-10 were reversed when the STAT3 pathway was blocked in the gCSCs. The gCSCs modulate innate immunity in glioblastoma by inducing immunosuppressive MΦs/microglia, and this capacity can be reversed by inhibiting phosphorylated STAT3.

MeSH Terms
Blotting, Western Brain Neoplasms/immunology,metabolism,pathology Cell Movement/immunology Cell Separation Cells, Cultured Chemotactic Factors/immunology,metabolism Chemotaxis, Leukocyte/immunology Cytokines/biosynthesis,immunology Enzyme-Linked Immunosorbent Assay Flow Cytometry Glioma/immunology,metabolism,pathology Humans Immunity, Innate/immunology Macrophages/immunology,metabolism Microglia/immunology,metabolism Neoplastic Stem Cells/immunology,metabolism,pathology Phosphorylation STAT3 Transcription Factor/immunology,metabolism Signal Transduction/immunology Transfection
Chemicals
Chemotactic Factors Cytokines STAT3 Transcription Factor STAT3 protein, human
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Wu Adam
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Wei Jun
Kong Ling-Yuan
Wang Yongtao
Priebe Waldemar
Qiao Wei
Sawaya Raymond
Heimberger Amy B
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Article Info
Journal
Neuro-oncology
Abbr.
Neuro Oncol
ISSN
1523-5866
DOI
10.1093/neuonc/noq082
Published
2010-11-00
Epub
2010-00-28
Pages
1113-25
Language
English
Region
England
NLM ID
100887420
PMCID
PMC3098021
Subset
IM
Grants
NCI NIH HHS · R01 CA120813 · United States
NCI NIH HHS · CA120813-04 · United States
External Links
PubMed source DOI: 10.1093/neuonc/noq082 PMC Full Text View journal details
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