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Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing

机译：结合质谱和外显子组测序预测免疫原性肿瘤突变

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摘要

Human tumours typically harbour a remarkable number of somatic mutations. If presented on major histocompatibility complex class I molecules (MHCI), peptides containing these mutations could potentially be immunogenic as they should be recognized as 'non-self neo-antigens by the adaptive immune system. Recent work has confirmed that mutant peptides can serve as T-cell epitopes. However, few mutant epitopes have been described because their discovery required the laborious screening of patient tumour-infiltrating lymphocytes for their ability to recognize antigen libraries constructed following tumour exome sequencing. We sought to simplify the discovery of immunogenic mutant peptides by characterizing their general properties. We developed an approach that combines whole-exome and transcriptome sequencing analysis with mass spectrometry to identify neo-epitopes in two widely used murine tumour models. Of the ＞ 1,300 amino acid changes identified, ～13% were predicted to bind MHCI, a small fraction of which were confirmed by mass spectrometry. The peptides were then structurally modelled bound to MHCI. Mutations that were solvent-exposed and therefore accessible to T-cell antigen receptors were predicted to be immunogenic. Vaccination of mice confirmed the approach, with each predicted immunogenic peptide yielding therapeutically active T-cell responses. The predictions also enabled the generation of peptide-MHCI dextramers that could be used to monitor the kinetics and distribution of the anti-tumour T-cell response before and after vaccination. These findings indicate that a suitable prediction algorithm may provide an approach for the pharmacodynamic monitoring of T-cell responses as well as for the development of personalized vaccines in cancer patients.
机译：人类肿瘤通常具有大量的体细胞突变。如果在主要的组织相容性复合物I类分子（MHCI）上呈递，则包含这些突变的肽可能具有免疫原性，因为它们应被适应性免疫系统识别为“非自身新抗原”。最近的工作已经证实，突变肽可以用作T细胞表位。然而，很少描述突变表位，因为它们的发现需要费力筛选患者的肿瘤浸润淋巴细胞以识别其在肿瘤外显子组测序后构建的抗原文库的能力。我们试图通过表征其一般特性来简化免疫原性突变肽的发现。我们开发了一种将全外显子组和转录组测序分析与质谱相结合的方法，以在两种广泛使用的鼠类肿瘤模型中鉴定新表位。在发现的1300多个氨基酸变化中，预计约有13％会与MHCI结合，其中一小部分已通过质谱法确认。然后将肽与MHCI结合进行结构建模。被溶剂暴露并因此可被T细胞抗原受体接近的突变被预测为具有免疫原性。小鼠的疫苗接种证实了该方法，每种预测的免疫原性肽均产生治疗活性的T细胞应答。这些预测还使得能够产生肽-MHCI右旋聚合物，该肽可用于监测疫苗接种前后抗肿瘤T细胞反应的动力学和分布。这些发现表明，合适的预测算法可以为癌症患者的T细胞反应的药效学监测以及个性化疫苗的开发提供一种方法。

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  • 来源
    《Nature》 |2014年第7528期|572-576|共5页
  • 作者

    Mahesh Yadav; Suchit Jhunjhunwala; Qui T. Phung; Patrick Lupardus; Joshua Tanguay; Stephanie Bumbaca; Christian Franci; Tommy K. Cheung; Jens Fritsche; Toni Weinschenk; Zora Modrusan; Ira Mellman; Jennie R. Lill; Lelia Delamarre;

  • 作者单位

    Genentech, South San Francisco, California 94080, USA;

    Genentech, South San Francisco, California 94080, USA;

    Genentech, South San Francisco, California 94080, USA;

    Genentech, South San Francisco, California 94080, USA;

    Genentech, South San Francisco, California 94080, USA;

    Genentech, South San Francisco, California 94080, USA;

    Genentech, South San Francisco, California 94080, USA;

    Genentech, South San Francisco, California 94080, USA;

    Immatics Biotechnologies GmbH, 72076 Tubingen, Germany;

    Immatics Biotechnologies GmbH, 72076 Tubingen, Germany;

    Genentech, South San Francisco, California 94080, USA;

    Genentech, South San Francisco, California 94080, USA;

    Genentech, South San Francisco, California 94080, USA;

    Genentech, South San Francisco, California 94080, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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