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Review
. 2015:2015:717530.
doi: 10.1155/2015/717530. Epub 2015 Jun 17.

Dendritic Cell-Based Immunotherapy Treatment for Glioblastoma Multiforme

Liu Yang  1 , Geng Guo  2 , Xiao-yuan Niu  1 , Jing Liu  2
Affiliations
Review

Dendritic Cell-Based Immunotherapy Treatment for Glioblastoma Multiforme

Liu Yang et al. Biomed Res Int. 2015.

Abstract

Glioblastoma multiforme (GBM) is the most malignant glioma and patients diagnosed with this disease had poor outcomes even treated with the combination of conventional treatment (surgery, chemotherapy, and radiation). Dendritic cells (DCs) are the most powerful antigen presenting cells and DC-based vaccination has the potential to target and eliminate GBM cells and enhance the responses of these cells to the existing therapies with minimal damage to the healthy tissues around them. It can enhance recognition of GBM cells by the patients' immune system and activate vast, potent, and long-lasting immune reactions to eliminate them. Therefore, this therapy can prolong the survival of GBM patients and has wide and bright future in the treatment of GBM. Also, the efficacy of this therapy can be strengthened in several ways at some degree: the manipulation of immune regulatory components or costimulatory molecules on DCs; the appropriate choices of antigens for loading to enhance the effectiveness of the therapy; regulation of positive regulators or negative regulators in GBM microenvironment.

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Figures

Figure 1
Figure 1
Dendritic cell (DC)-based vaccination immunotherapeutic strategies for glioblastoma multiforme (GBM). Bone-marrow derived precursors are differentiated into DCs by Flt3L or GM-CSF. DCs can be divided into two distinct subtypes, types 1 and 2. They act differently and have synergistic effects in antitumor immunity. They can be loaded with GBM antigens derived from RNA, DNA, proteins, peptides, lysates, glioma stem cells antigens, apoptotic cells or fusion. They recognize and capture antigens, then they present processed peptides (derived from captured antigens) to T cells in the context of major histocompatibility complex (MHC) class I or II (signal 1). Then pulse tumor-loaded DCs with maturation stimuli to increase the expression of costimulatory molecules such as CD80 (signal 2) and the secretion of proinflammatory cytokines such as IL-12 (signal 3). Then CD4+ helper T cells secrete IL-2 to stimulate CD8+ cytotoxic T cells which then secrete IFN-γ and exhibit cytolytic immune responses against GBM cells. Upregulating costimulatory signals or suppressing coinhibitory signals can strengthen the efficacy of DC vaccines. Manipulation of these signals includes: TLR agonists, CD40 ligand, CD70, tumor necrosis factor receptor superfamily-member 4 (TNFRSF4) ligandDi, iNKTs agonists, and silencing A20 or SOCS1 by siRNA et al. Moreover, regulation of GBM microenvironment also can enhance the efficacy of DC vaccines. These regulation includes: the addition of some leukocytes and cytokines, Treg depletion, MDSCs inhibition, and VEGF inhibition et al. Ag: antigen, CTL: cytotoxic T-cell, CTLA-4: cytotoxic T-lymphocyte antigen 4, DC: dendtiric cell, DC1: type 1 polarizing DC, DC2: type 2 polarizing DC, Flt3L: fms-like tyrosine kinase 3 ligand, GM-CSF: glanulocyte monocyte-colony stimulating factor, IFN: interferon, IL: interleukin, iNKTs: Invariant natural killer T cells, MDSC: myeloid-derived suppressor cell, MHC: major histocompatibility class, siRNA: small interfering RNA, SOCS1: suppressor of cytokine signaling 1, TCR: T cell receptor, Th: helper T cells, TLR: Toll-like receptor, Treg: regulatory T cell, VEGF: vascular endothelial growth factor. ① Differentiation: GM-CSF/Flt3L. ② Selection of subpopulation: DC1/DC2. ③ Antigen loading: RNA, DNA, proteins, peptides, lysates, glioma stem cell antigens, fusion, and apoptotic cells. ④ Manipulation signals in DCs: TLR agonists, CD40 ligand, CD70, TNFRSF4 ligandDi, iNKTs agonists, silencing A20 or SOCS1 by siRNA. ⑤ Regulation of GBM microenvironment: the manipulation of some leukocytes and cytokines, Treg depletion, MDSCs inhibition, and VEGF inhibition.
Algorithm 1
Algorithm 1
Classification scheme of approaches to strengthen the efficacy of DC vaccines in the treatment of glioblastoma.
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