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Page 12 of 18 Yelton et al. Neuroimmunol Neuroinflammation 2018;5:46 I http://dx.doi.org/10.20517/2347-8659.2018.58

Other leukocytes that have been implicated in antitumor immunity among NK cells also include Treg
cells and microglia. Instead of priming the tumor cells for removal by the immune system, current
inquiry has looked into the role of these leukocytes in the tumor microenvironment, and how their
[84]
inhibition may increase the tumor’s susceptibly to clearance by the immune system . One pilot study
in particular looked at lymphodepletion of Treg cells through the use of monoclonal antibodies in those
with glioblastoma and showed enhanced antitumor immunity, as it had been shown in the past that these
[85]
Treg cells were associated with immunosuppression of glioblastoma . Depleting the Treg cells through
the use of the anti-CD25 monoclonal antibody daclizumab was able to paradoxically enhance antitumor
immunity. Additionally, another study looked at using anti-PD-1 and anti-CTLA-4 antibodies for the use
[86]
of inhibiting Treg cell function as well, which showed improved survival in mouse models . Microglia
have been similarly targeted to enhance antitumor immunity, as they have increased presence within
the GBM microenvironment and are assumed to have roles in local immunosuppression. Inhibition of
the signal transducer and activator of transcription 3 (STAT3) pathway within tumor cells has shown
improved outcomes in mouse models specifically, with one study using the siRNA-based method to
[87]
activate these cells within the tumor microenvironment and subsequently slow tumor growth . Another
study showed success using the same rationale but utilizing the miR-124 inhibition of the STAT3 pathway
[88]
to enhance antitumor immunity . While these studies have demonstrated promising concepts for future
investigation regarding antitumor immunity in leukocytes, these effects are largely limited to the tumor
microenvironment and the biggest successes have only been demonstrated in mouse models or had a
very small sample size. Additional investigation is obviously required before these potential therapeutic
modalities are ready for human trials.

Of the known HDAC inhibitors, TSA seems to show promise in the preclinical realm for enhancing
antitumor immunity; but unfortunately, when brought into the clinical arena, TSA showed high toxicity
and low efficacy. While this compound has been shown to upregulate NKG2DL expression on GBM cells
directly, it is unclear whether this action is due to epigenetic transcriptional alteration within the tumor
[69]
cell or this is due to reduction of secretion of MMPs . The immunostimulatory effect of TSA was shown
to be also dependent upon the presence of NK cells, as evident from the use of an anti-NKG2D antibody
significantly reducing the amount of observed GBM cell lysis in vitro. While this compound showed
considerable preclinical promise, its high toxicity and low efficacy has made other HDAC inhibitors such as
vorinostat, romidepsin, and valproic acid as more promising candidates for potential future monotherapy in
GBM. These HDAC inhibitors unfortunately do not display the same antitumor immunity as other HDAC
inhibitors in the preclinical arena but are the most likely candidates to be used for future monotherapy or
combination therapy in clinical trials.

While HDAC inhibitors have been used to treat cancers successfully in the past and have seen modest
success in their use against GBM specifically, this is the first time that these agents have been utilized as an
immunotherapy regimen in GBM. As it has already been described in this article, while an agent may see
mechanistic success in the laboratory setting this may or may not translate to the clinical realm through the
process of FDA approval and clinical trials. Studies such as these offer exciting possibility of new therapeutic
modalities for a formidable clinical challenge that is in desperate need of innovation.

IMMUNOTHERAPY IN CONTROLLING GROWTH OF GLIOBLASTOMA
One of the most exciting new therapy modalities being examined for the treatment of glioblastoma is
immunotherapy and immunomodulation, or harnessing/modifying the body’s immune system to help fight
the tumor directly. However, while in theory these therapies may be very promising, in practice the tumors
themselves have multiple mechanisms of immunosuppression that lead to promising in vitro results, but
[89]
further studies do not necessarily see the same in vivo or clinical results . These tumors cause systemic
immunosuppression through their release of cytokines, which inhibit lymphocyte proliferation and promote