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Investigation of immunosuppressive mechanisms in a mouse glioma model

  • Laboratory Investigation - Human/Animal Tissue
  • Published:
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Abstract

The development of an immune competent mouse model for the study of immunosuppressive mechanisms is important for improving the efficacy of brain tumor immunotherapy. In the present study we investigated regulatory T cells (Tregs), TGF-β1 and other putative immunosuppressive cytokines using GL261 mouse glioma in C57BL mice. We explored whether tumor growth factor-beta1 (TGF-β1) is expressed and secreted by glioma cells constitutively or in response to a T-cell mediated immunity (simulated by conditioned media from T cells (TCM) activated by anti-CD3 antibody). We also investigated TGF-β1’s role in Treg mediated immunosuppression by quantifying TGF-β1secretion from T regulatory cells (Tregs) co-incubated with GL261 cells as compared to Tregs alone. Finally, we studied other newly identified cytokines that were secreted preferentially by glioma cells in response to CD3 activated TCM versus cytokines secreted by glioma cells in absence of T-cell activation (naïve TCM). TGF-β1expression was studied using RT-PCR and secretion was quantified using ELISA. A 308 protein cytokine array was used to identify and quantify cytokine expression. TGF-β1expression and secretion from glioma cells was found to be up-regulated by conditioned media from CD3-activated T cells, suggesting that this immunosuppressive cytokine is not secreted constitutively but in response to immunity. TGF-β1 was not found to be differentially secreted by Tregs co-incubated with glioma cells as compared to Tregs alone. This data suggest that TGF-β1immunosupppression may not be a Treg dependent mechanism in this glioma model. Finally, the cytokine array elucidated several other cytokines which were up-regulated or down-regulated by CD3-activated TCM. These results have several implications for enhancing immunotherapy treatment, including the potential benefit of TGF-β1inhibition in conjunction with immunotherapy, as well as the illumination of several other potential cytokine targets to be explored as shown by the cytokine array.

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Acknowledgement

This work was supported in part by the Chicago Institute of Neurosurgery and Neuroscience.

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Authors and Affiliations

  1. Chicago Medical School, North Chicago, IL, USA

    Alexander Ksendzovsky

  2. Department of Anesthesia, University of Illinois College of Medicine, Chicago, IL, USA

    Douglas Feinstein, Anthony Sharp & Paul Polak

  3. Jesse Brown VA Hospital, Chicago, IL, USA

    Douglas Feinstein, Anthony Sharp & Paul Polak

  4. Department of Neurosurgery, Rush Medical College, Chicago, IL, USA

    Ryan Zengou, Terry Lichtor & Roberta P. Glick

  5. Department of Neurosurgery, Mt. Sinai Hospital, Chicago, IL, USA

    Roberta P. Glick

  6. Department of Anatomy and Cell Biology, University of Illinois College of Medicine, Chicago, IL, USA

    Roberta P. Glick

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  1. Alexander Ksendzovsky
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  2. Douglas Feinstein
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  4. Anthony Sharp
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  7. Roberta P. Glick
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Correspondence to Roberta P. Glick.

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Ksendzovsky, A., Feinstein, D., Zengou, R. et al. Investigation of immunosuppressive mechanisms in a mouse glioma model. J Neurooncol 93, 107–114 (2009). https://doi.org/10.1007/s11060-009-9884-6

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  • DOI: https://doi.org/10.1007/s11060-009-9884-6

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