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Myeloid-derived Suppressor Cells – A New Target for GBM Treatment?

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Review of “Cancer Stem Cell-Secreted Macrophage Migration Inhibitory Factor Stimulates Myeloid Derived Suppressor Cell Function and Facilitates Glioblastoma Immune Evasion” from Stem Cells by Stuart P. Atkinson

Glioblastoma multiforme (GBM) is an unfortunately prevalent and aggressive brain tumor type which currently lacks effective treatment strategies. This is, in part, due to the presence of self-renewing, tumorigenic cancer stem cells (CSCs) and the suppression of the anti-tumorigenic immune response within GBM tumors.

Researchers from the laboratories of Justin D. Lathia and Michael A. Vogelbaum (Cleveland Clinic, Ohio, USA) sought to understand any link between CSCs and immune suppression in GBM and to apply this information to construct an effective anti-GBM strategy based. Their new Stem Cells study finds that a type of tumor-associated immunosuppressive cell, known as myeloid-derived suppressor cells (MDSCs) [1-3], is present within the GBM microenvironment and that CSC-secreted factors boost their activity [4]. Could this represent a new and exciting target for anti-GBM treatment?

Assessments of GBM patient samples readily established evidence of MDSCs in close proximity to GBM CSCs and the authors also identified a link between the increased presence of MDSCs and poorer patient prognosis. Moving to a GBM mouse model, the study demonstrated that elimination of MDSCs via low-dose 5-fluorouracil (5-FU) treatment increased tumor latency, reduced tumor growth, an increase in cytotoxic T cells, and a decrease in suppressive T regulatory cells (T Regs) in the tumor. 

The close proximity of MDSCs and CSCs suggested to the authors of a functional link, and indeed, CSC-conditioned medium (CM) upregulated MDSC function, increased survival, and promoted the emergence of an immunosuppressive phenotype in immature splenic T cell coculture experiments. SO what exactly is the magic ingredient in that CM? Cytokine array analysis highlighted a potential role for macrophage migratory inhibitory factor (MIF), and addition of this cytokine to MDSC medium mediated an upregulation in MDSC activity working through the CXCR4 receptor. 

Excitingly, when the authors depleted MIF in GBM carrying mice, they observed increased tumor latency, and an increase in cytotoxic T cells and a significant decrease in T Regs in the brains (See figure). However, they observed no overt changes to CSC biology indicating that MIF acts as an indirect promoter of GBM progression via modulation of the immune microenvironment.

Not only does this exciting study deepen our understanding of the basic biology of GBM, but it also highlights a potentially important new target for GBM treatment. Can targeting myeloid-derived suppressor cells rather than CSCs generate better therapeutic efficacy and perhaps even a generic effect, irrespective of GBM grade/type? And even further, does MDSC-targeting represent a means to target CSC-associated solid tumor types? What is certain is that modulation of the immune microenvironment is an important new therapeutic modality in cancer treatment.

Discussion Points

  • Will new single or combinatorial drug treatments, including those that target myeloid-derived suppressor cells, be effective in combating GBM?
  • Will this work for other CSC-associated or non-associated tumor types?
  • Will such treatments stop treatment resistance and tumor recurrence?

References

  1. Ko JS, Zea AH, Rini BI, et al. Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin Cancer Res 2009;15:2148-2157.
  2. Ostrand-Rosenberg S Myeloid-derived suppressor cells: more mechanisms for inhibiting antitumor immunity. Cancer Immunol Immunother 2010;59:1593-1600.
  3. Ozao-Choy J, Ma G, Kao J, et al. The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immune-based cancer therapies. Cancer Res 2009;69:2514-2522.
  4. Otvos B, Silver DJ, Mulkearns-Hubert EE, et al. Cancer Stem Cell-Secreted Macrophage Migration Inhibitory Factor Stimulates Myeloid Derived Suppressor Cell Function and Facilitates Glioblastoma Immune Evasion. STEM CELLS 2016;34:2026-2039.