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Identification of novel MAGE-A6- and MAGE-A12-derived HLA-A24-restricted cytotoxic T lymphocyte epitopes using an in silico peptide-docking assay

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Abstract

Many cancer-testis antigen genes have been identified; however, few human leukocyte antigen (HLA)-A24-restricted cytotoxic T cell (CTL) epitope peptides are available for clinical immunotherapy. To solve this problem, novel tools increasing the efficacy and accuracy of CTL epitope detection are needed. In the present study, we utilized a highly active dendritic cell (DC)-culture method and an in silico HLA-A24 peptide-docking simulation assay to identify novel CTL epitopes from MAGE-A6 and MAGE-A12 antigens. The highly active DCs, called α-type-1 DCs, were prepared using a combination of maturation reagents to produce a large amount of interleukin-12. Meanwhile, our HLA-A24 peptide-docking simulation assay was previously demonstrated to have an obvious advantage of accuracy over the conventional prediction tool, bioinformatics and molecular analysis section. For CTL induction assays, peripheral blood mononuclear cells derived from six cases of HLA-A24+ melanoma were used. Through CTL induction against melanoma cell lines and peptide-docking simulation assays, two peptides (IFGDPKKLL from MAGE-A6 and IFSKASEYL from MAGE-A12) were identified as novel CTL epitope candidates. Finally, we verified that the combination of the highly active DC-culture method and HLA-A24 peptide-docking simulation assay might be tools for predicting CTL epitopes against cancer antigens.

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Abbreviations

HLA:

Human leukocyte antigen

DC:

Dendritic cell

CTL:

Cytotoxic T cell

BIMAS:

Bioinformatics and molecular analysis section

PBMC:

Peripheral blood mononuclear cell

CMV:

Cytomegalovirus

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Acknowledgments

We thank Dr. Mochizuki for supplying several synthetic peptides and technical assistance. This work was supported by a grant from the Cooperation of Innovative Technology and Advanced Research in Evolutional Area (CITY AREA) program from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

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The authors declare that they have no conflict of interest.

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Correspondence to Yasuto Akiyama.

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262_2012_1298_MOESM1_ESM.ppt

Expanded view of the subset of genes whose expression was specifically increased in melanoma cell lines, not in melanocytes, from a high density oligonucleotide assay. Each row corresponds to a single gene, and the columns correspond to gene expression levels in different samples. The color saturation reflects the fold increase of expression intensity compared to that of melanocytes ranging from blue to red. The top 30 genes specifically expressed in melanoma (positive in more than 6 of 10 melanoma cell lines), not in melanocytes, are shown. The MAGE-A1, -A2, -A3 and -A12 genes were all included in the top 30. Supplementary material 1 (PPT 373 kb)

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Akiyama, Y., Komiyama, M., Nakamura, Y. et al. Identification of novel MAGE-A6- and MAGE-A12-derived HLA-A24-restricted cytotoxic T lymphocyte epitopes using an in silico peptide-docking assay. Cancer Immunol Immunother 61, 2311–2319 (2012). https://doi.org/10.1007/s00262-012-1298-1

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