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或新表位的肽，是肿瘤免疫的基石，并构成了包括个性化癌症疫苗在内的新免疫治疗方法的基础。然而，由于它们源自自身肽，因此免疫原性新表位克服免疫自身耐受的方式通常尚不清楚。在这里，我们展示了非主要组织相容性复合体锚定位置的点突变诱导免疫活性卵巢癌新表位的结构和动态变化。这些变化将肽预先组织成最适合新表位特异性 T 细胞受体识别的构象，使受体能够以高亲和力结合新表位并传递有效的 T 细胞信号。我们的结果强调了结构和物理变化在新表位免疫原性中相对于自身的重要性。从广义上讲，这些发现可以帮助解释仅从序列中识别免疫原性新表位的一些困难，并为开发基于新表位的新型个性化疗法提供指导。