The role of STAT3 activation in modulating the immune microenvironment of GBM.

Abstract

Glioblastoma multiforme (GBM) modulates the immune system to engance its malignant potential. Signal transducer and activator of transcription 3 (STAT3) activation is a regulatory node in modulating the immune microenvironment in several human tumors, including GBM. To investigate whether STAT3 inhibition might enhance anti-tumor responses, we inhibited STAT3 signaling using small interfering RNA against STAT3. We tested the human GBM cell lines U87, U251, and HS683, which are known to constitutively express high levels of phospho-STAT3. STAT3 inhibition resulted in enhanced expression of several pro-inflammatory cytokines and chemokines and supernatants from STAT3-silenced human GBM cell lines increased lipopolysaccharide-induced dendritic cell activation in vitro. We obtained comparable results when STAT3 activity was suppressed with specific small molecule inhibitors. Our results support the hypothesis that activated STAT3 contributes to the immunosuppressive microenvironment in GBM and support previous studies implicating STAT3 as a potential target for immunotherapy.

• Authors: Alfred P See, James E Han, Jillian Phallen, Zev Binder, Gary Gallia, Fan Pan, Dilini Jinasena, Christopher Jackson, Zineb Belcaid, Sung Jin Jeong, Chelsea Gottschalk, Jing Zeng, Jacob Ruzevick, Sarah Nicholas, Young Kim, Emilia Albesiano, Drew M Pardoll, Michael Lim
• Journal: Journal of neuro-oncology (J Neurooncol) Vol. 110 Issue 3 Pg. 359-68 (Dec 2012) ISSN: 1573-7373 [Electronic] United States
• PMID: 23096132 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aminosalicylic Acids
• Benzenesulfonates
• Chemokines
• Cytokines
• Lipopolysaccharides
• NSC 74859
• RNA, Messenger
• RNA, Small Interfering
• STAT3 Transcription Factor

Topics

• Aminosalicylic Acids (pharmacology)
• Benzenesulfonates (pharmacology)
• Blotting, Western
• Brain Neoplasms (drug therapy, immunology, metabolism)
• Chemokines (metabolism)
• Cytokines (metabolism)
• Dendritic Cells (cytology, drug effects, metabolism)
• Electrophoretic Mobility Shift Assay
• Glioblastoma (drug therapy, immunology, metabolism)
• Humans
• Lipopolysaccharides (pharmacology)
• RNA, Messenger (genetics)
• RNA, Small Interfering (genetics)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• STAT3 Transcription Factor (antagonists & inhibitors, genetics, metabolism)
• Signal Transduction
• Tumor Cells, Cultured