Dendritic Cell-Based Immunotherapy Treatment for Glioblastoma Multiforme

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.