Neoantigens are tumor-specific peptide sequences resulting from sources such as somatic DNA mutations. Upon loading onto major histocompatibility complex (MHC) molecules, they can trigger recognition by T cells. Accurate neoantigen identification is thus critical for both designing cancer vaccines and predicting response to immunotherapies. Neoantigen identification and prioritization relies on correctly predicting whether the presenting peptide sequence can successfully induce an immune response. Because most somatic mutations are single-nucleotide variants, changes between wild-type and mutated peptides are typically subtle and require cautious interpretation. A potentially underappreciated variable in neoantigen prediction pipelines is the mutation position within the peptide relative to its anchor positions for the patient’s specific MHC molecules. Whereas a subset of peptide positions are presented to the T cell receptor for recognition, others are responsible for anchoring to the MHC, making these positional considerations critical for predicting T cell responses. We computationally predicted anchor positions for different peptide lengths for 328 common HLA alleles and identified unique anchoring patterns among them. Analysis of 923 tumor samples shows that 6 to 38% of neoantigen candidates are potentially misclassified and can be rescued using allele-specific knowledge of anchor positions. A subset of anchor results were orthogonally validated using protein crystallography structures. Representative anchor trends were experimentally validated using peptide-MHC stability assays and competition binding assays. By incorporating our anchor prediction results into neoantigen prediction pipelines, we hope to formalize, streamline, and improve the identification process for relevant clinical studies.

中文翻译：

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MHC 锚定位置的计算预测指导新抗原识别和优先排序

新抗原是由体细胞 DNA 突变等来源产生的肿瘤特异性肽序列。当装载到主要组织相容性复合体 (MHC) 分子上后，它们可以触发 T 细胞的识别。因此，准确的新抗原鉴定对于设计癌症疫苗和预测免疫疗法的反应至关重要。新抗原的识别和优先级排序依赖于正确预测呈递肽序列是否能够成功诱导免疫反应。由于大多数体细胞突变是单核苷酸变异，野生型和突变肽之间的变化通常是微妙的，需要谨慎解释。新抗原预测管道中一个可能被低估的变量是肽内相对于患者特定 MHC 分子锚定位置的突变位置。虽然肽位置的子集被呈递给 T 细胞受体进行识别，但其他肽位置负责锚定到 MHC，因此这些位置考虑因素对于预测 T 细胞反应至关重要。我们通过计算预测了 328 个常见 HLA 等位基因的不同肽长度的锚定位置，并确定了其中独特的锚定模式。对 923 个肿瘤样本的分析表明，6% 至 38% 的候选新抗原可能被错误分类，可以使用锚定位置的等位基因特异性知识来挽救。使用蛋白质晶体学结构对锚定结果的子集进行正交验证。使用肽-MHC 稳定性测定和竞争结合测定对代表性锚定趋势进行了实验验证。通过将我们的锚定预测结果纳入新抗原预测流程中，我们希望规范、简化和改进相关临床研究的识别过程。