Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10901908 | Cancer Letters | 2015 | 12 Pages |
Abstract
Eukaryotic elongation factor-2 (eEF2) is overexpressed in many human cancers and is an attractive target for cancer immunotherapy. The eEF2 derived polypeptides have been shown to be able to induce cytotoxic T lymphocytes from healthy donor. Here, we demonstrate the evidence indicating that modification of a segment of peptides from wild type eEF2-derived immunogenic peptides is able to further enhance its capacity of inducing antigen-specific cytotoxic T lymphocytes (CTLs) against colon cancer cells. Using peptide-MHC binding algorithms, potential HLA-A2.1-restricted epitopes capable of inducing specific CD8+ CTLs were identified. By analyzing HLA-A2.1 affinity and immunogenicity, we further identified one novel immunogenic peptide, P739-747 (RLMEPIYLV), that elicited specific CTL responses in HLA-A2.1/Kb transgenic mice and culture with peripheral blood lymphocytes from colon cancer patients. Furthermore, replacing certain amino acids (at positions 1, 3, 7) within the P739-747 sequence improved the immunogenicity against eEF2. Several analogs containing the auxiliary HLA-A*0201 anchor residues were able to stably bind to HLA-A*0201 and enhance CTL responses compared with the native sequence; two of them showed increased anti-tumor effects during the adoptive immunotherapy in vivo. Thus, these results support that modified immunogenic analogs are promising candidates for peptide-based cancer vaccination and immunotherapy.
Keywords
PBMCsmean fluorescence intensitiesPBSmAbGRBFITCMFICTLeEF2Granzyme BTCrOVAPBLsDMSOE:TMonoclonal antibodytumor-associated antigensOvalbuminadoptive immunotherapyTransgenicTAAsDimethyl sulfoxideColon cancerDendritic cellperipheral blood mononuclear cellsfluorescence indexeukaryotic elongation factor-2fluorescein isothiocyanatecytotoxic T lymphocyteperipheral blood lymphocytesPhosphate-buffered salineeffector:targetT cell receptor
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Biochemistry, Genetics and Molecular Biology
Cancer Research
Authors
Weihong Sun, Xiaofang Wei, Airong Niu, Xuezhen Ma, Jian Jian Li, Daiqing Gao,