MESENCHYMAL TYPE GLIOMA STEM CELL EXPRESS ICOS LIGAND AND UPREGULATE ICOS+IL-10+ T CELLS
MESENCHYMAL TYPE GLIOMA STEM CELL EXPRESS ICOS LIGAND AND UPREGULATE ICOS+IL-10+ T CELLS
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间充质型胶质瘤干细胞表达 ICOS 配体并上调 ICOS IL-10 T 细胞
DOI：
10.1093/neuonc/nov217.16
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发表时间：
2015
期刊：
影响因子：
15.9
通讯作者：
Akio Asai
中科院分区：
文献类型：
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作者：
Ryoichi Iwata;Tomoki Ito;Muneo Inaba;Taro Koike;Hideyuki Oshige;Kunikazu Yoshimura;Masahiro Nonaka;Hisao Yamada;Shosaku Nomura;Umberrto Dianzani;Ichiro Nakano;Akio Asai
背景：支链多肽具有增加多肽分子量的作用，可以提高机体稳定的免疫原性。我们鉴定并合成了HLA-A* 0201分子的BIRC5、CD99和ERBB2肽及其相应的支链多肽。我们研究了利用分枝多肽脉冲树突状细胞（DCs）产生的细胞毒性T淋巴细胞（ctl）免疫治疗胶质母细胞瘤的可能性。材料和方法：我们选择了三个肽（BIRC5， CD99和ERBB2），根据它们的结合亲和力，通过肽- t2结合实验确定，并使用mini-聚乙二醇（mini- peg）间隔剂合成相应的支链多肽。通过免疫表型和细胞因子的分泌比较多肽-鸡尾酒法和支链多肽法诱导的树突细胞的功能。采用IFN-γ-酶联免疫吸收点（ELISPOT）法测定ctl的功能活性。结果：与多肽鸡尾酒相比，分支多肽- t2细胞结合的稳定性相对较好地维持了24小时。基于FACS分析，比较了多肽鸡尾酒和分支多肽脉冲DCs的表型，两种DCs都表现出CD80、CD83和CD86的高表达，这意味着两种DCs都能在不改变成熟DCs表型的情况下高效生成DCs。两种多肽脉冲dc均显示IL-12p70、il -12p40和IL-10的产生增加。与未受脉冲dc刺激的ctl相比，两种多肽脉冲dc刺激的ctl显示出更多的IFN-γ分泌细胞，以对抗装载多肽和胶质母细胞瘤细胞系的T2细胞。结论：BIRC5、CD99和ERBB2的支链多肽与T细胞结合稳定，对靶细胞的细胞毒活性与多肽鸡尾酒相似。支链多肽可作为胶质母细胞瘤免疫治疗的候选药物。本研究由韩国科学、信息通信技术与未来规划部（2014R1A1A1004469）资助的韩国国家研究基金（NRF）基础科学研究计划资助。主题:
BACKGROUND: Branched-multipeptide has the increased molecular weight of the peptide which can elevate stable immunogenicity in the body. We identified and synthesized BIRC5, CD99 and ERBB2 peptides and their corresponding branched-multipeptide for HLA-A* 0201 molecules. We investigated the possibility of immunotherapy for glioblastoma using cytotoxic T lymphocytes (CTLs) generated by branched-multipeptides pulsed dendritic cells (DCs). MATERIALS AND METHODS: We selected three peptides (BIRC5, CD99 and ERBB2), on the basis of their binding affinity, as determined by a peptide-T2 binding assay and their corresponding branched-multipeptide was synthesized using mini-polyethylene glycol (mini-PEGs) spacer. The function of DCs pulsed with multipeptide-cocktail was compared with DCs pulsed with branched-multipeptide by immunephenotype and cytokine secretion. We measured the functional activity for CTLs by using IFN-γ-enzyme linked immune absorbent spot (ELISPOT) assay. RESULTS: The stability of branched-multipeptide-T2 cells binding was relatively well maintained up to 24 hours compared to multipeptide cocktail. Based on FACS analysis which compared the phenotypes of multipeptide-cocktail and branched-multipeptide pulsed DCs, both DCs exhibited high expression of CD80, CD83 and CD86, which meant that both DCs resulted in efficient generation of DCs without altering the phenotype of the mature DCs. The both multipeptides pulsed DCs showed similarly increased IL-12p70, IL-12p40and IL-10 production. The CTLs that were stimulated by both multipeptides pulsed DCs displayed a greater number of IFN-γ-secreting cells against T2 cells loaded with both multipeptides and glioblastoma cell lines compared to those stimulated by un-pulsed DCs. CONCLUSION: Branched-multipeptide of BIRC5, CD99 and ERBB2 showed the stable binding with T cells and similar cytotoxic activity to target cells compared with multipeptide-cocktail. Branched-multipeptide can be the candidate of useful immunotherapeutic modalities for glioblastoma. This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (2014R1A1A1004469).Topic: