Bladder cancer-associated cancer-testis antigen-derived long peptides encompassing both CTL and promiscuous HLA class II-restricted Th cell epitopes induced CD4+ T cells expressing converged T-cell receptor genes in vitro
Bladder cancer-associated cancer-testis antigen-derived long peptides encompassing both CTL and promiscuous HLA class II-restricted Th cell epitopes induced CD4+ T cells expressing converged T-cell receptor genes in vitro
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DOI：
10.1080/2162402x.2017.1415687
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发表时间：
2018-01
期刊：
影响因子：
7.2
通讯作者：
Miki Tsuruta;S. Ueda;P. Yew;Isao Fukuda;S. Yoshimura;H. Kishi;H. Hamana;Masatoshi Hirayama;Junji Yatsuda;A. Irie;S. Senju;E. Yuba;T. Kamba;M. Eto;H. Nakayama;Y. Nishimura
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文献类型：
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作者：
Miki Tsuruta;S. Ueda;P. Yew;Isao Fukuda;S. Yoshimura;H. Kishi;H. Hamana;Masatoshi Hirayama;Junji Yatsuda;A. Irie;S. Senju;E. Yuba;T. Kamba;M. Eto;H. Nakayama;Y. Nishimura
摘要含DEP结构域1（DEPDC 1）和M期磷蛋白1（MPHOSPH 1）是人睾丸癌抗原，在膀胱癌中频繁过表达。在I/II期临床试验中，DEPDC 1和MPHOSPH 1衍生的短肽疫苗在预防膀胱癌复发方面表现出有希望的功效。在这里，我们的目的是确定来自DEPDC 1和MPHOSPH 1的长肽（LP）诱导T辅助细胞（Th）和肿瘤反应性细胞毒性T淋巴细胞（CTL）。用计算机算法预测可与混杂的人类白细胞抗原（HLA）II类分子结合的合成DEPDC 1-和MPHOSPH 1-LP刺激健康供体的外周血单核细胞（PBMC），诱导特异性CD 4 + T细胞，如干扰素-γ酶联免疫斑点试验所示。6个LP中有3个包含HLA-A2或-A24限制性CTL表位或两者兼有，所有6个LP刺激DEPDC 1或MPHOSPH 1特异性Th细胞，这些Th细胞受日本人群中混杂和经常观察到的HLA II类分子的限制。一些LP是从DC中的蛋白质天然加工的，并且使用HLA-A2或-A24转基因小鼠在体内证实了这些LP交叉致敏CTL的能力。在膀胱癌患者的PBMC中也观察到LP特异性和HLA II类限制性T细胞应答。用DEPDC 1-LP和MPHOSPH 1-LP重复刺激PBMC产生表达特异性T细胞受体（TCR）-α和β基因的克隆性Th细胞。这些DEPDC 1或MPHOSPH 1衍生的LP可能在膀胱癌患者的免疫治疗中具有应用，并且所鉴定的TCR基因可能用于监测体内对LP特异性的Th细胞。
ABSTRACT DEP domain containing 1 (DEPDC1) and M-phase phosphoprotein 1 (MPHOSPH1) are human cancer testis antigens that are frequently overexpressed in urinary bladder cancer. In a phase I/II clinical trial, a DEPDC1- and MPHOSPH1-derived short peptide vaccine demonstrated promising efficacy in preventing bladder cancer recurrence. Here, we aimed to identify long peptides (LPs) derived from DEPDC1 and MPHOSPH1 that induced both T-helper (Th) cells and tumor-reactive cytotoxic T lymphocytes (CTLs). Stimulation of peripheral blood mononuclear cells (PBMCs) from healthy donors with the synthetic DEPDC1- and MPHOSPH1-LPs predicted to bind to promiscuous human leukocyte antigen (HLA) class II molecules by a computer algorithm induced specific CD4+ T cells as revealed by interferon-γ enzyme-linked immunospot assays. Three of six LPs encompassed HLA-A2- or -A24-restricted CTL epitopes or both, and all six LPs stimulated DEPDC1- or MPHOSPH1-specific Th cells restricted by promiscuous and frequently observed HLA class II molecules in the Japanese population. Some LPs are naturally processed from the proteins in DCs, and the capacity of these LPs to cross-prime CTLs was confirmed in vivo using HLA-A2 or -A24 transgenic mice. The LP-specific and HLA class II-restricted T-cell responses were also observed in PBMCs from patients with bladder cancer. Repeated stimulation of PBMCs with DEPDC1-LPs and MPHOSPH1-LPs yielded clonal Th cells expressing specific T-cell receptor (TCR)-α and β genes. These DEPDC1- or MPHOSPH1-derived LPs may have applications in immunotherapy in patients with bladder cancer, and the TCR genes identified may be useful for monitoring of Th cells specific to LPs in vivo.