Abstract
Glioblastoma multiforme (GBM) is a recurrent and fatal cancer. EGFRvIII, MAGE-3 and GLEA-2 are antigens that are found in this highly heterogeneous tumor and that are absent in normal tissue. Usually, conventional GMB treatments do not prevent recurrence, reinforcing the need for new therapeutic strategies. Vaccination can be an alternative GMB therapy capable to induce long-lasting and specific immune responses to tumors antigens but requires the activation of strong cellular responses. Fusion of tumor antigens with microbial-derived proteins is a rather simple approach that can enhance the immunogenicity of vaccines, particularly, DNA vaccines. In this study, we constructed DNA vaccines encoding GBM tumor antigens fused to glycoprotein D from herpes simplex virus-1 and evaluated their immunogenicity in C57BL/6 mice. The tumor antigens were correctly expressed by the DNA vaccines and induced cell mediated immune responses under experimental conditions. The vaccines encoding antigens genetically fused with gD induced higher cellular immune responses, associated with IFN-γ and IL-10 production, than vaccines encoding non-fused GMB antigens. Therefore, DNA vaccinations induced a Th1-biased immune response. We concluded that the strategy could be an effective immunotherapeutic approach for GBM.
Highlights
Glioblastoma multiforme (GBM) (WHO grade IV astrocytoma) is the most common and malignant primary cancer in the central nervous system (CNS) [1,2,3]
The gDEGFRvIII, gDMAGE, gDGLEA fragments were constructed by Epoch Biolabs (Missouri, TX) and cloned into the pBluescript II SK vector
The pBSKgDEGFRvIII, pBSKgDMAGE and pBSKgDGLEA plasmids were cleaved with NheI and XbaI restriction enzymes (Fermentas, Thermo Scientific, Cat. #FD0974, #FD0684), whose sites were included at the beginning and end, respectively, of all fragments
Summary
Glioblastoma multiforme (GBM) (WHO grade IV astrocytoma) is the most common and malignant primary cancer in the central nervous system (CNS) [1,2,3]. The primary line of active immunological defense for the brain is composed of specialized resident cells called microglia [10]. These cells are activated when they migrate toward inflammatory areas, where they obtain phagocytic properties and produce cytokines and chemokines, allowing the recruitment of other immune cells [10]. Subpopulations of activated T cells expressing a particular phenotype 4/7 integrin overexpression exhibit tropism for the brain and cross the blood-brain barrier (BBB) [15]. Taken together, these findings represent the evolution of the knowledge regarding the interactions
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