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

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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.

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Acknowledgments

This research was partially funded by The Johns Hopkins School of Medicine Dean’s Year of Research Program, The W. W. Smith Charitable Trust Medical Research Grant, the Association for Academic Surgery Joel J. Roslyn Faculty Research Award, and the Neurosurgery Research and Education Foundation (NREF). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

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Authors and Affiliations

  1. Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA

    Alfred P. See, Christopher Jackson & Jacob Ruzevick

  2. Department of Neurosurgery, The Johns Hopkins Hospital, Johns Hopkins University School of Medicine, Phipps Building, Room 123, 600 North Wolfe Street, Baltimore, MD, 21287, USA

    James E. Han, Jillian Phallen, Zineb Belcaid, Sung Jin Jeong, Chelsea Gottschalk, Sarah Nicholas & Michael Lim

  3. Ludwig Collaborative Laboratory, Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA

    Zev Binder & Gary Gallia

  4. Johns Hopkins Physical Sciences in Oncology Center and Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, 21218, USA

    Zev Binder

  5. Immunology and Hematopoiesis Division, Department of Oncology and Medicine, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA

    Fan Pan, Dilini Jinasena, Emilia Albesiano & Drew M. Pardoll

  6. Department of Radiation Oncology and Molecular Radiation Sciences, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, 21231, USA

    Jing Zeng

  7. Department of Otolaryngology-Head and Neck Surgery, Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA

    Young Kim

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  1. Alfred P. See
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Correspondence to Michael Lim.

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Alfred P. See and James E. Han contributed equally to this study.

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See, A.P., Han, J.E., Phallen, J. et al. The role of STAT3 activation in modulating the immune microenvironment of GBM. J Neurooncol 110, 359–368 (2012). https://doi.org/10.1007/s11060-012-0981-6

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