表位
主要组织相容性复合体
生物
蛋白质组
转录组
抗原
突变体
外显子组
细胞毒性T细胞
外显子组测序
计算生物学
基因组
突变
基因
遗传学
基因表达
体外
作者
Mahesh Yadav,Suchit Jhunjhunwala,Qui Phung,P.J. Lupardus,Joshua Tanguay,Stephanie Bumbaca,Christian Franci,Tommy K. Cheung,Jens Fritsche,Toni Weinschenk,Zora Modrušan,Ira Mellman,Jennie R. Lill,Lélia Delamarre
出处
期刊:Nature
[Springer Nature]
日期:2014-11-26
卷期号:515 (7528): 572-576
被引量:960
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.
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