Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA.
Department of Oncology UNIL CHUV, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland.
Nat Chem Biol. 2020 Nov;16(11):1269-1276. doi: 10.1038/s41589-020-0610-1. Epub 2020 Aug 17.
T-cell recognition of peptides incorporating nonsynonymous mutations, or neoepitopes, is a cornerstone of tumor immunity and forms the basis of new immunotherapy approaches including personalized cancer vaccines. Yet as they are derived from self-peptides, the means through which immunogenic neoepitopes overcome immune self-tolerance are often unclear. Here we show that a point mutation in a non-major histocompatibility complex anchor position induces structural and dynamic changes in an immunologically active ovarian cancer neoepitope. The changes pre-organize the peptide into a conformation optimal for recognition by a neoepitope-specific T-cell receptor, allowing the receptor to bind the neoepitope with high affinity and deliver potent T-cell signals. Our results emphasize the importance of structural and physical changes relative to self in neoepitope immunogenicity. Considered broadly, these findings can help explain some of the difficulties in identifying immunogenic neoepitopes from sequence alone and provide guidance for developing novel, neoepitope-based personalized therapies.
T 细胞识别包含非同义突变（即新抗原）的肽是肿瘤免疫的基石，也是新免疫疗法的基础，包括个性化癌症疫苗。然而，由于它们源自自身肽，免疫原性新抗原克服免疫自身耐受的途径往往不清楚。在这里，我们表明，非主要组织相容性复合物锚定位点的突变会诱导卵巢癌免疫原性新抗原的结构和动态变化。这些变化将肽预先组织成一种构象，使其最适合与新抗原特异性 T 细胞受体识别，从而使受体能够高亲和力地结合新抗原并传递有效的 T 细胞信号。我们的研究结果强调了结构和物理变化相对于自身在新抗原免疫原性中的重要性。广义地说，这些发现可以帮助解释仅从序列识别免疫原性新抗原的一些困难，并为开发新的基于新抗原的个性化治疗方法提供指导。
