Identification of the Cryptic HLA-I Immunopeptidome
Identification of the Cryptic HLA-I Immunopeptidome
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DOI：
10.1158/2326-6066.cir-19-0886
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发表时间：
2020-08-01
影响因子：
10.1
通讯作者：
Schlosser, Andreas
中科院分区：
文献类型：
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作者：
Erhard, Florian;Doelken, Lars;Schlosser, Andreas
癌症免疫治疗的成功依赖于细胞毒性T细胞基于HLA-I呈递的肽特异性识别和消除肿瘤细胞的能力。虽然引发相应免疫应答的肽表位通常仍未被识别，但通常认为由于肿瘤特异性突变，新抗原是最常见的靶标。在这里，我们使用质谱方法来显示一类未被充分认识的表位，其占各种肿瘤和患者中某些HLA等位基因的HLA-I肽的高达15%。这些肽从基因组中假定的非编码区中的隐蔽开放阅读框翻译，并且大多数无法用质谱（MS）数据的常规计算分析识别。我们的方法Peptide-PRISM在肿瘤免疫肽组中鉴定了数千种这样的隐蔽肽。约20%的这些HLA-I肽代表相应的翻译产物的C-末端，这表明频繁的蛋白酶体非依赖性加工。我们的数据还揭示了隐藏肽的HLA-I等位基因依赖性呈递，其中HLA-A*03和HLA-A*11呈递隐藏肽的百分比最高。我们的分析驳斥了报告频繁介绍HLA肽产生的蛋白酶催化肽剪接。因此，肽PRISM代表了全面鉴定HLA-I免疫肽段的重要一步，并揭示了隐藏肽作为一类丰富的表位，与新的免疫学方法具有潜在的相关性。
The success of cancer immunotherapy relies on the ability of cytotoxic T cells to specifically recognize and eliminate tumor cells based on peptides presented by HLA-I. Although the peptide epitopes that elicit the corresponding immune response often remain unidentified, it is generally assumed that neoantigens, due to tumor-specific mutations, are the most common targets. Here, we used a mass spectrometric approach to show an underappreciated class of epitopes that accounts for up to 15% of HLA-I peptides for certain HLA alleles in various tumors and patients. These peptides are translated from cryptic open reading frames in supposedly noncoding regions in the genome and are mostly unidentifiable with conventional computational analyses of mass spectrometry (MS) data. Our approach, Peptide-PRISM, identified thousands of such cryptic peptides in tumor immunopeptidomes. About 20% of these HLA-I peptides represented the C-terminus of the corresponding translation product, suggesting frequent proteasome-independent processing. Our data also revealed HLA-I allele-dependent presentation of cryptic peptides, with HLA-A*03 and HLA-A*11 presenting the highest percentage of cryptic peptides. Our analyses refute the reported frequent presentation of HLA peptides generated by proteasomecatalyzed peptide splicing. Thus, Peptide-PRISM represents an important step toward comprehensive identification of HLA-I immunopeptidomes and reveals cryptic peptides as an abundant class of epitopes with potential relevance for novel immunotherapeutic approaches.