Ohtake Junya, Ohkuri Takayuki, Togashi Yuji, Kitamura Hidemitsu, Okuno Kiyotaka, Nishimura Takashi
Division of Immunoregulation, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
Bioimmulance Co. Ltd., Sapporo, Japan.
Immunol Lett. 2014 Sep;161(1):20-30. doi: 10.1016/j.imlet.2014.04.010. Epub 2014 Apr 30.
We identified novel helper epitope peptides of Survivin cancer antigen, which are presented to both HLA-DRB101:01 and DQB106:01. The helper epitope also contained three distinct Survivin-killer epitopes presented to HLA-A02:01 and A24:02. This 19 amino-acids epitope peptide (SU18) induced weak responses of Survivin-specific CD4(+) and CD8(+) T cells though it contained both helper and killer epitopes. To enhance the vaccine efficacy, we synthesized a long peptide by conjugating SU18 peptide and another DR53-restricted helper epitope peptide (SU22; 12 amino-acids) using glycine-linker. We designated this artificial 40 amino-acids long peptide containing two helper and three killer epitopes as Survivin-helper/killer-hybrid epitope long peptide (Survivin-H/K-HELP). Survivin-H/K-HELP allowed superior activation of IFN-γ-producing CD4(+) Th1 cells and CD8(+) Tc1 cells compared with the mixture of its component peptides (SU18 and SU22) in the presence of OK-432-treated monocyte-derived DC (Mo-DC). Survivin-H/K-HELP-pulsed Mo-DC pretreated with OK-432 also exhibited sustained antigen-presentation capability of stimulating Survivin-specific Th1 cells compared with Mo-DC pulsed with a mixture of SU18 and SU22 short peptides. Moreover, we demonstrated that Survivin-H/K-HELP induced a complete response in a breast cancer patient with the induction of cellular and humoral immune responses. Thus, we believe that an artificially synthesized Survivin-H/K-HELP will become an innovative cancer vaccine.
我们鉴定出了生存素癌抗原的新型辅助表位肽，这些肽可呈递给HLA-DRB101:01和DQB106:01。该辅助表位还包含三个不同的呈递给HLA-A02:01和A24:02的生存素杀伤表位。这条19个氨基酸的表位肽（SU18）尽管同时包含辅助表位和杀伤表位，但诱导出的生存素特异性CD4(+)和CD8(+) T细胞反应较弱。为提高疫苗效力，我们使用甘氨酸连接子将SU18肽与另一条DR53限制性辅助表位肽（SU22；12个氨基酸）偶联，合成了一条长肽。我们将这条包含两个辅助表位和三个杀伤表位的40个氨基酸长的人工合成肽命名为生存素-辅助/杀伤杂交表位长肽（Survivin-H/K-HELP）。与在OK-432处理的单核细胞衍生树突状细胞（Mo-DC）存在下其组成肽（SU18和SU22）的混合物相比，Survivin-H/K-HELP能更有效地激活产生IFN-γ的CD4(+) Th1细胞和CD8(+) Tc1细胞。与用SU18和SU22短肽混合物脉冲处理的Mo-DC相比，用OK-432预处理的Survivin-H/K-HELP脉冲处理的Mo-DC也表现出刺激生存素特异性Th1细胞的持续抗原呈递能力。此外，我们证明Survivin-H/K-HELP在一名乳腺癌患者中诱导了细胞免疫和体液免疫反应，产生了完全应答。因此，我们相信人工合成的Survivin-H/K-HELP将成为一种创新型癌症疫苗。
