Abstract
We investigated the use of cytotoxic T-lymphocyte (CTL) epitopes in peptide immunotherapy for glioblastoma. Three peptides (ERBB2, BIRC5 and CD99) were selected based on their peptide-T2 cell binding affinities and combined in a multipeptide cocktail or a branched multipeptide synthesized with mini-polyethylene glycol spacers. Dendritic cells (DCs) pulsed with the multipeptide cocktail or branched multipeptide were compared based on their immunophenotype and cytokine secretion. FACS analysis of alpha-type 1 polarized dendritic cells (αDC1s) revealed that both groups highly expressed CD80, CD83 and CD86, indicating that both treatments efficiently generated mature αDC1s with the expected phenotype. Production of IL-12p70, IL-12p40 and IL-10 also increased upon αDC1 maturation in both groups. CTLs stimulated by either αDC1 group (“DC-CTLs”) included numerous IFN-γ-secreting cells against T2 cells loaded with the corresponding multipeptides. Large numbers of IFN-γ-secreting cells were observed when human glioblastoma cell lines and primary cells were treated with multipeptide-pulsed DC-CTLs. Both multipeptide-pulsed DC-CTL groups exhibited cytotoxic activity of 40-60% against the U251 cell line and 60-80% against primary cells. Branched multipeptide from ERBB2, BIRC5 and CD99 stably bound with T2 cells, and its cytotoxicity toward target cells was similar to that of the multipeptide cocktail. Thus, branched multipeptides could be promising candidates for immunotherapeutic glioblastoma treatment.
Highlights
Gliomas are the most common primary tumors of the central nervous system [1, 2]
We investigated the use of cytotoxic T-lymphocyte (CTL) epitopes in peptide immunotherapy for glioblastoma
In cells treated with the branched multipeptide, the mean mean fluorescence intensity (MFI) increased until the total peptide concentration reached 22.5 μg/mL (7.5 μg/mL/ peptide) and decreased thereafter
Summary
Despite advances in conventional treatments such as surgical resection, radiation therapy and chemotherapy, the prognosis for most patients with glioblastomas is poor. Glioblastomas frequently recur due to continued growth of the residual microscopic disease located beyond surgical resection margins [3]. Numerous attempts have been made to develop immunotherapies and adjuvant therapies to more effectively treat glioblastomas [3,4,5,6]. One promising modality for glioblastoma treatment is specific immunotherapy using dendritic cells (DCs) [4, 7]. This modality requires information about the target antigens and their epitope peptides that are recognized by T cells. A major challenge for in vitro induction of glioblastoma-reactive cytotoxic T-lymphocytes (CTLs) for adoptive immunotherapy is the identification of major histocompatibility complex (MHC)
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