Efficiency of G2/M-related tumor-associated antigen-targeting cancer immunotherapy depends on antigen expression in the cancer stem-like population
Efficiency of G2/M-related tumor-associated antigen-targeting cancer immunotherapy depends on antigen expression in the cancer stem-like population
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DOI：
10.1016/j.yexmp.2011.09.016
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发表时间：
2012-02-01
影响因子：
3.6
通讯作者：
Sato, Noriyuki
中科院分区：
文献类型：
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作者：
Mori, Takashi;Nishizawa, Satoshi;Sato, Noriyuki
本研究的目的是建立一种新的有效的肿瘤DNA疫苗的方法。已经报道了许多肿瘤相关抗原（TAA）;然而，几乎没有关于每种TAA的效率的信息。正常细胞几乎不进行有丝分裂，而癌细胞分裂频繁，生长良好。因此。G2/M相关抗原是癌细胞特异性的，被认为是作为癌症免疫治疗靶点的合适候选物。在这项研究中，我们比较了G2/M相关抗原，包括Birc 5，Aurka，Nke 2和Plk 1的效率，通过使用DNA疫苗接种模型。用G2/M相关抗原编码质粒免疫小鼠，用CT 26结肠癌细胞攻击。有趣的是，Birc 5和Aurka免疫的小鼠显示出抗肿瘤作用，而Nek 2和Plk 1免疫的小鼠没有显示出任何抗肿瘤作用。我们研究了G2/M相关抗原在癌症干细胞样细胞（CSC）/癌症起始细胞（CIC）群体中的表达，以验证抗肿瘤效果的差异。使用Hoechst 33342染料从CT 26细胞中分离CSC/CIC作为侧群（SP）细胞。发现Birc 5和Aurka在CSC/CIC和非CSC/CIC（共享抗原）两者中表达，而Nek 2和Plk 1优先在非CSC/CIC（非CSC抗原）中表达。因此，CSC/CIC群体中的抗原表达可能与癌症免疫治疗的抗肿瘤效率有关。此外，我们建立了一个热休克蛋白（Hsp 90）融合Birc 5质粒，以提高抗癌免疫。与Hsp 90的N-末端区域融合的Birc 5显示出更强的抗肿瘤作用，而与Hsp 90的C-末端区域融合的Birc 5与Birc 5相比没有显示出增强。这些观察结果表明，CSC/CIC群体中的表达对于实现肿瘤消退是必不可少的，并且将抗原融合到Hsp 90的N-末端区域增强了抗肿瘤作用。(C)2011 Elsevier Inc. All rights reserved.
The aim of this study was to establish a novel efficient cancer DNA vaccine approach. Many tumor-associated antigens (TAAs) have been reported; however, there is little information of the efficiency of each TAA. Normal cells barely undergo mitosis, whereas cancer cells divide frequently and grow well. Thus. G2/M-related antigens are cancer cell-specific and are regarded to be suitable candidates as targets of cancer immunotherapy. In this study, we compared the efficiencies of G2/M-related antigens including Birc5, Aurka, Nke2 and Plk1 by using a DNA vaccination model. Mice that had been immunized with G2/M-related antigens coding plasmid were challenged with CT26 colon cancer cells. Interestingly, Birc5- and Aurka-immunized mice showed an anti-tumor effect, whereas Nek2- and Plk1-immunized mice did not show any anti-tumor effect. We investigated the expression of G2/M-related antigens in cancer stem-like cell (CSC)/cancer-initiating cell (CIC) population to verify the difference in the anti-tumor effect. CSCs/CICs were isolated as side population (SP) cells using Hoechst 33342 dye from CT 26 cells. It was found that Birc5 and Aurka are expressed in both CSCs/CICs and non-CSCs/CICs (shared antigens), whereas Nek2 and Plk1 are expressed preferentially in non-CSCs/CICs (non-CSC antigens). Therefore, antigen expression in the CSC/CIC population might be related to the anti-tumor efficiency of cancer immunotherapy. Furthermore, we established a heat shock protein (Hsp90)-fused Birc5 plasmid to improve anti-cancer immunity. Birc5 fused to the N-terminal region of Hsp90 showed a stronger anti-tumor effect, whereas Birc5 fused to the C-terminal region of Hsp90 did not show enhancement compared with Birc5. These observations indicate that expression in the CSC/CIC population is essential to achieve tumor regression and that fusing antigens to the N-terminal region of Hsp90 enhances the anti-tumor effect. (C) 2011 Elsevier Inc. All rights reserved.