Exploiting the glioblastoma peptidome to discover novel tumour-associated antigens for immunotherapy
Exploiting the glioblastoma peptidome to discover novel tumour-associated antigens for immunotherapy
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DOI：
10.1093/brain/aws042
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发表时间：
2012-04-01
期刊：
影响因子：
14.5
通讯作者：
Dietrich, Pierre-Yves
中科院分区：
文献类型：
--
作者：
Dutoit, Valerie;Herold-Mende, Christel;Dietrich, Pierre-Yves
出现在细胞表面的肽反映了细胞的蛋白质含量；HLA I类分子上的这些分子包括与CD8 T淋巴细胞相互作用的关键肽肽元件。我们假设来自离体肿瘤样本的肽集包含免疫原性肿瘤抗原。在这里，我们从HLA-A*02（+）胶质母细胞瘤中发现了大约6000个hla结合肽，其中超过3000个受到HLA-A*02的限制。我们优先深入研究了10种胶质母细胞瘤相关抗原，这些抗原在肿瘤中高表达，在健康组织中表达极低或不表达，与胶质瘤形成和免疫原性有关。胶质母细胞瘤患者对这些肽没有T细胞耐受性。此外，我们在体外证明了患者的CD8(+) T细胞对肿瘤细胞的特异性裂解。在体内，胶质母细胞瘤特异性CD8(+) T细胞存在于肿瘤部位。总的来说，我们的数据显示了肽穹窿方法的生理学相关性，并为设计合理的胶质母细胞瘤免疫疗法提供了关键的进展。在我们的研究中发现的多肽目前正在胶质母细胞瘤患者中作为多肽疫苗（IMA950）进行测试。
Peptides presented at the cell surface reflect the protein content of the cell; those on HLA class I molecules comprise the critical peptidome elements interacting with CD8 T lymphocytes. We hypothesize that peptidomes from ex vivo tumour samples encompass immunogenic tumour antigens. Here, we uncover >6000 HLA-bound peptides from HLA-A*02(+) glioblastoma, of which over 3000 were restricted by HLA-A*02. We prioritized in-depth investigation of 10 glioblastoma-associated antigens based on high expression in tumours, very low or absent expression in healthy tissues, implication in gliomagenesis and immunogenicity. Patients with glioblastoma showed no T cell tolerance to these peptides. Moreover, we demonstrated specific lysis of tumour cells by patients' CD8(+) T cells in vitro. In vivo, glioblastoma-specific CD8(+) T cells were present at the tumour site. Overall, our data show the physiological relevance of the peptidome approach and provide a critical advance for designing a rational glioblastoma immunotherapy. The peptides identified in our study are currently being tested as a multipeptide vaccine (IMA950) in patients with glioblastoma.