Abstract
BackgroundVaccination against tumor-associated antigens is one promising approach to immunotherapy against malignant gliomas. While previous vaccine efforts have focused exclusively on HLA class I-restricted peptides, class II-restricted peptides are necessary to induce CD4+ helper T cells and sustain effective anti-tumor immunity. In this report we investigated the ability of five candidate peptide epitopes derived from glioma-associated antigens MAGE and IL-13 receptor α2 to detect and characterize CD4+ helper T cell responses in the peripheral blood of patients with malignant gliomas.MethodsPrimary T cell responses were determined by stimulating freshly isolated PBMCs from patients with primary glioblastoma (GBM) (n = 8), recurrent GBM (n = 5), meningioma (n = 7), and healthy controls (n = 6) with each candidate peptide, as well as anti-CD3 monoclonal antibody (mAb) and an immunodominant peptide epitope derived from myelin basic protein (MBP) serving as positive and negative controls, respectively. ELISA was used to measure IFN-γ and IL-5 levels, and the ratio of IFN-γ/IL-5 was used to determine whether the response had a predominant Th1 or Th2 bias.ResultsWe demonstrate that novel HLA Class-II restricted MAGE-A3 and IL-13Rα2 peptides can detect T cell responses in patients with GBMs as well as in healthy subjects. Stimulation with a variety of peptide antigens over-expressed by gliomas is associated with a profound reduction in the IFN-γ/IL-5 ratio in GBM patients relative to healthy subjects. This bias is more pronounced in patients with recurrent GBMs.ConclusionsTherapeutic vaccine strategies to shift tumor antigen-specific T cell response to a more immunostimulatory Th1 bias may be needed for immunotherapeutic trials to be more successful clinically.
Highlights
Vaccination against tumor-associated antigens is one promising approach to immunotherapy against malignant gliomas
We focused on five candidate peptide epitopes derived from MAGE family and interleukin-13 receptor α2 (IL-13Rα2) antigens that were designed for recognition by class II-restricted T helper cells
A recent clinical trial examined the IFN-γ/IL-5 ratio after polyclonal stimulation of PBMCs in patients with metastatic melanoma treated with immunomodulators given to restore the Th1/Th2 balance [21], and we performed a similar analysis of our data (Figure 1b)
Summary
Vaccination against tumor-associated antigens is one promising approach to immunotherapy against malignant gliomas. While previous vaccine efforts have focused exclusively on HLA class I-restricted peptides, class II-restricted peptides are necessary to induce CD4+ helper T cells and sustain effective anti-tumor immunity. Passionate debate for over 100 years [1] has surrounded the concept that host immunity can protect against tumor development without external therapeutic intervention. There are many potential explanations for the lack of efficacious therapeutic cancer vaccines, including the challenges of inducing potent immunity given the poor inherent immunogenicity of most tumor-associated antigens, the presence of regulatory T cell populations, and the immunosuppressive tumor environments in which tumor-specific T cells are needed to exert their function [7,8]. Peptide-based cancer vaccines in particular have overwhelmingly relied on only one or a few HLA class I-restricted cytotoxic T lymphocyte (CTL) epitopes typically without inclusion of any HLA class II-restricted T helper cell epitopes [13,14]
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