Identification of interleukin-13 receptor α2 peptide analogues capable of inducing improved antiglioma CTL responses
Identification of interleukin-13 receptor α2 peptide analogues capable of inducing improved antiglioma CTL responses
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DOI：
10.1158/0008-5472.can-06-0363
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发表时间：
2006-06-01
期刊：
影响因子：
11.2
通讯作者：
Okada, Hideho
中科院分区：
文献类型：
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作者：
Eguchi, Junichi;Hatano, Manabu;Okada, Hideho
白细胞介素-13受体α 2 （IL-13R α 2）在大多数人类恶性胶质瘤中的有限和高水平表达使该蛋白成为一个有吸引力的疫苗靶点。我们之前已经描述了IL-13R α 2（345-353）肽作为人类白细胞抗原a2 （HLA-A2）限制性CTL表位的鉴定。然而，由于目前尚不清楚基于肽的疫苗在恶性胶质瘤患者中诱导特异性ctl的效率如何，我们研究了类似表位是否可以引发与野生型肽相比的异源抗肿瘤t细胞反应。我们用cooh末端的异亮氨酸(1)代替缬氨酸(V)，用n112末端的色氨酸(W)代替丙氨酸(A)、谷氨酸(E)或非取代的（W，分别命名为1A9V、1E9V和9V），合成了三个IL-13R α 2类似肽。与天然IL-13R α - 2表位相比，类似肽9V和1A9V在HLA-A2复合物中表现出更高的结合亲和力和稳定性，并且对患者来源的特异性ctl对HLA-A2（+）胶质瘤细胞表达的天然表位产生了更好的刺激指数。在hla - a2 -突变HHD小鼠中，与含有天然IL-13R α 2表位的疫苗相比，用肽9V和1A9V免疫可诱导CTL反应性水平增强，并对表达11,1l13 α 2的同源肿瘤的颅内攻击产生保护性免疫。这些发现表明，高免疫原性IL13R α 2肽类似物可能有助于开发能够在胶质瘤患者中有效扩增IL-13R α 2特异性肿瘤反应性ctl的疫苗。
Restricted and high-level expression of interleukin-13 receptor alpha 2 (IL-13R alpha 2) in a majority of human malignant gliomas makes this protein an attractive vaccine target. We have previously described the identification of the IL-13R alpha 2(345-353) peptide as a human leukocyte antigen-A2 (HLA-A2)-restricted CTL epitope. However, as it remains unclear how efficiently peptide-based vaccines can induce specific CTLs in patients with malignant gliomas, we have examined whether analogue epitopes could elicit heteroclitic antitumor T-cell responses versus wild-type peptides. We have created three IL-13R alpha 2 analogue peptides by substitutions of the COOH-terminal isoleucine (1) for valine (V) and the N112-terminal tryptophan (W) for either alanine (A), glutamic acid (E), or nonsubstituted (W; designated as 1A9V, 1E9V, and 9V, respectively). in comparison with the native IL-13R alpha 2 epitope, the analogue peptides 9V and 1A9V displayed higher levels of binding affinity and stability in HLA-A2 complexes and yielded an improved stimulatory index for patient-derived, specific CTLs against the native epitope expressed by HLA-A2(+) glioma cells. In HLA-A2-tranggenic HHD mice, immunization with the peptides 9V and 1A9V induced enhanced levels of CTL reactivity and protective immunity against an intracranial challenge with 11,1L13 alpha 2-expressing syngeneic tumors when compared with vaccines containing the native IL-13R alpha 2 epitope. These findings indicate highly immunogenic IL13R alpha 2 peptide analogues may be useful for the development of vaccines capable of effectively expanding IL-13R alpha 2-specific, tumor-reactive CTLs in glioma patients.